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PREVALENCE OF ANTIBODIES TO HUMAN T- 
LYMPHOTROPIC VIRltf; TYPE I AMONG 
BLOOD DONORS 
AT THE 37th MILITARY 
HOSPITAL, ACCRA, GHANA.
BY 
EDWIN GBLI NARTER-OLAGA
Pathology Department, University of Ghana Medical School, College of Health
Sciences, Korle-Bu, Accra.
This thesis is submitted to the University of Ghana, Legon in partial fulfilment of the 
requirement for the award of M.Phil degree in Pathology
June 2004
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DECLARATION 
The author carried out the work in this thesis alone unless 
otherwise indicated. Whenever the work of others is included, 
references are made to the source of information. This thesis 
has not in its present form or otherwise been submitted to this 
University for a degree, diploma, or other qualification.
Edwin Gbli Narter-Olaga 
(Author)
Prof. Andrew A. Adjei 
(Supervisor)
Prof. Edwin K. Wiredu 
(Supervisor)
Prof. Yao Tettey 
(Supervisor)
Dr. Richard K. Gyasi 
(Supervisor)
Dr. (Brig. Gen.) Jaswant M. Wadhwani 
(Supervisor)
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ACKNOWLEDGEMENT
Without the Almighty God we cannot be alive to continue with His work o f saving lives through  
science. I am sincerely grateful to all who contributed in diverse ways to help me enter the M. Phil 
programme, especially Dr. O. A. Duah, Head of the Department of Chemical Pathology, Korle-Bu. 
I wish to thank Prof. Andrew Anthony Adjei, Head of Medical Laboratory Science, School of 
Allied Health Sciences, College of Health Sciences, for his immeasurable assistance in this project. 
Many thanks also to my supervisors Prof. Edwin K. Wiredu, Dean, School o f Allied Health 
Sciences, Korle-Bu, Prof. Y. Tettey, Head, Department of Pathology, Dr. Richard K. Gyasi, 
Department of Pathology, and Dr. (Brig. Gen.) Jaswant W. Wadhwani, Head o f the Department of 
Morbid Anatomy, 37th Military Hospital. I am also grateful to all the Clinical Heads who are keen 
on making sure the M.Phil. programme is successful. I am also grateful to all the doctors in room 4 
for tolerating my presence.
I must thank the secretaries in the departments of Pathology and Chemical Pathology for typing 
and printing some o f my papers for me.
Finally to all the voluntary blood donors who consented to take part in the project, I render my 
Heart-felt thanks.
To all of you, I say a big THANK YOU.
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ABBREVIATIONS
AIDS=Acquired immune-deficiency syndrome 
HIV= Human immunodeficiency virus
HTLV-1 = Human T- lymphotropic virus type-I 
LAV= Lymphoadenopathy associated virus 
HCV= Hepatitis C virus 
HBV= Hepatitis B virus 
ATL=Adult T-cell leukaemia 
CD =Cluster o f  differentiation 
HAM=HTLV-1 associated myelopathy 
RNA=Ribonucleic acid 
DNA=Deoxyriboncleic acid
MHBTC=Military Hospital Blood Transfusion Centre 
NBTS= National Blood Transfusion Service 
RIBA= Recombinant immuno-blot assay 
RIA = Radio immunoassay 
EIA = Enzyme immunoassay
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Title
Declaration  
Acknowledgement 
Abbreviations 
Table of Contents
Chap 1 -  Summary ........................................ 1 - 2
Chap 2 -  Introduction ........................................ 3 - 6
Chap 3 - Literature Review ........................................ 7 - 1 7
Chap 4 -  Diseases of HTLV Infections   1 8 - 2 5
Chap 5 - Pathogenesis of HTLV Infections ........................................ 2 6 - 2 8
Chap 6 - Epidemiology of HTLV Infections .......................................  2 9 - 3 3
Chap 7 - Diagnosis of HTLV Infection .......................................  3 4 - 3 5
Chap 8 - Materials and Method   3 6 - 3 9
Chap 9 -  Results   4 0 - 4 7
Chap 10 -  Discussion   4 8 - 5 0
Chap 11 -  Conclusion ........................................ 51
Ethical Aspects ........................................ 52
References   5 3 - 9 2
Appendix   9 3 - 9 6
TA B L E  O F  C O N T EN T
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CHAPTER 1
SUMMARY
Several infectious diseases have been found to be associated with transfusion o f  whole blood or 
blood components. Reports from studies conducted in many African countries indicate a high 
incidence o f blood-borne pathogens such as human T-lymphotropic virus type-I (HTLV-I) among 
healthy blood donors. Experimental data indicate that a r. ajor route for transmission o f  the HTLV-I 
is through blood transfusion. The prevalence o f  HTLV-I antibodies among blood donors in Ghana 
is not well documented. Population surveys cannot be conducted for financial reasons and therefore 
sentinel studies are the only means for providing information on the transmissions o f infections 
such as HTLV-I, as well as monitoring the changes over time. The study was therefore undertaken 
to determine the prevalence o f  HTLV-I antibodies among blood donors, between the months o f 
January to April 2004 at the 37th Military Hospital Blood Transfusion Service, Accra, Ghana. A 
combination o f  particle agglutination test and enzyme-linked immunosorbent assay (ELISA) was 
used to assess the prevalence and distribution o f antibodies to HTLV-I. A structured questionnaire 
was also administered to the blood donors after an informed oral and written consent was taken.
This involved questions on personal information, knowledge about HTLV-I transfusion, sexual 
behaviour, lifestyle and histories o f  transfusion-transmitted diseases.
Beginning from January to April 2004, blood samples were collected from blood donors, serum 
separated and analysed for the presence o f antibodies to HTLV-I. A total o f 1225 samples (1158 
males and 67 females) were analysed. Their ages ranged from 20-69 years; with majority 
(75.5%; 925/1225) of the blood donors studied between the 30-^9 years age group. O fthe  1225 
samples tested, 1196 were negative and 29 were positive lor HTLV-I antibodies giving a prevalence 
rate o f 2.4%. Two females were positive out o f 67 (2.9%) and 27 males were positive out o f  1158
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(2.3%) male donors. Majority o f the donors were married (914; 74.6%) and the rest (311; 25.4%) 
were not married. O f the married donors, 21 were positive for HTLV-I antibodies, giving a 
prevalence rate o f  2.3% among married donor. Most of <he positive male donors were married 
with one wife (19; 65.5%), and one positive case had two wives (3.4%). Seroprevalence 
increased with marital status, suggesting marital status as the primary mode o f transmission 
rather than number o f wives. There was no association o f tattoo marks with HTLV-I infection 
(X2 = 1.72; or =2.07; 95% Cl =0.16- 1.46). Knowledge about HTLV-I infection among blood 
donors was found to be very poor. Only 10 (0.82%) said they had heard o f  HTLV-I infection whilst 
1215 (99.18%) had never heard about it. The results reported herein, suggest that HTLV-I is 
prevalent among healthy blood donors at the 37th Military Hospital Blood Transfusion Centre 
(MHBTC); and that there is the need for screening blood honors for circulating antibodies to 
HTLV-I infection. However, the economic burden/ benefit must also be looked at before including 
HTLV-I in the screening protocol.
Key words: blood donors, HTLV-I, 37th Military Hospital.
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CHAPTER 2
INTRODUCTION
One important danger of blood transfusion is the transmission o f blood borne infections. In the 
developed countries, during the past two decades, transfusion-transmitted infectious disease has 
become extremely rare because o f  improved donor selection processes, universal serologic 
screening o f  donors for blood-borne pathogens, and the shift from transfusion o f  fresh blood 
components to transfusion o f refrigerated products (13,36?.)- On the other hand, less developed 
countries, including Ghana, are not able to fully implement the above procedures to ensure safety of 
transfused donor blood. The demand for blood transfusion service in the  less developed countries 
is high, because o f  high prevalence o f infections that cause anaemia, malnutrition, the all too 
frequen t road traffic accidents, and  the surgical, and obstetric  emergencies associated with blood 
loss (210).
The 37th Military Hospital Blood Transfusion Centre (MHBTC), Accra and National Blood 
Transfusion Service (NBTS), Accra, Ghana screen donor olood for human immunodeficiency virus 
(HTV) I & II, hepatitis B virus (HBV), hepatitis C virus (HCV) and syphilis. A strong case has not 
been made for screening for other blood-borne pathogens (such as human T-lymphotropic viruses) 
because o f  financial constraints th a t lead to fa ilu re  to acquire  enough test kits for serologic 
screening o f other transfusion-associated pathogens and partly because o f  lack o f technical support 
and interest by medical scientists and health authorities.
One o f the infections that can be transmitted by blood transfusion is that caused by human T- 
lymphotropic virus type I (HTLV-I) (255). HTLV-I causes adult T-cell leukaemia and is common
in Africa and among persons with African ancestry (289).
