Southern African Journal of HIV Medicine 
ISSN: (Online) 2078-6751, (Print) 1608-9693
Page 1 of 9 Original Research
Immune activation and arterial stiffness in lean 
adults with HIV on antiretroviral therapy
Authors: Background: Greater T-cell activation was associated with reduced vascular compliance 
Longa Kaluba1 
2,3 amongst persons living with HIV (PLWH) especially among overweight and obese individuals. Fastone Goma  
Chris Guure4 There is a paucity of data regarding immune activation and arterial stiffness amongst PLWH 
Sody Munsaka5 in sub-Saharan Africa (SSA).
Wilbroad Mutale6 
Douglas C. Heimburger7 Objective: To determine the association between immune activation and arterial stiffness in 
Theresa Chikopela8 lean PLWH in SSA.
John R. Koethe7 
Method: Forty-eight human immunodeficiency virus positive (HIV+) adults on antiretroviral 
Affiliations: therapy (ART) >5 years and 26 HIV-negative adults, all with BMI < 25 kg/m2 and no history 
1School of Medicine, 
Cavendish University Zambia, of CVD, were enrolled. The relationship of vascular compliance with circulating CD4+ and 
Lusaka, Zambia CD8+ naïve, memory, activated and senescent T cells, and serum 8-isoprostane was assessed 
by HIV status.
2Eden University, Lusaka, 
Zambia Results: Increased immune activation was observed  in the CD4+ and CD8+ T cells of PLWH, 
16.7% vs. 8.9% and 22.0% vs. 12.4% respectively; p < 0.001 (both). Furthermore, a higher 
3Department of Physiological proportion of senescent CD4+ T cells were associated with a lower carotid-femoral pulse wave 
Sciences, School of Medicine, velocity (cfPWV; p = 0.01), whilst a higher proportion of activated CD8+ T cells were associated 
University of Zambia, Lusaka, 
Zambia with a lower carotid-radial pulse wave velocity (crPWV; p = 0.04), after adjustment for BMI 
and age. However, PLWH also had a higher median carotid-femoral augmentation index 
4Department of Biostatistics, (cfAiX) (21.1% vs. 6.0%; p < 0.05) in comparison to their HIV controls.
School of Public Health, 
University of Ghana, Legon, Conclusion: Our population of lean PLWH had increased immune activation and higher 
Ghana cfAiX, a marker of arterial stiffness, compared to HIV-negative persons. The negative 
association between immune activation and arterial stiffness as measured by crPWV in PLHW 
5Department of Biomedical 
Sciences, School of Health on long-term treatment needs further elucidation.
Sciences, University of 
Zambia, Lusaka, Zambia Keywords: endothelial dysfunction; immune activation; lean adults; antiretroviral therapy; 
arterial stiffness.
6Department of Health Policy 
and Management, School of 
Public Health, University of 
Zambia, Lusaka, Zambia Introduction 
The prevalence of non-communicable diseases in sub-Saharan Africa (SSA) has continued to rise 
7Vanderbilt Institute for over the last two decades1,2 with cardiovascular-related disorders being a leading cause of death 
Global Health and 
Department of Medicine, in persons living with HIV (PLWH).
3 Endothelial dysfunction, a proposed mechanism leading to 
Vanderbilt University Medical this increased cardiovascular disease (CVD ) risk, results in diminished relaxation of the vascular 
Centre, Nashville, TN, United smooth muscle and to arterial stiffness.4,5,6
States of America
8 In the general population, a meta-analysis
7 found that an increase of 1 metre per second (m/s) in 
Department of Human 
Physiology, Faculty of pulse wave velocity (PWV), a marker of greater arterial stiffness, was associated with a 14% 
Medicine, Lusaka Apex increased risk of cardiovascular events and 15% increased risk of all-cause mortality when 
University, Lusaka, Zambia adjusted for age, sex and cardiovascular risk factors. Increased arterial stiffness and immune 
activation have been reported in PLWH.8,9
Persons living with human immunodeficiency virus (HIV) have reduced levels of endothelial 
nitric oxide synthase (eNOS), an important regulator of vascular compliance.10 Further, other 
factors such as immune activation, inflammation, oxidative stress and HIV proteins have also been 
associated with impaired vascular compliance in PLWH.
Read online:
Scan this QR Corresponding author: Longa Kaluba, kalubalonga@gmail.com
code with your Dates: Received: 04 Nov. 2020 | Accepted: 02 Dec. 2020 | Published: 19 Mar. 2021
smart phone or 
mobile device How to cite this article: Kaluba L, Goma F, Guure C, et al. Immune activation and arterial stiffness in lean adults with HIV on antiretroviral 
to read online. therapy. S Afr J HIV Med. 2021;22(1), a1190. https://doi.org/10.4102/sajhivmed.v22i1.1190
Copyright: © 2021. The Authors. Licensee: AOSIS. This work is licensed under the Creative Commons Attribution License.