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Reports from studies conducted in other African countrie indicate high incidence o f  blood-borne 
pathogens such as HTLV-I, HCV and HBV among healthy blood donors (196,262,362). In a study 
conducted in Nigeria, Fleming et al. (66) found a prevalence o f antibody to HTLV-I o f  2.0% in 
Nigerian blood donors. Similarly, Sarkodie et al., (285) in a recent study in Kumasi, Ghana, found 
the sero-prevalence o f  HTLV-I among blood donors to be 0.5%. In a related study, Lai et al. (163) 
reported a sero-prevalence rate o f HTLV-I among urban and rural dwellers in southern Ghana to be 
1-2%. More recently, Adjei et al. (2b) in a study conducted among healthy blood donors at the 
Korle-Bu Teaching Hospital (KBTH), Accra, Ghana found the serc-prevalence to be 4.2%.
In a similar study conducted in Dar Es Salaam, Tanzania (196), 1% o f the healthy subjects among 
the population studied had antibodies to HTLV-I. Similarly, Verdier et al. (349) in a study, 
conducted in La Cote d ’Voire, found the sero-prevalence o f antibodies to HTLV-I to be 3.5% in the 
general population. In Egypt, out o f  14 patients fulfilling the diagnostic criteria for tropical spastic 
paraparesis (TSP) presenting to the Neurology Department o f Cairo University, 2 (14.3%) were 
confirmed to be associated with HTLV-I (11). Reports from other studies suggest that HTLV-I 
infection is prevalent in others parts o f Africa; and that the sero-prevalence rate o f  antibodies to 
HTLV-1 in healthy African blood donors ranged from 0-9% and as high as 30% in several at risk 
groups (66,114,337). Prevalence rate o f HTLV in South Africa is very low, about 0.01% among 
healthy blood donors (283).
In some o f the technologically advanced countries such as Japan, Britain, United States o f  America 
donated blood and blood components are always screened for HTLV-I antibodies. In Ghana, 
because o f financial reasons, screening o f donated blood and blood components for other 
transfusion-transmissible pathogens cannot be done. Moreover, population surveys cannot be
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conducted, and therefore sentinel studies are the only means for providing information regarding the 
transmissions o f  transfusion-transmitted infections as well as for monitoring changes over time.
OBJECTIVES
The present study was therefore conducted to:
1. Determine the prevalence o f antibodies to HLTV-I infection among blood donors seen at the 
MHBTC.
2. Determine some risk factors associated with HTLV-I infection.
3. Evaluate the knowledge of HTLV-1 among blood donors in the general population. 
OUTPUT OF THE STUDY
The study will provide the following outputs:
•  Preliminary data on the prevalence o f HTLV-I infection in blood donors at the MHBTC, 
Accra, Ghana.
• A description o f the risk factors and mode o f  transmission o f  HTLV-I infection. 
BENEFICIARIES OF THE STUDY
The beneficiaries o f  the study will be primarily the Ministries o f Defence and Health. The citizens 
o f Ghana (especially blood donors and patients) will also benefit by having, a more accurate 
information on the prevalence and/or transmission o f HTLV-I infections among blood donors.
JUSTIFICATION
The proposed study aims at a better understanding o f the mode o f transmission o f  HTLV-I infection 
among blood donors and to create awareness o f the need to evaluate the impact o f  HTLV-I on 
“walk-in’' and voluntary blood donors at the MHBTC and surrounding communities. The relation 
between blood transfusion and high transmission o f certain infections is an interesting field o f
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research that has not been explored in Ghana. Research into this area in detail could provide useful 
information as to the identification o f  blood donors who are carriers of or sero-positives for HTLV-
I. The in-depth study o f blood donors at the MHBTC might provide a better understanding o f  the 
risk factors for the transmission o f  such diseases. This information will be useful for advocacy to 
change life habits that put people at risk o f developing the infection and provide a means o f 
controlling transmission.
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CHAPTER 3
LITERATURE REVIEW
History o f Human T-cell Leukaemia Virus Discovery and Association with Disease 
HUMAN T-cell Leukaemia virus type-I (HTLV-I)
HTLV-1 is an enveloped RNA virus and belongs to the retrovirus group. Four HTLV types were 
identified between 1977 and 1984. Type I is associated with adult T-cell leukaemia and tropical 
spastic paraparesis (HTLV-I-associated myelopathy). Ty_ s II is linked with hairy-cell leukaemia. 
Type III has been renamed HIV. Type IV is not yet linked to any human disease.
Adult T-cell leukaemia (ATL), was first described in 1977 by Takatsuki et al in Japan (342).
Since then, ATL has also been found in most parts o f  the world. The etiologic role for HTLV-I in 
ATL was established by:
(a) seroepidemiologic surveys associating the virus with disease in patients with ATL and close 
contacts
(b) the clonality o f  ATL tumour cells which correlates with monoclonal or oligoclonal pattern o f 
integration o f  the viral genome in tumour cell DNA
(c) infection o f  lymphocytes in vitro, resulting in immortalization o f  the same cell type (T-cells) as 
the tumour cell, and
(d) HTLV-I being oncogenic in animal models.
HTLV-I was first identified in a lymphoblastoid cell line (HUT 102) established from a patient with
a cutaneous T-cell lymphoma (257) and C type retrovirus particles were identified in this cell type.
In retrospect, it is likely that this original patient had ATL. In 1981 it was shown that another cell
line (MT-1) derived from a patient with ATL also harbored the virus and produced antigens that
reacted with sera from patients with ATL (103,379). T h t viruses produced from these cell lines
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were subsequently shown to be the same and were given the name HTLV I (259). Since the initial 
description o f ATL and discovery o f  HTLV —I, the virus is now known to be associated with human 
disease other than ATL. The most notable o f these is a neurologic disorder known as tropical 
spastic paraparesis (TSP) or more commonly HTLV - I  associated myelopathy (HAM).
HUMAN T-CELL LEUKEMIA VIRUS TYPE- II
HTLV —II was first identified in a T-cell line established from a patient with hairy-cell leukaemia 
(291). This cell line (Mo-1) was derived from splenic tissue in 1978 (292) and in 1982 was shown 
to harbor a retrovirus. Based on serologic cross-reactivi*v, this virus was shown to be related to 
(but distinct from) HTLV - 1 and was termed HTLV II (136). Like HTLV - 1, HTLV II also, 
infects and immortalises T- lymphocytes in vitro. A few HTLV -II  -  infected patients have been 
characterised in detail, providing limited molecular evidence supporting an etiologic role o f HTLV 
-  II in a form o f atypical hairy-cell leukaemia (276,277). The limited number o f the individuals 
shown to harbor HTLV -II  in association with specific diseases, has to date produced convincing 
epidemiological demonstration o f  a definitive etiologic role for HTLV -II  in human malignancy.
HTLV-111 AND HTLV-1V
In April o f  1984, Montagnier (211) and Gallo (260) independently identified a cytopathic retrovirus 
that was called lymphadenopathy associated virus (LAV) or human T-cell lymphotropic virus type 
-III (HTLV-III). This lOOnm RNA virus now called human immunodeficiency virus (HIV), has an 
affinity for T-helper (T4) lymphocytes. The HIV virus is in the family Retroviridae (313).
Included in this family are oncoviruses such as HTLV-I and HTLV-II, which primarily induce 
proliferation o f infected cells and formation o f tumours. HIV is a lentivirus, a slow growing type 
o f virus that causes chronic infection. The core o f the virus contains an enzyme, reverse 
transcriptase that enables, the virus to copy the single stranded RNA into double stranded DNA 
(93). The genome o f the virus is then integrated into the host DNA. The provirus can, through
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transcription produce both viral genomic RNA and messenger RNA, which is translated into viral 
proteins. The virus is then, released by the host cell. In this process the host cell is often destroyed 
(93).
GENETIC STRUCTURE.
The overall genetic structure o f HTLV is similar to but distinct from that o f  other retrovirus. 
(42,299)
GENOMIC STRUCTURE III
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GENOMIC STRUCTURE IV
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Figure 2
In addition to the usual complement o f  gag, pol, and, env jenes, there is a region at the 3’ end o f the 
genome not found in other replication -  competent retroviruses. Because o f  its unknown function, 
this portion o f the genome was initially referred to as the X region. Two genes have now been 
identified within the X  region o f  HTLV I and II; the tax gene which encodes a protein responsible 
for transcriptional activation o f  the long terminal repeat (LTR) and a second gene, rex which is 
necessary for expression o f structural proteins and partially overlaps tax in an alternative frame. 
Three messengers RNA (mRNA) species have been identified for HTLV (figure 1). Like other 
retroviruses, full length RNA is utilised for synthesis o f  gag and pol gene products and is also the 
genomic RNA packaged into virions. The primer used ft r reverse transcription o f  the genomic 
RNA is tRNA. A single- spliced subgenomic mRNA has two introns removed and encodes the tax 
and rex proteins. The tax gene initiation codon is the same as that used for the env gene and is 
contained within the second exon o f the tax/rex mRNA. The initiation codon for the rex protein is 
also located within the second exon o f this mRNA, a further 59 nucleotides upstream. Fig I above 
show the arrangements o f the HTLV genome, genes, gene products and the three mRNA species.