http://www.sajhivmed.org.za Open Access
Page 2 of 9 Original Research
Immune activation is increased in PLWH compared to HIV- Materials and methods
negative persons.6,11 Recent studies, predominantly from 
cohorts in the United States (US), report associations between We conducted an analytical cross-sectional study at 
circulating T-cell subsets and vascular compliance in PLWH. University Teaching Hospital (UTH) in Lusaka, Zambia 
Kaplan, Sinclair12 reported a positive association between between September 2018 and June 2019 amongst PLWH on 
long-term ART with BMI’s <25 kg/m2activated  CD4+ T cells and arterial stiffness after adjusting for . Persons accompanying 
HIV ribonucleic acid (RNA) and total peripheral CD4+ T-cell patients to the ART clinic and general medicine outpatients 
9 department were recruited as HIV-negative controls. The count. A longitudinal study by Karim, Mack  also reported a 
HIV infection status was confirmed in all HIV-negative 
positive correlation between activated CD4+ T cells and 
participants by rapid test. All PLWH were on a regimen of 
carotid arterial stiffness both pre- and post-highly active 
efavirenz, emtricitabine, and tenofovir disoproxil fumarate 
antiretroviral therapy (HAART) initiation. CD8+ T-cell 
for more than 5 years. Persons who were pregnant, or with 
activation was associated with reduced smooth muscle known CVD, rheumatologic disease or any other 
relaxation independent of other cardiovascular risk factors in self-reported pathology, active infectious conditions aside 
PLWH with viral suppression.13,14 from HIV, or with a history of diabetes and habit of tobacco 
smoking were excluded. Socio-demographic data were 
Whilst the mechanistic link between T-cell activation and collected using the WHO STEPS questionnaire.25 Randomly 
vascular compliance is not fully understood, immune cells sampled participants provided written informed consent, 
are capable of generating reactive oxygen species and and ethical approval was obtained. 
contributing to oxidative stress.15 Higher levels of reactive 
oxygen species and circulating pro-inflammatory cytokines, Endothelial dysfunction 
two conditions commonly increased in PLWH despite 
effective plasma viral suppression on antiretroviral therapy measurements
(ART), contribute to endothelial dysfunction and reduced Carotid-femoral pulse wave velocity (cfPWV) and 
vascular compliance.16,17,18,19,20 Higher 8-isoprostane, a marker carotid-radial pulse wave velocity (crPWV) are measures of 
of oxidative stress, is associated with subsequent all-cause arterial stiffness, calculated from the time taken for the 
mortality in PLWH independent of CD4+ T-cell count arterial pulse to propagate from the carotid to the femoral or 
and high-sensitivity C-reactive protein (hsCRP).21 The radial artery, respectively. Carotid-femoral pulse wave 
overproduction of reactive oxygen species such as velocity is said to be the gold standard in the measure of 
superoxide, which is formed when oxygen is reduced by a aortic stiffness.26 Other derivatives of PWV measurement 
single electron, has been associated with the progression of include augmentation index (AiX) which is the measure of 
cardiovascular disorders.18 Increased superoxide binds to the enhancement of the central aortic artery reflective wave 
the increased nitric oxide (NO) to form peroxynitrite, and is said to be a more sensitive marker for vascular 
which results in the production of a powerful oxidant that compliance.27 All these parameters were measured using the 
traverses into the endothelial cell and directly damages ALAM Complior Analyse device (ALAM medical, France). 
the deoxyribonucleic acid (DNA); compromising the Non-invasive probes were applied to the surface of the skin 
bioavailability of NO and resulting in reduced relaxation.16,18 over the carotid, femoral and radial arteries with participants 
In addition, HIV proteins have also been implicated in lying in a supine position, after resting for a minimum of 
endothelial dysfunction.22 5 min. Participants were not allowed to move, speak, or sleep 
during the measurements.28
In SSA, the burden of CVD in PLWH has tripled over the last 
two decades.23 However, much of our current understanding Biochemical measurements
of HIV and cardiovascular function arises from cohort studies Fasting blood was collected in an ethylenediamine tetraacetic 
in the US and Europe, which often include a high proportion acid (EDTA) tube and analysed by flow cytometry. A 
of overweight and obese individuals reflective of the general lyse-wash protocol (Becton Dickinson) was used to stain 
population.24 Whilst rates of obesity are rising in many SSA lymphocytes. A 100 microlitres (µL) of whole blood was 
countries, particularly South Africa, there remains a broad stained with the following monoclonal antibodies: CD3 APC 
distribution of body composition amongst PLWH in the (Sigma Aldrich, clone MEM-57), CD4 PerCP (Thermofisher, 
region which includes a substantial number of individuals clone RM4-5), CD8 APC-Cy7 (Biolegend, clone HIT8a), HLA 
with lower body mass index (BMI) values. At present, there DR PE-Cy7 (Thermofisher, clone L243), CD57 PE 
is a paucity of data on whether inflammation and immune (Thermofisher, CD57, clone TB01), CD45RA FITC (Sigma 
activation in ‘lean’ (i.e. BMI < 25 kilogram per square metre Aldrich, clone MEM-56). Fluorescence-activated cell sorting 
[kg/m2]) PLWH is accompanied by a similar degree of (FACS) lysing solution was added, followed by centrifugation 
arterial stiffness as observed in higher BMI individuals. To to isolate the WBCs.29
this end, we assessed relationships between cellular immune 
activation, oxidative stress and arterial stiffness in a cohort of T-cell subsets were identified using sequential gating on a 
lean PLWH on long-term ART. FACSverse flow cytometer using FACSuite software (Becton 
http://www.sajhivmed.org.za Open Access
Page 3 of 9 Original Research
Dickinson, San Diego, CA). Lymphocytes were gated using Results
forward, and side scatter (forward scatter [FSC] and side 
scatter [SSC]) (Appendix Figure 1). A total of 74 adult participants were enrolled in the study: 
48 with HIV (28 female; 20 male) and 26 HIV-negative 
The cells were then gated by the expression of fluorochromes. (15 female; 11 male). The median age of the PLWH was 
To overcome the physical overlap of the emission spectra of 41 years versus 23 years amongst the HIV-negative group 
common fluorochromes, unstained and single stained (Table 1). People living with HIV had a lower BMI compared 
controls, and fluorescence minus one (FMO) controls were to the HIV-negative group (18.9 kg/m2 vs. 20.7 kg/m2, 
used as a reference to automatically generate compensation respectively) but had comparable waist circumferences 
matrices using the Flowjo version 10 software. These matrices (72 centimetres [cm] vs. 70 cm). Median central blood 
were manually verified. pressure measurements were also comparable between 
groups (112/78 vs. 116/77). Both cfPWV and crPWV fell 
Oxidative stress measurements within normal ranges of 9.1 m/s ± 3.2 m/s31,32 (Table 2). 
Carotid-femoral augmentation index was significantly higher 
Serum samples stored at −80 °C were thawed for measurement in PLWH (Table 2). Other measurements of endothelial 
of 8-isoprostane. An enzyme-linked immunosorbent assay function and 8-isoprostane were similar between groups.
(ELISA) was performed using an immobilised monoclonal 
antibody of 8-isoprostane (Detroit R&D, Cat # 8iso1) as Naïve CD8+ cells were lower in PLWH compared to the 
specified by the manufacturer’s instructions.30 HIV-negative controls (p < 0.001). Both activated and memory 
CD4+ and CD8+ T cells were significantly higher in the 
Statistical analyses PLWH as well (Table 3). Higher activated CD8+ T cells were 
Because of inconsistent distribution of outcome variables, associated with lower crPWV only in the PLWH (p = 0.04). 
Activated CD4+ T cells were significantly associated with 
medians and interquartile ranges were calculated for 
8-isoprostane (Table 4). A 1% increase in activated CD4+ T 
continuous variables and percentages for categorical variables. cells correlated with a 0.11 picogram/microliter (pg/µL) 
The relationships between clinical and demographic decrease in 8-isoprostane. Higher senescent CD4+ T cells 
characteristics were assessed using Mann-Whitney U test or were associated with lower cfPWV (Table 4). A 1% increase 
chi-squared test as appropriate. We assessed whether T-cell in senescent CD4+ T cells corresponded to a 0.22 m/s 
subsets were associated with markers of endothelial function decrease in the cfPWV. These relationships were absent or 
(crPWV, cfPWV, carotid-radial augmentation index [crAiX], differed in HIV-negative persons (see Appendix Table 2-A2); 
carotid-femoral augmentation index [cfAiX]) and oxidative notably, greater senescent CD4+ T cells was associated with 
stress (8-isoprostane) using multivariate models adjusted for higher cfPWV in this group (a finding contrary to that of 
age and BMI in the PLWH. The normality of the outcome data participants with HIV).
was assessed using Q-Q plots and validated with the Shapiro–
Wilk test. Only crPWV required log-transformation. Higher memory CD4+ T cells were associated with lower 
8-isoprostane concentrations (p < 0.001). Each per cent 
Multiple linear regression models were used to assess increase in memory CD4+ T cells correlated with a 0.09 pg/µL 
relationships between the independent variables (CD4+ decrease in 8-isoprostane. Higher memory CD8+ cells 
and CD8+ T-cell subsets) and the dependent variables were associated with higher crPWV (Table 4; p = 0.01). 
(PWV, AiX and 8-isoprostane); these models were adjusted Higher naïve CD8+ cells were associated with higher log-
for BMI and age in the HIV+ group only, because of the transformed, crPWV (Table 4; p = 0.01). 
small sample size. 
Finally, we performed an interaction analysis given the 
Linear regression models incorporating an interaction differing directionality of the relationship between senescent 
between CD4+ and CD8+ T-cell subsets with HIV status, CD4+ T cells and cfPWV in the participants with, versus 
adjusted for BMI and age, were also performed without, HIV. After adjusting for age and BMI, the 
(Appendix Table 1-A1). The results of regression models are relationship of senescent CD4+ T cells with cfPWV differed 
reported using Beta (β) coefficients, confidence intervals (CI) by HIV status (Figure 1 and Appendix Table 3-A3; interaction 
and p-values. Analyses were performed using STATA term β = −0.22; p = 0.05). Similarly, the relationship of 
version 15 software. senescent CD4+ T cells with carotid-radial augmentation 
index differed by the HIV status (Figure 2 and Appendix 
Ethical considerations Table 4-A4; interaction term β = −3.46; p = 0.03).