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HTLV  GENE PRODUCTS 
The gag Gene
As in other re trov iruses, the gag region is initially translated as a polyprotein precursor, which is 
subsequently cleaved to form the mature gag polypeptides; the 19 kd matrix (MA), 24 -  kd capsid 
(CA) and 15-kd nucleocapsid (NC) proteins (51, 95, 242). Like other retrovirus gag products, p i 9 
is post-transcriptionally modified and contains myristic acid at the NH-terminus (203,242). 
Myristoylation targets the p55 (gag) precursor polypeptide to the inner surface o f  the cell membrane 
(97). In other retroviruses, this has been shown to be important in the assembly and budding of 
virus particles from infected cells, and it is likely that this is also the case for HTLV.
Protease
In HTLV, the protease is encoded by a reading frame which spans the 3’ part o f  the gag region and 
5’ part o f  the pol region. Synthesis o f  the protease as part o f the gag polyprotein precursor is 
accomplished by ribosomal frame shifting (225). In some molecular clones o f  HTLV - 1, this 
protease open-reading frame contains stop codons (299), which may account for the lack o f 
infectivity o f  these clones. Molecular clones have now been obtained which contain an intact 
protease, coding region (69,184,341). The function o f the HTLV -  1 protease has been examined in 
vitro, and these studies have shown that (a) protease is re: jonsible for processing the mature gag 
products and (b) autocatalized self- cleavage is responsible for generating the mature protease 
molecule (150,224,225).
The pol Region
The polymerase region is potentially able to encode an 896- amino acid product in HTLV-I and a 
982 amino acid product in HTLV-II. However, a second -ibosomal frame-shifting event is 
necessary to express the pol gene (225), resulting in polypeptides o f 864 and 865 amino acids in
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length for HTLV-I and HTLV -II  respectively. The 5 ’ portion o f the pol gene is predicted to 
encode the reverse transcriptase protein and sequences f i r  "her downstream the probable integrase 
and RNaseH functions. Human T-cell leukaemia virus reverse transcriptase, functions most 
efficiently using Mg2 + as the required divalent cation (257,265).
The env Gene
The product o f  translation o f the envelope open reading frame is a glycoprotein o f  61 kd to 69 kd 
depending on the laboratory and cell line studied (170,171,293,294,376). This precursor protein is 
detected on the surface o f HTLV- infected cells. Treatmi it  with tunicamycin or endoglucosamine 
H results in a non-glycosylated precursor species o f 54 kd (171,293). Some higher molecular 
weight env-related species have been shown to be the result o f abnormal env-tax fusion proteins 
(202,333). The envelope protein is cleaved into the mature products the 46-kd surface glycoprotein 
(SU) (gp-46) and 21-kd transmembrane protein (TM) (p21). Culture media from HTLV -  
transformed cells contain large amounts o f free gp -46 , which are shed from the surface o f the cells 
(291,373).
The tax Gene
Two unique genes are found in HTLV, tax and rex (40,92,122,149,217,300,304,354,357) fig 1.
Both genes are essential for viral replication (44). Antibodies against synthetic peptides provided 
definitive evidence that, proteins were encoded by these genes (82,172,202,311). The HTLV -II  
tax genes encode proteins o f  40 and 37 kd, respectively. Both the 40-kd product o f  the HTLV-I tax 
gene and the 37-kd product o f  the HTLV-II tax gene are located primarily in the nucleus o f  the 
infected cells in the region defined as the nuclear matrix (82,172,310,311). The amino-terminal 48 
residues o f HTLV-1 tax protein comprise a nuclear localisation signal distinct from the highly basic
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amino acid sequence, which performs this function in most nuclear proteins (312). Mutants o f tax, 
which fail to localise to the nucleus, act as trans-dominant mutants o f the wild-type protein.
The tax protein is a trans-acting transcriptional activator and increases the rate o f  transcription 
initiation from the promoter in the 5’ LTR o f the provirus genome. It was originally found that the 
transcription o f  the HTLV LTR was stimulated in virus-infected cells when compared with non­
infected cells (42,314).
The rex Gene
The rex gene encodes proteins o f 27/21 kd for HTLV-1 and 26/24 kd for HTLV-II. Antisera 
directed against peptides from the carboxy-terminal portion o f the rex open-reading frame immuno- 
precipitate both proteins (figl).
Structure of the LTR
The U3 region contains sequences that control transcription o f the provirus (fig 2). In particular, 
three imperfect 21-nucleotide repeats are necessary for transacting transcriptional activation by tax 
(29,69,147,237,254,274,306). The U3 region also contains sequences responsible for termination 
and polyadenylation o f m RNA’s. The polyadenylation signal AATAAA, is an unusually long 
distance away from the polyadenylation site (-250  nucleotides) and is hypothesized to be brought 
into proximity with the polyadenylation site by secondary structure (3,16,306). The 5 ’ part o f the 
U3 region also encodes the carboxy terminus o f the tax protein. Comparison o f the LTRs o f 
HTLV-I and HTLV-II reveals that those elements, which are found to be critical for viral gene 
expression (e.g. the 21-nucleotide repeats, polyadenylation signal and TATA box) are well 
conserved, whereas other regions are usually long in comparison to other retroviruses. These 
regions form the leader sequence encoded at the 5’ end o f  the messenger RNAs (306).
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The interaction o f  the HTLV LTR with proteins involved in regulation o f transcription has been 
investigated (230,231), showing that multiple factors bind to different regions o f the LTR in a 
complex pattern (fig 2). DNAse-protected regions are evident over each o f the three 21-nucleotide 
repeats, as well as other regions within U3, and binding o f these factors is critical for regulation o f 
HTLV transcription.
The Non-translated region
A region o f about 600 nucleotides is present between the end o f  the env gene and the beginning of 
the third exon o f the tax and rex genes. The nucleotide homology o f this region between HTLV-I 
and HTLV-II is relatively low compared to the rest o f  the genome. While there is an open-reading 
frame within this region in HTLV-I, in HTLV-II, there are termination codons in the equivalent 
reading frame. In an infectious clone o f HTLV-II, deletion o f approximately 300 nucleotides from 
within this region had no major deleterious effect on HTLV-II replication.
Genetic Variation of HTLV
HTLV-I and HTLV-II share about 65% overall similarity at the nucleotide sequence level. The 
homology is lowered in the LTR and non-translated region and highest in the tax and rex genes. 
Among different HTLV-I isolates, there is remarkable sequences homogeneity. Isolates from 
Japan show 97% to 99% homology and even isolates obtained from geographically diverse regions 
such as the Caribbean, Japan and Africa show 96% to 99% homology
(85,101,184,249,263,295,341). Indeed it has been suggested that sequencing HTLV-I isolates 
endemic in different races might be a means o f monitoring the movement o f ancient human 
populations, and might be useful in anthropologic studies (77). However, HTLV-I isolates from 
Malanesia show marked heterogeneity (approximately 7%) from the Japanese prototype o f HTLV-
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I, suggesting that HTLV-I may have originated in the Indo-Malay region rather than in Africa 
(75,80,302). Sequence homology among different HTLV-I isolates is equally high (167). 
However, it has been claimed that two distinct but closely related molecular subtypes o f  HTLV-II, 
designated HTLV-IIb, can be distinguished (58, 87). In spite o f considerable effort, there is no 
indication that specific subtypes o f  HTLV are associated with particular pathologic consequences 
(52,146,151). The lack o f  genetic variability in HTLV may be due to the relatively low levels o f 
viral replication in vitro. Replication o f the provirus in dividing cells would result in a mutation 
frequency much lower than that o f reverse transcription (57,174). In addition, cell associated 
replication i.e., passive replication o f integrated viral genomes in dividing cells, may allow the 
HTLV to escape a degree o f  evolutionary pressure from antibody response. Compared to HIV, the 
HTLV, envelope genes, appears to be unable to tolerate many mutations without becoming non­
functional. This might provide an additional basis for conservation o f  what might otherwise be a 
highly variable region o f  the virus genome (256).
HTLV INFECTIVITY
Cells Susceptible to HTLV infection
Direct cell-to-cell contact is usually required for efficient HTLV infection, although infection with 
cell-free virus preparation can occur (55, 279,301,368,372). In vitro infection o f cells with HTLV 
is usually accomplished by co-cultivation o f target cells with X-ray irradiated or mitomycin C- 
treated virus producing cells. By comparison with other retrovirus, infection by HTLV o f 
susceptible cells is inefficient with a slow course. Usually only a small proportion o f  the cells 
express viral antigens, and this number may gradually increase over a course o f weeks. The reason 
for this slow kinetics may relate to positive and negative regulation by tax/rex genes or other 
unknown processes o f  infection. Infection o f human and or peripheral blood cells by HTLV- 
I/HTLV-II results in virus production and eventual immortalisation o f the cells. Only T cells, have 
been shown to be transformed by HTLV. Cord and peripheral blood T cells o f humans are
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efficiently transformed. Productive infection with HTLV has only been demonstrated in a few 
cells o f  lymphoid origin (46, 107, 109,113,334,357,367,381).
Conversely, HTLV-I appears to infect but not transform a number o f different cell types in vivo.
On several occasions Epstein Barr virus (EBV) -transformed B-cell lines productively infected with 
HTLV have been established from patients (1, 156, 375). B cells can also be infected in culture. 
There is also evidence that HTLV is capable o f infecting immature cells from human bone marrow, 
which, do not have a T-cell phenotype (188). Infection o f  macrophages and cells o f  neural origin 
has been documented in vitro but not in vivo (4, 108, 157, 173, 266). Although cases o f  ATL with 
central nervous system (CNS) involvement are rare, direct infection o f the CNS may account for 
such symptoms in a few patients (328). Ninety to 99% o f HTLV-I DNA in peripheral blood from 
infected patients is found in CD4, CD8 cells (266). In contrast, HTLV-I DNA is found 
predominantly in CD8 cells (116,276).
The HTLV Receptor
The cellular receptor for HTLV has not been identified but has been demonstrated by various assays 
to exist on a wide variety o f human and animal cells, including primate, canine, feline and rodent 
cells (47, 158, 220,). The presence of a cell-surface receptor for HTLV has also been demonstrated 
by virus-induced cell fusion, leading to syncytium formation (110,219). The absence o f syncytium 
formation when HTLV-I and HTLV-II infected cells are l ixed has been cited as evidence that the 
two viruses utilise the same receptor molecule, whereas the receptor for bovine leukaemia virus 
(BLV) is distinct (316, 317, 357)
T-cell Transformation by HTLV
Both HTLV-I and HTLV-II will immortalise primary human peripheral blood T-cells in vitro (43, 
45, 204, 258, 375). Transformation in this sense is defined as continuous cellular proliferation in
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the absence o f  exogenous IL-2 and is distinct from oncogenesis. In addition to human T-cells T- 
lymphocytes from monkeys (205), rabbits (207), cats (111), and rats (335), have been transformed 
in vitro by HTLV-I.
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CHAPTER 4
DISEASES OF HTLV-I INFECTIONS 
ATL and HTLV-I
Several categories have been proposed as stages in ATL (143,145,191,309). These have 
been termed as follows:
a) asymptomatic carriers state
b) pre-leukaemic state (pre-ATL)
c) chronic/smoldering ATL
d) lymphoma type and
e) acute ATL.
In some but not all cases, these categories may be temporarily related (140). The vast 
majority o f  HTLV-I-infected individuals are asymptomatic carriers for the virus (23, 83, 100, 
103). These infected individuals are capable o f  transmitting the virus, since the proviral 
genome is integrated into host-cell DNA sequence (83). An infected individual has about 1% 
chance o f developing a tumour over a lifetime o f infection (153,154) although the cumulative 
lifetime chance o f  developing any HTLV-associated condition is slightly higher, 5% to 10% 
(56).
ATL generally occurs in adulthood, at least 20 to 30 years following infection (140). Some 
patients manifest a disorder known as pre-ATL, which is usually asymptomatic. Diagnosis o f 
this condition was originally made by incidental detection of leukocytosis and/or
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morphologically abnormal lymphocytes or more recently as a result o f  serological screening 
(143, 331). HTLV-1 can be identified in the cells o f those individuals by polymerase chain 
reaction amplification and the provirus, can be found to be integrated in abnormal T- 
lymphocytes in a monoclonal or oligoclonal pattern by Southern blot hybridisation. These 
findings indicated the beginning o f  the development o f a cloral population o f cells, some of 
which may progress to the malignancies found in acute ATL. Approximately 50% o f 
patients with pre-ATL undergo spontaneous regression o f lymphocytosis.
About 30% o f patients with clinical manifestations o f HTLV-I infections have 
chronic/smoldering ATL (140, 307, 370). These forms o f ATL are less aggressive than the 
acute stage o f the disease and are characterised by skin lesions, low levels o f  circulating 
leukaemic cells, and absence o f visceral involvement. Patients in the smoldering ATL 
category present with skin lesions and marrow involvement, whereas patients with chronic 
ATL generally have elevated numbers o f  circulating ATL cells accounting for an increased 
leukocyte count. Patients in both the smoldering and chronic stages o f  ATL can progress into 
acute ATL within a period o f months. Pre-ATL, smoldering ATL, and chronic ATL may 
represent transitional states in the development o f the malignant clone that is evident in acute 
ATL.
In acute ATL (27, 33, 140, 307, 309), a dominant clone o f malignant cells is present as 
evidenced by the process of:
a) a single re-arrangement o f T-cell antigen receptor gene (131, 192) and
b) one or a few proviruses arranged in an oligoclonal fashion in the population o f  tumour 
cells (109, 298).
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These patients have an elevated white blood cell count, with many morphologically abnormal
T-lymphocytes having characteristic lobulated or flower-shaped nuclei. There is this also,
often prominent eosinophilia and neutrophilia. Findings in acute ATL include
lymphoadenopathy that does not involve the mediastinum hepatosplenomegally, and skin
lesions due to infiltration o f  leukemic cells. Intestitial pneumonitits, also caused by
leukemic cell infiltration, is sometime present. Patients manifest abnormalities in certain
serum chemistries, including elevation o f  lactate dehydrogenase (LDH) hyperbilirubinaemaia
and hypercalcemia. Hypercalcaemia is associated with the presence o f  lytic bone lesions
detected on the skull and long bones (28, 40, 89). Recent work has shown that hypercalcaemia
in acute ATL may involve production o f IL - l a  and parathyroid hormone-related protein by
HTLV-I infected cells (61, 118, 119, 356). Patients with ATL are also immunocompromised
and may present w ith opportunistic infections, including disseminataed fungal infections,
Pneumocystis carinii pneumoniasis, cytomegalovirus pneumonia, and bacterial infections (33,
38, 140, 344, 382). The only significant prognostic factor in acute ATL is the presence o f
ascites, which is associated with shorter survival. The median survival in acute ATL is
approximately 6 months (39, 90, 129, 140,309), der.ute aggressive intervention with
chemotherapy. The morphology o f peripheral blood cells in ATL is variable. Typical ATL
cells have a highly lobulated nucleus, but the degree o f nuclear irregularity is variable (39,
232, 330). The histopathology o f  lymph nodes from patients with ATL is also heterogenous,
but it most frequently falls into the large cell, immunoblastic classification (59, 90, 88, 129,
232). Nodal histopathology has no correlation with the patients’ prognosis or therapy.
Immunologic studies o f ATL cells have revealed phenotypic heterogeneity for T-cell subset
markers (213, 366). However, virtually all ATL cells have markers for CD4 antigen (39, 89,
94, 320), with rare exceptions having CD8 makers v r0, 91). Although these markers usually
indicate a helper/inducer phenotype, assays reveal that these cells have suppressor activity for
immunoglobulin synthesis (197,328, 353, 367). Further studies suggested that this
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suppression is not directly due to ATL cells but is instead, mediated via suppressor CD8 cells 
that are activated by the ATL cells (213). One chz acteristic marker o f  ATL tumour cells is 
high level o f  expression o f the IL-2R-alpha chain (Tac antigen) (175, 342). The form o f 
disease in some patients with ATL is predominantly that o f a T-cell lymphoma rather than a 
leukaemia (38, 309, 369). These non-Hodgkins lymphomas have differing histologies and 
can involve any organ. Lymph node biopsy specimens from these patients contain 
oligoclonally integrated HTLV-1, indicating a clonal malignancy (370, 380). The differential 
diagnosis o f  ATL includes other T-cell malignancies such as non-Hodgkins’ lymphoma, 
mycosis fungoides, Sezary syndrome, and T-cell chronic lymphocytic leukaemia. However, 
clearly, not all cases o f  these secondary conditions ; e associated with HTLV infection (37).
A variety, o f  laboratory studies can help establish a diagnosis o f ATL, including, HTLV-1 
serum positivity, hypercalcemia, elevated serum LDH, staining for terminal deoxynucleotidyl 
transferase (typically negative in ATL), and inmmunologic typing o f  ATL cells for CD4 and 
Tac antigen ( IL-2R-alpha chain). The definitive evidence of disease is obtained if  
monoclonally or oligoclonally integrated HTLV-1 genome is present.
HTLV-1-ASSOCIATED MYELOPATHY
In 1985, a group o f West Indian patients with a neurologic disease known as tropical 
spastic paraparesis (TSP) were found positive for HTLV-1 (79). Subsequently, a report from 
Japan described a number o f patients with a slowly progressing myelopathy and pyramidal 
disturbances, all o f whom had elevated HTLV-1 antibody titres (247). This neurologic 
disease was termed HTLV-1 associated myelopathy (HAM), now considered to identical to
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Human T-cell leukaemia virus type 1-associated myelopathy has been described in all areas o f 
the world known to be endemic for HTLV-1 (79,76, 179, 227, 246, 273, 349), and the risk 
factors are the same as those for HTLV infection (142). The lifetime risk for development of 
HAM has been estimated at less than 1% (138). Neurologic findings in HAM include 
weakness and spasticity o f  the extremities, hyper-reflexia, Babinski sign (either positive or 
negative), urinary/fecal incontinence, and mild peripheral sensory loss (244,349). The 
cerebrospinal fluid (CSF) o f  these patients contains anti-HTLV-1 antibodies and may show a 
lymphocytic pleocytosis, as well as elevated protein levels.