Participants provided written informed consent, and approval 
was obtained from the University of Zambia Biomedical Discussion
Research Ethics Committee (UNZABREC reference number In the cohort of lean individuals in Lusaka, Zambia, PLWH 
003-01-18) and the National Health Research Authority on long-term ART had greater arterial stiffness (through 
(NHRA). increased cfAiX), immune activation, and more senescent 
http://www.sajhivmed.org.za Open Access
Page 4 of 9 Original Research
TABLE 1: Clinical and demographic characteristics.
Variable PLWH (n = 48) HIV-negative (n = 26) P
Mdn IQR % SD Mean Mdn IQR % SD Mean
Age (years) 41 36, 43.5 - - - 22.5 20, 27 - - - < 0.001
Female (%) 28 - 58 - - 15 - 58 - - 0.96
Height (cm) 164.5 157.5, 171 - - - 166.5 160, 173 - - - 0.38
Weight (kg) 51.7 47.9, 55.2 - - - 55.2 52.8, 61.6 - - - 0.01
BMI 18.9 17.4, 20.6 - - - 20.7 19.1, 22.9 - - - < 0.01
Waist (cm) 72 67.2, 74.1 - - - 70 66.3, 73 - - - 0.81
Hip (cm) 86.4 83.5, 92.8 - - - 89.3 86.5, 97.8 - - - 0.06
Heart rate (beats/min) 67 61, 74 - - - 67 59, 77 - - - 0.62
Central systolic blood pressure (mmHg) - - - ± 19 112.4 - - - ± 19.6 116.1 0.27
Central diastolic blood pressure (mmHg) - - - ± 10.3 78.2 - - - ± 7.8 77.4 0.99
Body fat (%) 18.5 12.3, 26.2 - - - 18.6 9.7, 26.1 - - - 0.74
Fat mass (kg) 9.5 6, 12.6 - - - 11.2 4.9, 14.3 - - - 0.67
Trunk fat (%) 16.7 8.3, 21.8 - - - 15.7 8.4, 21.5 - - - 0.77
Trunk fat mass (kg) 4.7 2.8, 6.5 - - - 4.3 2.5, 6.7 - - - 0.93
Total trunk free fat mass (kg) 23.4 21.1, 26.1 - - - 25.7 23.7, 27.4 - - - 0.01
Note: Medians and interquartile ranges. Body composition measurements utilised body impedance analysis (BIA) by the Tanita BC418 MA. Mann-Whitney U test or chi-squared test was used. 
p-values < 0.05 are shown in bold.   
HIV, human immunodeficiency virus; PLWH, persons living with HIV; BMI, body mass index.
TABLE 2: Pulse wave velocity and oxidative stress indices. and increased atherosclerosis.9,12,13,14 Furthermore, most of the 
Variable PLWH (n = 48) HIV-negative (n = 26) P associations between T-cell subsets and vascular compliance 
Median IQR Median IQR were not observed in the HIV-negative controls. Whilst this 
Pulse wave velocity indices may have been because of fewer participants in the HIV-
cfPWV (m/s) 7.3 6.1, 8.8 7.0 5.8, 7.7 0.15 negative arm, the direction and magnitude of the relationships 
crPWV (m/s) 9.9 8.8, 10.8 8.7 7.3, 10.8 0.09
between senescent CD4 cells with cfPWV and crAiX were 
cfAiX 21.1 5.9, 35.6 6.0 -5.7, 24.5 0.04
crAiX 12.9 2.7, 41.4 13.7 -9.7, 26.3 0.20 different in the two groups. This suggests that our findings 
Oxidative stress may be specific to lean PLWH as opposed to lean persons in 
8-isoprostane (pg/µL) 2.6 0.9, 3.7 1.1 0.6, 2.8 0.17 general. This may explain the observed inverse relationship 
Note: Medians and interquartile ranges. Mann-Whitney U test or chi-squared test was used. of CD8+ T-cell activation and CD4+ T-cell senescence and 
p-values < 0.05 are shown in bold. arterial stiffness in PLWH with a low BMI.
HIV, human immunodeficiency virus; cfAiX, carotid-femoral augmentation index; crAiX, 
carotid-radial augmentation index; PLWH, persons living with HIV; cfPWV, carotid-femoral 
pulse wave velocity; crPWV, carotid radial pulse wave velocity. The augmentation index is said to be a composite measure of 
TABLE 3: T-cell subsets. wave reflection and arterial stiffness, and has been suggested 
Variable PLWH (n = 48) HIV-negative (n = 26) P to be a more sensitive marker for endothelial function 
27
Median IQR Median IQR compared to PWV.  The median values of cfAiX and crAiX 
CD4 T-cells (%) were more than twice higher in PLWH than the HIV-negative 
CD45RA+ (naïve) 20.0 11.1, 28.1 25.3 17.7, 33.2 0.06 persons. The significant difference observed in the cfAiX by 
CD45RA- (memory) 78 69, 87.6 72.4 64.3, 77.9 0.04 HIV status may indicate that endothelial dysfunction is more 
HLADR-CD57+ (senescent) 4.4 2.7, 6.5 3.2 2.0, 5.6 0.28 pronounced in more elastic vessels as compared to more 
HLADR+CD57- (activated) 15.9 9.2, 21.7 8.4 6.3, 10.9 < 0.001 muscular vessels. Carotid femoral pulse wave velocity is a 
CD8 T-cells (%)
measure of arterial stiffness in elastic vessels, whereas crPWV 
CD45RA+ (naïve) 42.6 31.8, 52.2 55.0 49.0, 65.1 < 0.001
CD45RA- (memory) 52.7 44.7, 63.7 41.7 29.5, 46.3 < 0.001 in muscular vessels.