Patients with HAM generally have normal lymphocyte numbers, but morphologically atypical 
lymphocytes resembling ATL cells can be seen in peripheral blood or in the CSF (71, 243). 
Magnetic resonance imaging has demonstrated lesions in both the white matter and the 
paraventricular regions o f  the brains in patients with HAM (198,339, 349). Autopsy studies 
show significant abnormalities in the thoracic spinal cord, including demyelination, capillary 
proliferation, and perivascular cuffing with lymphocytic infiltration (5).
OTHER DISEASES ASSOCIATED WITH HTLV-1
A number o f  reports have suggested that hematologic malignancies other than ATL are 
associated with infection with HTLV-1 (78, 81, 86, 193, 290, 315, 318, 366). Cases o f  T-cell 
non-Hodgkin’s lymphoma, T-prolymphocytic leukaemia, Sezary’s syndrome, mycosis 
fungoides, small cell carcinoma and large granular lymphocytic leukaemia (T-gamma 
lymphoproliferative disease) have been described to be serologically or molecularly linked to 
HTLV-1 infection.
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B-cell Chronic Lymphocytic Leukemia
One malignancy distinct from ATL, in which HTLV-1 may play an indirect role occurs in 
certain cases o f  chronic lymphocytic leukaemia o f  B-cell origin (B-cell CLL). In Jamaica, a 
region in which HTLV-1 infection is endemic, HTLV seropositivity was significantly higher 
in patients with B-cell CLL than in the general population (25). When leukaemic cells o f 
these patients were examined for HTLV-1, no integrated HTLV-1 provirus was found in the 
leukemic B-cell clones (48, 50). In two cases, hybridoma cell lines derived from the tumor 
cells o f  the B-cell CLL produced monoclonal antibodies that preferentially reacted with 
HTLV-1 proteins (185). It was proposed that the B-cell CLL is derived from the clonal 
outgrowth o f  a B-cell clone reactive against an HTLV-1 antigen. If  B -cell CLL is related to 
HTLV-1 infection, then additional factors must also be involved.
IMMUNOSUPPRESSION
There is some evidence for functional impairment o f the cellular immune response in 
patients with ATL as well as among some HTLV-1 carriers (38, 100, 120). Defects in cell- 
mediated immunity may result in particular problems, with parasitic infections (227, 272). 
Immunosuppressive effects may lead to opportunistic infections (221, 227, 233). In this 
context, it is important to distinguish between patients who may be co-infected with HIV. 
Nevertheless, there is clear evidence that HTLV infection may result in some degree of 
immune system impairment (176,212, 215, 323).
CHRONIC INFLAMMATORY ARTHROPATHY
Recent clinical reports have shown that chronic inflammatory arthropathy may occur in a few 
HTLV-1 infected individuals as a rare complication o f infection (148, 229, 284). HTLV-1 
infection is implicated in certain chronic arthritis in human (126).
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HTLV-1 ASSOCIATED UVEITIS
Studies in HTLV-1 endemic areas have indicated an association between HTLV-1 infection 
and an mtra-ocular inflammatory disorder, uveitis. The sero-prevalence o f HTLV in patients 
with uveitis without any other defined etiology is significantly higher than that in patients 
with non-uveitic ocular diseases (60,208,209,223).
HTLV II DISEASE
The first individual from whom HTLV -  II was isolated had a disease termed hairy-cell 
leukaemia (136,291). Although most hairy-cell leukemiaias are o f  B-cell phenotype this 
patient’s leukemic cells were T cells. The term atypical hair} -cell leukaemia is used to 
distinguish the disease from other T- and B-cell haky cell leukemias, the majority o f  which 
are not associated with HTLV-II infection (276).
In 1985, a second HTLV-II infected patient was identified (277). Both patients shared the 
following features: T- cells lymphocytosis was evident: some circulating atypical 
lymphocytes were positive for tartrate-resistant acid phosphatase (TRAP) and had 
characteristic hairy cell leukaemia. A detailed analysis o f HTLV-II with second patients 
provides evidence for an etiologic role o f HTLV-II in this disease (276,277). There have 
now been several other reports o f  HTLV-II in association with T-cell malignancy (276,277).
One patient had T-cell CLL, characterised by marked neutropenia. Serologic evidence for 
HTLV-II infection has been obtained in populations by relatively crude enzyme-linked 
immunosorbent assays (ELISA) assays that distinguish between HTLV-I and HTLV-II 
antibodies. HTLV-II has been reported among intravenous drug abusers (IVDA) in Great 
Britain (336) and New York (271). The use o f PCR has identified a high incidence o f
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HTLV-II infection among IVDA in New Orleans (167,278). CD8 T-cells elevation was 
observed in three o f  four HTLV-I infected IVDA.
Other complications o f  HTLV-II infection reported from diverse patient populations are 
highly reminiscent o f  HTLV-I associated diseases. These include spontaneous lymphocyte 
proliferation (363), mycosis fungoides (384), large granular lymphocyte leukaemia (180, 
189), and neurologic complications similar if  not identical to HAM (91,127,275,276).
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CHAPTER 5
PATHOGENESIS OF HTLV INFECTIONS 
ONCOGENESIS
When HTLV-1 infected lymphocytes are present in individuals at a sufficiently high proportions to allow 
detection o f viral sequences by Southern blotting, the viral sequences are always present as integrated 
forms and are generally oligoclonal or monoclonal with respect to integrated sites (298,378). Initial 
infection by HTLV-1 results in transformation o f a polyclonal population o f  cells and subsequent 
selection processes result in the evolution o f clones, which may ultimately develop into malignant cells. 
Chromosomal abnormalities commonly exist in ATL cells (70,125,190,200,345,361) and the degree o f 
cytogenetic aberration is often related to the severity o f  the disease, i.e. abnormalities are frequently 
found in acute ATL, but are less likely to be seen in chronic or smouldering ATL, suggesting the 
possibility o f  clonal evolution during disease progression. HTLV-transformation o f  T-lymphocytes 
results in a pool o f  proliferating cells which are not oncogenic themselves (64), but which provide a 
population from which a malignant clone may subsequently arise. This accounts for the long latent 
period between infection and manifestation o f a tumor in HTLV disease. Thus T-cells transformation 
and oncogenesis are separate but related processes.
During the acute phase o f  ATL, when patients have an elevated leukocyte count with many malignant 
ymphocytes the viral DNA can be easily detected by southern blotting and is generally monoclonal with 
espect to integration sites. However, examinations o f  viral ‘ntegration sites from different patients with 
\TL  demonstrate that these are distinct and present on different chromosomes (298).
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One o f the distinguishing features o f  the virus in the acute phase and perhaps also in pre-ATL and 
chronic/smouldering ATL is that although the viral genome is present as a provirus in all o f  the tumor 
cells, there is no detectable expression o f  viral genes within the cells (39,83,264,338).
HTLV-ASSOCIATED MYELOPATHY
The pathogenesis o f HAM remains poorly understood. In contrast to ATL, which generally occurs 20 to 
30 years following HTLV-I infection, HAM may develop in aome patients within a few years following 
infection often after transfusion o f  infected blood (53,245). The presence o f intrathecal antibody titers to 
HTLV-I indicates that the virus has infected the CNS in addition to the blood (105,244). Immune 
:omplexes have also been detected in the blood o f patients with HAM (305). A number o f studies have 
demonstrated the presence o f  HTLV-1 DNA in blood and lymphocytes o f the CSF (19,380). It is 
loteworthy that polyclonal integration o f the virus is detected in patients with HAM, as opposed to 
oligoclonal or monoclonal integration in ATL. Thus, development o f HAM is not a consequence o f the 
levelopment o f  a malignant clone o f cells. Characterisation o f viral isolates from patients with HAM 
loes not show any distinguishing features from HTLV-I from those with ATL and provides no evidence 
hat a variant virus is involved in HAM (52,105, 129, 146, 151,341). Some authors have concluded that 
>ersistent active replication o f HTLV-1 is an important factor in the pathogenesis o f HAM (218), 
ompared with the mostly quiescent state of the virus in ATL. Hypothetical mechanisms for the 
levelopment o f  HAM are based upon autoimmune models. Primary demyelination and remyelination by 
'ligodendrocytes occurs in the spinal cord lesions o f  HAM (234). O f note is the observation that patients 
vith HAM tend to have higher levels o f  circulating antibody to HTLV-1 antigens than do those with 
vTL (244, 346). High levels o f  cytotoxic T-Iymphocytes (CTLs), which predominantly recognise 
ITLV-1 infected cells, have been detected in patients with HAM (128,346), although this feature may 
iot be unique for HAM (253).
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HTLV-HIV CO-INFECTION
Several epidemiologic surveys have indicated the existence o f groups o f individuals who are currently 
infected with both HTLV-I/II and HIV. This is particularly common among intravenous drug abusers
(IVDA) who become infected by sharing contaminated needles cind syringe, a major route o f
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transmission o f  both viruses.
IMMUNE RESPONSE TO HTLV
All patients with ATL make humoral antibodies to various HTLV-I antigens. The major viral gene 
products recognised by sera infected individuals are those o f the gag,env and tax genes. As in all 
retroviruses, the gag proteins are the major immunogens and are responsible for the earliest antibodies to 
appear. Sera from infected individuals usually recognise all three gag proteins, p l5 , p24 and p 19.