26 A decrease in vascular compliance has 
HLADR+CD57- (activated) 21.55 13.2, 30.2 12.0 6.8, 15.2 < 0.001 been linked to reduced bioavailability of NO, which has 
Note: % total CD4 and CD8 T cells, respectively; Medians and interquartile ranges. Mann- several physiological roles, including vasodilation of 
Whitney U test was used. p-values < 0.05 are shown in bold. coronary arteries.33 Nitric oxide diffuses through the vascular 
HIV, human immunodeficiency virus; PLWH, persons living with HIV; CD4, cluster of 
differentiation 4; CD8, cluster of differentiation 8. smooth muscle cells where it activates guanylate cyclase, a 
process that leads to smooth muscle relaxation. The viral 
T cells compared to HIV-negative persons, which is consistent protein Nef has been implicated in the reduction of 
with studies conducted in other settings.8,9 However, amongst endothelial NO, an increase in the secretion of cytokines 
the lean PLWH in our study higher proportions of senescent from macrophages and inducing endothelial cell apoptosis.34 
CD4+ T cells and activated CD8+ T cells were negatively Using a rat model, Kline, Kleinhenz18 reported an association 
associated with arterial stiffness as measured by PWV (β = between the HIV proteins and a decrease in vascular and 
−0.22 and −0.01, respectively). This finding is in contrast to systemic NO bioavailability. This study also reported 
studies in predominantly US cohorts with a high proportion endothelial dysfunction because of the inability to relax 
of overweight and obese participants, in which greater T-cell maximally after the injection of acetylcholine. The decrease 
activation (measured by CD38+HLADR+) has been associated in NO was reported not to be from eNOS regulation but from 
with increased arterial stiffness, hypoxia-induced relaxation the overproduction of superoxide binding to increased NO 
http://www.sajhivmed.org.za Open Access
Page 5 of 9 Original Research
HIV negave HIV posive
10 Predicve margins of HIV status with 95% cl
8
6
4
2
1 4 7 10 13 16 19
CD4 Senescent cells
cfPWV, carotid-femoral pulse wave velocity; HIV, human immunodeficiency virus; CI, 
confidence interval; CD4, cluster of differentiation 4.
FIGURE 1: Relationship of carotid-femoral pulse wave velocity and senescent CD4 
T cells by human immunodeficiency virus status. Senescent CD4+ cells are shown 
as the proportion of total CD4+ cells. The model was adjusted for age and body 
mass index. 
HIV negave HIV posive
Predicve margins of HIV status with 95% Cls
100
50
0
-50
0 5 10 15 20
CD4 Senescent cells
crAiX, carotid-radial augmentation index; HIV, human immunodeficiency virus; CI, confidence 
interval; CD4, cluster of differentiation 4.
FIGURE 2: Relationship of carotid-radial augmentation index and senescent CD4 
T cells by human immunodeficiency virus status. Senescent CD4+ cells are shown 
as the proportion of total CD4+ cells. The model was adjusted for age and body 
mass index. 
to form peroxynitrite. However, even though increased in 
PLWH, our study found no significant difference in 
8-isoprostane levels in PLWH.
We observed an inverse association between CD4-activated T 
cells and 8-isoprostane, suggesting immune activation may 
not be a driver of increased oxidative stress in lean PLWH. 
However, the directionality of this relationship could not be 
assessed in our study. This is in contrast with other studies 
that reported an increase in immune activation and oxidative 
stress markers in PLWH as compared to HIV-negative 
persons.35 Mandas, Iorio36 reported both an increase in 
oxidative stress markers and a decrease in antioxidants in the 
PLWH when compared to the HIV-negative persons.
The cohort of PLWH had been on anti-retroviral therapy for 
more than 5 years and was assumed to be virally suppressed. 
http://www.sajhivmed.org.za Open Access
TABLE 4: Relationship of T-cell subsets with carotid-femoral pulse wave velocity, carotid-femoral augmentation index, carotid-radial augmentation index, log-transformed carotid-radial pulse wave velocity and 8-isoprostane in persons 
living with human immunodeficiency virus only.
Outcomes CD4/CD45RA+ (naïve) CD4/CD45RA- (memory) CD4/HLADR-CD57+ CD4/HLADR+CD57- CD8/CD45RA+  CD8/CD45RA-  CD8/HLADR+ 8- isoprostane
(senescent) (activated) (naïve) (memory) CD57- (activated)
β CI P β CI P β CI P β CI P β CI P β CI P β CI P β CI P
cfPWV -0.01 -0.07–0.07 0.95 -0.01 -0.07–0.07 0.99 -0.22 -0.37–-0.07 0.01 -0.01 -0.11–0.1 0.95 0.05 -0.02–0.12 0.18 -0.04 -0.11–0.03 0.22 -0.07 -0.15–0.01 0.08 -0.13 -0.68–0.43 0.64
cfAiX 0.04 -0.56–0.65 0.88 -0.06 -0.65–0.52 0.82 0.76 -0.74–2.27 0.31 0.20 -0.66–1.07 0.64 -0.01 -0.55–0.52 0.96 -0.01 -0.54–0.51 0.96 0.12 -0.51–0.74 0.71 -0.99 -6.89–4.90 0.73
crPWV 0.01 -0.007–0.009 0.79 -0.01 -0.009–0.007 0.81 -0.01 -0.02–0.01 0.66 -0.01 -0.01–0.01 0.37 0.01 0.002–0.01 0.01 -0.01 -0.01–0.002 0.01 -0.01 -0.01–0.0002 0.04 0.01 -0.05–0.06 0.75
crAiX 0.42 -0.34–1.18 0.27 -0.48 -1.20–0.23 0.17 -0.91 -2.66–0.85 0.29 0.17 -0.79–1.12 0.72 -0.26 -0.89–0.37 0.40 0.27 -0.36–0.89 0.38 0.35 -0.35–1.06 0.31 0.34 -5.72–6.40 0.91
8 isoprostane 0.09 0.05–0.14 < 0.001 -0.09 -0.13–0.05 < 0.001 -0.01 -0.15–0.12 0.84 -0.11 -17–0.05 < 0.01 0.02 -0.04–0.07 0.50 -0.02 -0.07–0.03 0.45 -0.04 -0.10–0.02 0.15 - - -
Note: The values of crPWV have been log-transformed. Model adjusted for age and BMI in the PLWH group only. p-values < 0.05 are shown in bold.   
CI, confidence interval; cfPWV, carotid-femoral pulse wave velocity; crPWV, carotid-radial pulse wave velocity; cfAiX, carotid-femoral augmentation index; crAiX, carotid-radial augmentation index.
CrAiX CfPWV (m/s)
Page 6 of 9 Original Research
However, we observed persistent immune activation of both Furthermore, because of the cross-sectional design, causality 
CD4+ and CD8+ T cells in the PLWH. could not be determined and may not be generalisable as a 
result of scarcity of information linking these parameters in 
With CD4+ and CD8+ T cells being the main components of the the African context. Additional longitudinal studies will be 
immune response, their activation has been associated with needed to explore mechanisms linking immune activation 
disease progression, particularly in those who are treatment and endothelial dysfunction.45 
naïve.37,38,39 Circulating activated immune cells can permeate 
through to the adventitia and adhere to the endothelium Conclusion
resulting in its dysfunction.13 The median values of both 
activation markers on CD4+ and CD8+ T cells were more than Lean adults with HIV had increased immune activation and 
double in PLWH when compared to the HIV-negative persons. arterial stiffness when compared to HIV-negative persons. 
We found a significant association between crPWV and Paradoxically, lower arterial stiffness was associated with 
activated CD8+ T cells. Paradoxically, this association was increasing CD8+ T-cell activation and CD4+ T-cell senescence, 
inversely related in PLWH and directly related in HIV-negative in contrast to prior studies in predominantly US cohorts with 
persons. This draws our attention to the nature of the vasculature high proportions of overweight and obese participants. To date, 
being investigated and whether the immune response to elastic there have been few studies of immune activation and arterial 
versus muscular vessels is different. stiffness amongst PLWH in SSA, and further research is needed 
to determine whether these findings are specific to PLWH with 
The study also saw an inverse association between CD4 a low BMI or to individuals in SSA in general. Furthermore, the 
senescence markers and cfPWV. Persons living with HIV on implications of these findings in the context of rising rates of 
treatment or naïve have been described to be immunologically CVD amongst PLWH in the region should be explored further.
aged when compared to HIV-negative persons, and this has 
been associated with increased immune activation.40,41 This has Acknowledgements
been attributed to a decrease in the telomere length in DNA 
molecules.40,41 Telomere shortening leads to the initiation of the The authors would like to specially thank the staff at 
DNA damage response leading to growth arrest, which if not TROPGAN laboratory and the NUSTART centre at the 
repaired, leads to permanent growth arrest that is irreversible. University Teaching Hospital, Lusaka.
At this stage, the cells are neither dead nor functional.