There is considerable cross-reactivity between HTLV-1 and HTLV-II, particularly in the region encoding 
p24 (134, 137, 267, 296, 297,332, 373).
Serologic profile o f  HTLV- infected individuals varies considerably, including some individuals who 
display a virtually monospecific pattern o f antibodies. Cellular immunity against HTLV- infected cells 
has also been described. Naturally, immunity to HTLV appears to be different from that o f  other 
retroviruses, in that human complement-mediated virolysis was not effective for HTLV virions, using 
either normal human serum or human serum from an HTLV antibody carrier. Thus the virus may have 
intrinsic resistance to humoral immune mechanisms (112).
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CHAPTER 6
EPIDEMIOLOGY OF HTLV INFECTIONS
Human T-cell lymphoma virus infection was originally discovered in Japan, but has now  been 
found in most parts o f  the world, including other areas in Asia, the Caribbean South America and 
Africa (21, 23, 40, 195, 289, 319, 352). Mapping the geographic distribution o f  HTLV-I/II has 
been complicated because conventional serologic approaches cannot distinguish between the two 
viruses. In general terms, HTLV-I predominates in southern Japan, the South Pacific, parts o f 
West Africa and in African populations o f the Western hemispheres, while HTLV-II clusters in 
Native American populations and among IVDA (183) the number o f  people around the world 
infected with HTVL-I has been estimated between 1 0 -2 0  million (56). Sero-epidemiologic 
studies have been based upon a wide variety o f assays, including ELISA’s utilizing whole virion 
preparations (287, 322), immunofluorescence o f  fixed wells o f  HTLV-infected cell lines (100, 103) 
radioimmunoassays (336) western blots and radioimmunoprecipitation (170, 267,293,275). In 
Japan, an assay based on agglutination o f  gelatine particles has been used to screen all blood donors 
(117). In comparison to HIV infections the antibody titres for HTLV-I are relatively low (H. Lee, 
personal communication) and development o f  detectable antibodies may increase slowly with age 
(24, 102, 326).
HTLV - I  IN JAPAN
The number o f  infected individuals in Japan has been estimated to be over 1 million (101) among a 
population o f approximately 121 million. Rates o f seropositivity in different regions vary widely 
35% in Okinawa, 8% to 10% in Kyushi Province, and 0% to 1.2 % in nonendemic areas (102,
191,327). Even the incidence o f  HTLV-I infection in individual cities and locals within the
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endemic regions is quite variable, probably due to the limited transmission o f HTLV-I between 
socially isolated population centres (102, 155, 303,325).
Infection with HTLV-I, generally occurs quite early in life, probably perinatally (12, 98, 99,
222,327) but, it has been estimated that 30,000 to 50,000 Japanese have been infected through 
blood transfusions (283). In Japan, the primary modes o f transmission within families are as 
follow:
a) from male to female, via passage o f  HTLV-I infected lymphocytes in semen and
b) from mother to child, primarily via lymphocytes in breast milk (12, 98,99). Female to male 
sexual transmission is also possible.
Many investigators have proposed hypothesis for the origin o f  HTLV-I in Japan. Some have 
theorised that Roman settlers who arrived in Japan between 300 and 1000 BC brought the virus to 
Japan (123). Other investigators have postulated that HTLV-I originated in Africa suggesting that 
Portuguese traders brought the virus to Japan in the 16th Century (66, 74)
HTLV-I IN OTHER COUNTRIES
Human T-cell leukaemia virus type I is also endemic in
a) other areas o f Asia such as Taiwan, Okinawa
b) the Caribbean basin, including northeastern South America and
c) Central Africa (21, 23, 40, 195, 216, 269, 289, 319).
HTLV-1 infection and a few cases o f  ATL have been reported in Italy (85, 186), Israel (18) the 
Arctic (268), New Guinea (141) and the United States o f  America (26, 33). Adult T-cell leukaemia 
cases in Hawaii have been identified among Japanese Americans (24). The incidence o f  HTLV-1 
infected individual appears to be increasing in Western E rope (336) and the United States o f 
America particularly among IVDA and homosexuals (22, 25, 49, 65, 66, 73, 81, 114, 178, 240, 289,
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358, 365). In one published study o f  IVDA in New York, a prevalence o f 9%, 18% and 41% of 
HTLV-I, HTLV-II and HIV respectively was reported (271). In Trinidad, 15% o f homosexuals 
were seropositive for HTLV-I, as opposed to 2.4% o f the general population (17). Although HTLV- 
I is endemic in Trinidad and HIV was only relatively recently introduced into the country, 
approximately 40% o f homosexuals were found to be infected with HIV, compared with less than 
1% o f the general population, suggesting that the same populations are at risk for infection with 
HTLV-1 and HIV, but that HTLV-I is spread less efficiently than HIV. Studies o f  HTLV-I/II 
among United States o f  America blood donors indicated that a significant proportion o f  blood 
samples are infected (169, 199). Human T-cell leukaemia virus seroprevalence is about three times 
greater than that for HIV-I (0.043% versus 0.013%); 52% o f these cases are due to HTLV-II 
infections and 43% HTLV-I. up to 2,000 individuals per s^ar may have been infected in the United 
States o f  America through blood transfusion before routine donor testing began (364). Some cases 
of transfusion-related ATL have also been reported (25,27, 31,33, 96). All blood supplies in the 
United States o f  America have been screened for HTLV-1 infection since 1988. In Europe, the 
general incidence o f  HTLV-1 infection appears to be lower than in the United States o f  America, 
although it is found at higher frequency in populations with known risk factors, in particular people 
of Caribbean origin and in IVDA (347). Human T-cell leukaemia virus infections, appears to be 
well established in IVDA in Italy (54, 85, 186). In the United Kingdom a recent survey o f  nearly 
100,000 blood donors indicates an overall seroprevalence o f 1:20,000 (30). A few European 
countries screen blood supplies for HTLV-1. In Africa HTLV-1 is found almost across the whole 
of the  continent.
Reports from studies conducted in other African countries indicate high incidence o f  blood-borne 
pathogens such as HTLV-1, hepatitis C virus (HCV) and HBV among healthy blood donors 
(196,262,362). In a study conducted in Nigeria, Fleming et al. (65) found a prevalence o f  antibody 
to HTLV-I o f  2.0% in Nigerian blood donors. Similarly, Sarkodie et al., (285) in a recent study 
done in Kumasi, Ghana, found the sero-prevalence o f HTLV-I among blood donors to be 0.5%. In
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a related study Lai et al. (163) reported a sero-prevalence rate o f HTLV-I among urban and rural 
dwellers in southern Ghana to be 1-2%. In a study conducted in Dar Es Salaam, Tanzania, (196), 
1% o f the healthy subjects among the population studied had antibodies to HTLV-I. Similarly, 
Verdier et al. (348) in a study conducted in La Cote d ’ Voire, founu the seroprevalence o f 
antibodies to HTLV-I to be 3.5% in the general population. Reports from other studies suggest 
that HTLV-I infection is prevalent in other parts o f Africa; and that the sero-prevalence rate of 
antibodies to HTLV-I in healthy African blood donors ranged from 0-9% and as high as 30% in 
several at risk groups (65,114,337).
HTLV-II
HTLV-II infection appears to be m ore common than previously thought although distribution o f the 
virus tends to be localised in certain population groups. HTLV-II infection is particularly high in 
IVDA (19, 54, 87, 106, 139, 161, 168). Although HTLV-II infection is extremely rare in Japan, 
certain ethnic groups elsewhere show higher incidence o f the infection. This is particularly true for 
people o f  native, American origin and a high prevalence o f HTLV -II infection has been identified 
in New Mexico.
TRANSMISSION OF HTLV
Human T-cell leukaemia virus type I transmission occurs through one o f  three different modes.
First, mothers infected with HTLV-I can transmit the virus to the fetus or new bom  (144, 152, 326, 
377). The mode o f transmission here  is either through transplacental passage o f infected maternal 
lymphocytes or through infected lymphocytes in breast milk. The overall prevalence o f HTLV-1 
among children bom to infected mothers was 16%. The prevalence o f HTLV-I among children 
breast-fed for over 3 months was significantly higher (27%) than that o f those breast-fed for under 3 
months. O f 78 bottle-fed children, 13% o f children bom to carrier mother are infected with HTLV-1
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by routes other than breast milk (104). Polymerase chain reaction amplification had detected 
HTLV proviral DNA in the peripheral blood and milk o f  all carrier neonates, indicating that 
transpacental infection with HTLV-I is rare and that post-partum infection via breast milk is major 
perinatal transmission route (280, 281, 340). These observations have produced recommendations 
that carrier mothers should refrain from breast feeding in order to reduce the incidence o f  HTLV-I 
transmission to their offspring. Secondly, HTLV-I can be transmitted from male to female during 
sexual intercourse via HTLV-I infected cells in semen (222, 326). It is possible that female to male 
sexual transmission also occurs but only a t a very low rate (32).
The third route o f  transmission is through infected blood and blood products. However, unlike HIV 
only blood products that involve passage o f whole lymphocytes from donor to recipient can 
transmit the virus (132, 182, 199, 201, 239, 238, 307). A retrospective study o f HTLV transmission 
via contaminated blood transfusion showed an apparent efficient transmission o f  12% (321). This 
study concluded that transfusion transmission o f HTLV-II to approximately 700 recipients per year 
occurred in the United States o f America before routine d.pnor testing began in 1988. In another 
study, antibodies were detected in 19 (0.3%) o f 6,286 plasma donors from five regions o f  the 
United States o f  America but no HTLV-I/II antibodies were detected in hemophiliacs who were 
transfused regularly with non-inactivated plasma or its derivates emphasising that the transfusion 
o f HTLV-seropositive plasma products do not transmit the viral infection (36). However, HTLV 
has recently been transmitted extensively among IVDA presumably through passage o f  infected 
blood lymphocytes in shared needles. Thus the overall mode o f  HTLV-I transmission is similar to 
that o f  AIDS virus with the exception that the virus is apparently not readily transmitted by cell -  
free body fluids. In Africa the transmission o f infected bit )d would increase because o f  the use of 
whole blood, which has not been leuco-depleted. Leuco-depletion actually deals with lymphocytes 
reduction in whole blood. Thus HTLV infection would be reduced.
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CHAPTER 7
DIAGNOSIS O F  HTLV  INFECTION  
Antibodies
Diagnosis o f  HTLV-I or HTLV-II infection requires both the ability to detect and discriminate 
between infections by either virus. Several methods have been utilised (102, 103, 117, 135, 199, 
287, 322, 364, 373). The development o f  suitably rapid and sensitive assays has been complicated 
by the relatively low antibody titres in individuals with HTLV-I/II as compared to individuals with 
HIV. Several commercial assays based on ELISA or particle agglutination formats are now 
available for screening o f HTLV-antibodies. An ELISA/agglutination assay is used as the primary 
screen, followed by confirmatory assays using Western blotting or radio immunoprecipitation. 
Screening o f  blood supplies since 1988 has reduced the o erall rate o f HTLV-I transmission via 
blood transfusion to an extremely low level although some HTLV-II infected blood is likely not to 
be detected by the assays currently available (10).
Serodia Fujirebio particle agglutination kit is available for screening o f donated units before use. 
This kit has been used in Japan to detect antibodies to HTLV-1. The Serodia Fujirebio gelatine 
reagent is the most reliable in detecting HTLV antibodies in serum. Confirmatory tests by second, 
third and fourth generation ELISA kits have shown Serodia, Fujirebio gelatine particle kits to be 
sensitive in detecting antibodies to HTLV. Serodia Fujirebio gelatine kits, detect both antibodies 
to HTLV-I and HTLV-II. Serodia Fujibero gelatine particle uses two cells; sensitised and 
unsensitised cells.
The choice o f  Serodia gelatine particle as the reagent for the exercise is due to the fact that it is 
comparable to other test kits and is equally sensitive. The main complication in antibody screening
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methods is an age-dependent increase in seropositivity, indicating that certain individuals may not 
develop antibodies until some time following infection (24, 48, 160, 235).
Detection o f  HTLV genetic material provides an alternative in patients with ATL, where the 
majority o f  lymphocytes harbor the provirus detection o f this DNA by Southern blotting is 
relatively straight forward, and reliable. However, asymptomatic carriers are more problematic, 
since only a small proportion o f  cells are infected with the virus. One means formerly employed 
was to first cultivate the cells for 3 to 5 weeks, allowing:
a) replication and spread o f  the virus and
b) consequent amplification o f viral genetic material. The virus can then be detected in these 
cultured cells by Southern hybridisation or in-situ hybridisation to HTLV RNA.
The d isadvan tage  o f  this method is that in vitro culture o f  cells is time-consuming and expensive 
and is therefore not suitable as a rapid clinical screening assay. These problems have been solved 
by the application o f PCR amplification o f  specific sequences in the virus genome (20, 60, 162). 
Polymerase chain reaction can be used to detect a single HTLV-I/II provirus and is now the method 
of choice for detection o f HTLV DNA directly from blood and many other tissues. Commercial 
PCR kits for HTLV are available, however, the unmatched sensitivity o f  PCR also has a draw back. 
False positive results from inadvertent contamination o f  samples is a major problem. Target 
inactivation protocols are available to circumvent this prc >lem in diagnostic laboratories. Although 
PCR is now a primary research tool, its use still presents problems o f cost in large-scale screening 
operations particularly in underdeveloped countries where HTLV infection may be endemic.
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CHAPTER 8
MATERIALS AND METHOD
Study population. Based on the assumption o f a prevalence rate o f 0.5% (282), a sample size o f 
1225 was calculated for a confidence interval o f  95% and a power o f 90% using standard methods. 
The study was carried out between the months o f January and April 2004 among blood donors at 
the 37th MHBTC. The hospital is situated about six miles from KBTH, and it is a 600 bed 
hospital, which serves the military personnel, their dependants, surrounding urban population, and 
also referred cases from other military health posts out ide Accra. In Ghana, blood donors are 
volunteers and are also sought from family members o f  patients and friends needing blood 
transfusion. Blood donors undergo clinical screening which involves a questionnaire (see 
appendix) and a routine medical examination; only those found to be healthy are bled. The criteria 
include checking the donor’s blood pressure and pulse, physical examination for leprosy patches, 
tattoos, fungal elements and eczema and also checking the haemoglobin level. The haemoglobin 
level o f male donor should be between 13.6g/dl to 18.0g/dl, that o f  the female must be between 
12.0g/dl to 14.6g/dl. Questions are also asked about the d ono r’s sexual behaviour and sexual 
preference.
Donated blood is routinely screened for HIV I & II antibodies, HBsAg, anti-HCV antibodies and 
fo r syphilis. In this study, additional blood was also taken from blood donors for detection o f 
antibodies to HTLV-I.
Sample collection. Blood samples (about 3 ml) were collected from blood donors into 5 ml plain 
tubes. Serum was separated and kept at -20°C until analyzed. In addition, a structured 
questionnaire (Appendix A) was administered to the blood donors after an informed oral and 
written consent was taken.
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Serological Test. Sera were screened for the presence o f  HTLV-I antibodies with a commercially 
available HTLV-I particle agglutination test kit and confirmed by ELISA (Serodia Fujirebio Inc., 
Japan) in accordance with the manufacturer’s instructions. The sensitivity and  specificity of the 
assay a re  100%  and  98.5% , respectively.
Pnnciple o f  Passive Particle-Agglutination, test for Detection o f  Antibodies to HTLV-I.
Principle and Advantages:
The reagent is prepared w ith  gelatin particles sensitized with HTLV-1 antigen on the principle that 
these sensitized particles can be agglutinated by anti-HTLV-1 antibody in human serum or plasma. 
HTLV-1 is prepared by disrupting purified HTLV-1 v iru s with detergent. This is prepared by
concentrating the culture fluid o f  a virus producing cell line; subjecting it to sucrose- gradient
*
centrifugation, collecting the virus fraction corresponding to a density o f  about 1.16g/cm3.
Seridia HTLV-1 has the following advantage:
1. The test procedure is extremely simple as a microtitre technique and is particularly suitable 
for mass- screening o f test samples.
2. The test is time- saving and results are readable by the naked eye after about 2 hours.
3. Serodia-HTLV-1 k it involves the use o f  a newly developed artificial carrier Fuji particle 
that does not show nonspecific agglutination usually observed with red cell carriers.
TEST PROCEDURE:
Preparation o f Serum Specimens
Erythrocytes or other visible components present in the serum or plasma samples are removed by 
centrifugation prior to testing in order to preclude interference with test results. Inactivation of 
serum samples is not necessary.
1. 25ul o f  serum diluent was placed in wells 1 through 3 o f a microtitre (U-shaped) plate
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2. After centrifugation, 25ul o f serum specimen was added to well 1 and mixed by filling and 
discharging the micropipette 3 or 4 times with fluid in well 1. 25ul o f  diluted solution well 
1 was transferred into 2, mixed and 25ul again transferred into well 3. The procedure was 
repeated again in well 3 to obtain 2nd dilution.
3. After this 25ul o f  unsensitized cells w ere pipetted into well 2 and 25ul o f sensitised cells 
was added to well 3 using the droppers supplied ii» kit.
4. The contents o f  the wells were thoroughly mixed using a tray mixer (automatic vibratory 
shaker).
5. The microtitre plates were then covered and placed on a level surface and allowed to stand 
at room temperature (15-25°C) for 2 hours.
6. The plates were read over a white sheet of paper.
7. Positive and negative controls were included and treated in a similar fashion.
PRINCIPLE OF ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA)
Enzyme-linked immunosorbent assay, commonly known as ELISA or EIA, is similar in 
principle to radioimmunoassay but depends on an enzyme rather than a radioactive label. An 
enzyme conjugated to an antibody reacts with a colourless substrate to generate a coloured 
reaction product. The colour generated is proportional to the concentration o f  antigen or 
antibody present in the sample under test. A number o f enzymes have been employed for 
ELISA, including alkaline phosphatase, horseradish peroxidase, and p-nitrophenyl phosphatase.