Competing interests  
Prior studies of vascular compliance and immune function 
The authors declare that they have no financial or personal 
have mainly been conducted in individuals with higher BMI 
9,12,13 relationships that may have inappropriately influenced them in cohorts outside of SSA.  Visceral fat, being metabolically 
in writing this article.
active, is an important site for the secretion of adipokines that 
influence inflammation, lipid metabolism and insulin 
sensitivity.42,43 Authors’ contributions
L.K., F.G., D.C.H. and J.R.K. conceived and planned the 
Lukich, Gavish42 suggested measuring abdominal fat content experiments. L.K. and T.C. carried out the experiments. L.K., 
by waist circumference, as it is a more sensitive measure of T.C. and S.M. contributed to sample preparation. L.K., F.G., 
endothelial dysfunction than overall body mass measured by C.G., S.M., W.M., D.C.H. and J.R.K. contributed to the 
BMI. Although our study population was all lean, PLWH interpretation of the results. L.K. took the lead in writing the 
had a significantly lower BMI compared to HIV-negative manuscript. All authors provided critical feedback and 
persons. However, waist circumferences were similar helped shape the research, analysis and manuscript.
between the two groups, potentially reflecting greater 
visceral obesity in the participants with HIV.44 
Funding information
Strengths and limitations This work was supported by the Fogarty International Centre of 
the U.S. National Institutes of Health under the Award Number 
Our study groups had a far lower median BMI (18.9 kg/m2 in D43 TW009744, the NIH-funded Vanderbilt Clinical and 
the PWLH and 20.7 kg/m2 in the HIV-negatives) as compared Translational Science Award from NCRR/NIH Grant UL1 
to similar studies from cohorts in the US and other settings, RR024975, the NIH-funded Tennessee Centre for AIDS Research 
and we excluded smokers and persons with known Grant P30 AI110527, and National Institutes of Health grant 
cardiovascular pathology. We also assessed a range of T-cell K01HL130497. The content is solely the responsibility of the 
phenotypes and multiple indices of vascular compliance. authors and does not necessarily represent the official views of 
However, a major limitation of our study is the significantly the National Institutes of Health.
greater age and small sample size amongst the PLWH 
compared to HIV-negatives in our study, which precludes 
attributing the lack of a similar association between T-cell Data availability
activation and vascular compliance to HIV status. Also, The data that support the findings of this study are available 
information on the duration of HIV infection before treatment from the corresponding author, L.K., upon reasonable 
and total CD4 and CD8 T-cell counts were not available. request.
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Page 7 of 9 Original Research
Disclaimer 21. Masia M, Padilla S, Fernandez M, et al. Oxidative stress predicts all-cause mortality in HIV-infected patients. PLoS One. 2016;11(4):e0153456. https://doi.
The views and opinions expressed in this article are those of org/10.1371/journal.pone.0153456
22. Low H, Hoang A, Pushkarsky T, et al. HIV disease, metabolic dysfunction and 
the authors and do not necessarily reflect the official policy or atherosclerosis: A three year prospective study. PLoS One. 2019;14(4):e0215620. 
position of any affiliated agency of the authors. https://doi.org/10.1371/journal.pone.0215620
23. Shah ASV, Stelzle D, Lee KK, et al. Global burden of atherosclerotic cardiovascular 
disease in people living with HIV: Systematic review and meta-analysis. Circulation. 
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Appendices start on the next page →
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Appendix
TABLE 1-A1: Interaction of T-cell subsets and human immunodeficiency virus status with carotid-femoral pulse wave velocity, carotid femoral augmentation index, carotid-radial augmentation index, log-transformed carotid-radial 
pulse wave velocity and 8-isoprostane.
Outcomes CD4/CD45RA+ (naïve) CD4/CD45RA- (memory) CD4/HLADR-CD57+ CD4/HLADR+CD57- CD8/CD45RA+  CD8/CD45RA-  CD8/HLADR+ 8- isoprostane
(senescent) (activated) (naïve) (memory) CD57- (activated)
β CI P β CI P β CI P β CI P β CI P β CI P β CI P β CI P
cfPWV 0.01  -0.09 – 0.09 0.94 -0.01 -0.09 – 0.09 0.95 -0.22 -0.44 – 0.04 0.05 -0.04 -0.25 – 0.17 0.73 0.05 -0.04 – 0.13 0.27 -0.04 -0.12 – 0.05 0.39 -0.12 -0.28 – 0.04 0.13 -0.23 -0.97 – 0.51 0.54
cfAiX 0.79 -0.33 – 1.92 0.16 -0.86  -2.0 – 0.28 0.14 0.42 -2.78 – 3.62 0.79 -0.14 -2.88 – 2.60 0.92 0.14 -1.02 – 1.29 0.81 -0.25 -1.40 – 0.90 0.66 -0.12  -2.29 – 2.04 0.91 8.95 -0.72 – 18.62 0.07
crPWV -0.01 -0.02 – 0.004 0.24 0.01 -0.004 – 0.02 0.23 -0.01 -0.03 – 0.02 0.93 0.01 -0.02 – 0.03 0.63 0.001 -0.01 – 0.01 0.92 -0.001 -0.01 – 0.01 0.99 -0.01 -0.03 – 0.01 0.32 0.04  -0.04 – 0.11 0.35
crAiX 0.43 -0.81 – 1.67 0.49 -0.56 -1.81 – 0.68 0.37 -2.30 -5.42 – 0.82 0.14 0.32 -2.33 – 2.97 0.81 -0.30 -1.51 – 0.90 0.61 0.18 -1.02 – 1.38 0.76 0.49 -1.61 – 2.60 0.64 5.35 -5.12 – 15.82 0.31
8-isoprostane 0.09 -0.002 – 0.18 0.05 -0.09 -0.18 – 0.002 0.06 0.05 -0.24 – 0.34 0.72 0.02 -0.24 – 0.28 0.89 0.04 -0.04 – 0.13 0.32 -0.04 -0.13 – 0.04 0.32 -0.10 -0.28 – 0.08 0.27 - - -
Note: Bold indicates statistically significant value.