THE ELISA TEST PROCEDURE
The ELISA is based on a one step “sandwich” principle. Briefly, sera diluted 20-fold in 
phosphate buffered saline (PBS; pH 7.2) containing 0.05% Tween 20 and 20% goat serum were 
incubated overnight at 4°C in microtitre wells previously coated with a preparation o f disrupted 
HTLV-1. After being washed with PBS-Tween, the wells were incubated for 1 hour at room
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temperature with peroxidase-conjugated goat anti-human IgG appropriately diluted in PBS- 
Tween, containing 1% goat serum. Following washes with PBS-Tween and PBS, the wells were 
incubated for 20 minutes at room temperature with peroxidase substrate solution (which consists 
o f  Sorenson’s phosphate citrate buffer, pH 5.0, containing 0.005% H2O2 and 0.05% ct- 
phenylenediamine). The enzyme reaction was stopped, by adding 50ul 2M H2SO4, and the 
resulting colour was read on a Titertek plate reader at *92nm. All sera were assayed in 
duplicate and results were compared with those o f standard HTLV-1 antibody positive and 
negative sera.
Statistical Analysis
Statistics were calculated using EPI INFO 2002. The associations between HTLV-I and risk 
factors and covariates were assessed by a two-tailed Fisher’s exact or Student’s t-tests. Odds 
ratios (OR’s) and 95% confidence intervals (95% C l’s) for risk factors were calculated by a logistic 
regression model. P values < 0.05 were considered statistically significant.
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CHAPTER 9
RESULTS
A total o f  1225 donors, (1158 males and 67 females) were enrolled for the study (fig .l). Majority o f 
the blood donors studied were in the 30-39 years age group forming 75.5% o f the whole group 
(Table 1). These 1225 donors had various educational backgrounds with 1006, forming 82.1%, 
having had at least some form o f basic education (Table 2). Majority o f the donors were traders 
(701; 57.2%) (Table 3) and were in the Hospital to donate blood for their relatives and friends. O f 
the 1225 donors, 311 (25.4%) were single and 914 (74.6%) were married (Table 4). Out o f  the 914 
(74.6%) married donors, 43 (4.7%) had two wives and 871 (95.3%) had one wife (Table 4).
The donors were asked about the usage o f contraceptive. Two (0.2%) did not use any form o f 
contraceptive, whereas 1223 (99.8%) used some form o f contraceptives (Table 5). Five (0.4%) 
used female condom, 42 (3.5%) did not use condom, and 1176 (96.0%) sometimes used male 
condoms (Table 5). The contraceptives used included male condom, female condom, injectable 
(Norplant) and oral contraceptive. The condoms were used as protection against sexually 
transmitted infections and not necessarily for the prevention o f pregnancy. Injectable (Norplant) 
and oral contraceptive were for the prevention o f pregnancy.
O f the 1225 donors, 1089 (88.9%) have donated blood before, while 136 (11.1%) were donating 
blood for the first time. Those that have donated blood beiore have done so between 1 and 7 times 
(Table 6). Also none o f the donors had tattoo marks.
Knowledge about HTLV-1 infection among the blood donors was found to be very poor. Only 10 
(0.82%) said they had heard o f HTLV-1 infection whilst 1215 (99.18%) had never heard about it 
(Figure 2). There was a statistically significant difference (P<0.0001) between them.
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Table 2 — Educational Status of Blood Donors
Type o f Education Frequency Percentage (%)
Primarv 130 10.61
Junior Secondary School 485 39.60
Middle school 391 31.92
Secondary school 100 8.16
Senior Secondary School 80 6.53
University 10 0.82
No schooling 27 2.20
Other 2 0.16
Total 1225 100
Table 3 -  Occupation of Blood Donors
Occupation Frequency Percentage %
Accountant 1 0.1
Baker 10 0.8
Caterer 5 0.4
Catechist 2 0.2
Cleaner 14 1.1
Factory Hand 35 2.9
Hairdresser 8 0.6
Housewife 12 1.0
Messenger 18 1.5
Nurse 2 0.2
Seamstress 9 0.7
Salesgirl 51 0.4
Secretary 4 0.3
Social worker 1 0.1
Student 8 0.6
Tax officer 1 0.1
Teacher 87 7.1
Telephonist 2 0.2
Trader 701 57.2
Unemployed 300 24.5
Total 1225 100
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sensitised, with HTLV-I antigen are agglutinated by ?nti-HTLV-I antibodies in human serum 
specimens. The sensitivity and specificity o f the assay are 100% and 98.5%, respectively (251, 
115). Positive results from this test only confirm previous exposure to HTLV-I and not necessarily 
active disease. This study highlights the need for screening blood donors for circulating antibodies 
to HTLV-I infection. This is especially important because o f  recent reports o f  close association 
between HIV and HTLV-I infections (177,196) although my study was not designed to explore 
such relationships.
The results o f  this study showed an overall prevalence rate o f 2.4% o f antibody to HTLV-I among 
blood donors at the MHTBC, Accra, Ghana. Study by Lai, et al showed a rate o f  1 -2% prevalence 
in urban and rural areas o f Southern Ghana. The age distribution o f HTLV-I positive donors ranged 
from 30-39, a group that has been described as being sexually most active and productive in terms 
of economic development and recovery. Although blood transfusion has been known as one o f the 
major means o f  transmission o f  HTLV-I (182, 194), many HTLV-; positive donors did not admit to 
a past history o f  blood transfusion. This is an import ,it finding because it means that though 
transfusion is a significant means o f  transmitting HTLV-I, attention must also be given to 
preventing HTLV-I infections from other sources other than blood transfusion. My observed 
increase in sero-prevalence of HTLV-1 with marital status (21 out of the 29 donors found to be 
HTLV-1 positive were married), points to marital status (vis-a-vis sexual contact) as the 
primary mode of transmission o f HTLV-1. My sample o f blood donors was largely comprised of 
males (1158 out o f  1225 donors) and only 2 out o f 67 screened female donors were positive for 
HTLV-I antibodies. The sero-prevalence was lower in males (2.33%; 27/1158) than females 
(2.99%; 2 /67 ), P<0.05.
The HTLV-I seroprevalence of 2.4% among the healthy blood donors in the current study 
was somewhat lower than the seroprevalence of 4.2% reported recently in healthy blood 
donors at the National Blood Transfusion Centre, Korle-Bu Teaching Hospital, Korle-Bu, 
Accra (2b). The difference cannot be discerned in this study but is probably due to the 
sample size (1225 in the current study versus 265 in reference 2b).
The present study, which is mainly descriptive was undertaken to investigate the prevalence of 
antibodies to HTLV-I among blood donors at the MHBTC. Despite this limitation, the general 
observation is that blood donated at MHBTC, Accra, contain relatively high prevalence of 
antibodies to HTLV-1. Further studies are in progress to determine the magnitude and the true 
prevalence using reverse transcriptase-polymerase chain reaction (RT-PCR). However, the 
prevalence rate reported herein is higher than those observed in Senegal (1.2%), and Liberia (1.6%) 
(216,360), and similar to the rate (2%) observed in Nigeria. Thus emphasizing the importance of
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ETHICAL ASPECTS
Approval- The protocol for the study was submitted ;to and approved by the University of 
Ghana Medical School, Research and Ethical Committee..
Confidentially- All data was handled anonymously and confidentially.
Safety Precautions- All materials were collected under maximum safety measures 
required for the handling o f human tissues.
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APPENDIX
QUESTIONNAIRE
1. Age o f respondent
2. Educational level o f respondent
Date of Birth
No schooling □
Primary School □
Middle School
□
Secondary School □
Jun ior'  ec. School □
Senior Sec. School □
University □
Other
3. Occupation of respondent:.......................................................................
4a. Marital status M/S
4b. Sexual preference Homosexual/Heterosexual
5a. If married, how many other wives/husbands do >; u have?
1 □
2 □
3 □
4 □
None d
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5b. How many people have you been married to
1 □
2 □
3 □
4 □
6. Can you estimate the number male/ 
female sexual partners you have had? ./Don’t know
7. Have you been involved in any military 
duties outside/Ghana? Yes/No
8. If yes to question 7, were you involved in any 
sexual activity during your military duties? Yes/No
9. Did you use any contraceptive? Yes/No
10. What contraceptive method do you use?
Oral contraceptives 
Injectable 
Norplant 
Barrier method 
Condom
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Female condom 
Diaphragm 
« None
• Other, please state
11. Have you ever donated blood? Yes/No
12. If yes to question 11, how many times?
1 □  
2 □
3 □
4 □
5 □
13. Have you been transfused with blood or blood
components? Yes/No.
14. If yes to question 13, how many times?
1 □
2 □
3 □
4 □
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5 □
15. Do you have any tattoo marks on your body? Yes/No.
15.b When was the tattoo done?/How long have y u had the tattoo?
16. If yes to question 15 which part(s) of the body?
Chest □
Arm □
Thigh □
Back [-|
"tomach □
Other
17. Have you heard o f human T-lymphotropic
virus type-1 disease ? Yes/No
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