CI, confidence interval; cfPWV, carotid-femoral pulse wave velocity; crPWV, carotid-radial pulse wave velocity; cfAiX, carotid-femoral augmentation index; crAiX, carotid-radial augmentation index.
TABLE 2-A2: Relationship of T-cell subsets with carotid-femoral pulse wave velocity, carotid-femoral augmentation index, carotid-radial augmentation index and log-transformed carotid radial pulse wave velocity in human 
immunodeficiency virus negative participants.
Outcomes CD4/CD45RA+ (naïve) CD4/CD45RA- (memory) CD4/HLADR-CD57+ CD4/HLADR+CD57- CD8/CD45RA+  CD8/CD45RA-  CD8/HLADR+ 8- isoprostane
(senescent) (activated) (naïve) (memory) CD57- (activated)
β CI P β CI P β CI P β CI P β CI P β CI P β CI P β CI P
cfPWV 0.02  -0.04 – 0.08 0.52 -0.02 -0.08 – 0.05 0.59 0.01  -0.16 – 0.17 0.93 0.04 -0.12 – 0.20 0.60 -0.01 -0.07 – 0.05 0.76 0.001 -0.06 – 0.06 1.0 0.05 -0.74 – 0.18 0.40 0.15 -0.33 – 0.62 0.52
cfAiX -0.94 -2.18 – 0.29 0.13 0.98 -0.29 – 2.26 0.12 0.29 -3.00 – 3.57 0.86 0.36 -2.89 – 3.60 0.82 -0.17 -1.37 – 1.03 0.77 0.27 -0.92 – 1.45 0.64 0.41 -2.19 – 3.02 0.75 -12.49 -20.33 – 4.64<0.01
crPWV 0.01 -0.004 – 0.02 0.21 -0.01 -0.02 – 0.004 0.24 -0.01 -0.02 – 0.02 0.57 0.01 -0.03 – 0.02 0.80 0.01 -0.01–0.01 0.62 -0.01 -0.01 – 0.01 0.58 0.01 -0.01 – 0.03 0.55 -0.04 -0.10 – 0.03 0.26
crAiX -0.26 -1.39 – 0.87 0.64 0.35 -0.81 – 1.51 0.54 1.22 -1.58 – 4.01 0.38 0.18 -2.63 – 3.0 0.89 -0.15 -1.19 – 0.89 0.77 0.30 -0.73 – 1.32 0.55 0.21 -2.05 – 2.47 0.85 -5.41 -15.30 – 4.49 0.26
Note: Bold indicates statistically significant value.
CI, confidence interval; cfPWV, carotid-femoral pulse wave velocity; crPWV, carotid-radial pulse wave velocity; cfAiX, carotid-femoral augmentation index; crAiX, carotid-radial augmentation index.
Page 9 of 9 Original Research
TABLE 3-A3: Analysis of variance table for the interaction effect of CD4 senescent TABLE 4-A4: Analysis of variance table for the interaction effect of senescent CD4 
cells and human immunodeficiency virus on carotid-femoral pulse wave velocity. T cells and human immunodeficiency virus on carotid-radial augmentation index.
Variable Degrees of freedom F P Variable Degrees of freedom F P
Age 1 1.66 0.21 Age 1 3.22 0.08
BMI 1 0.99 0.33 BMI 1 1.93 0.17
HIV status 1 0.20 0.66 HIV status 1 3.23 0.08
CD4 senescent cells 1 0.00 0.99 CD4 senescent cells 1 1.03 0.32
HIV status: CD4 senescent cells 1 4.21 0.05 HIV status: CD4 senescent cells interaction 1 4.81 0.03
interaction Regression 5 3.23 0.01
Regression 5 2.65 0.04 Total 51 - -
Total 51 - -
BMI, body mass index; HIV, human immunodeficiency virus; CD4, cluster of differentiation 4.
BMI, body mass index; HIV, human immunodeficiency virus; CD4, cluster of differentiation 4.
250K
250K 250K
200K
200K 200K
150K
150K 150K
100K 100K 100K
50K 50K 50K
0 0 0
0 50K 100K 150K 0 50K 100K 150K 200K 250K -3.0K 0 3.0K 6.0K
FSC-H FSC-H Comp-APC-A :: CD3 APC-A
105
Q1 Q2
120 27.0 7.97
90 10
4
60 103
0
30
Q4 Q3
-103 52.5 12.5
0 -103 0 103 104 105
-103 0 103 Comp-PE-A :: CD57 PE-A
FIGURE 1-A1: T-cell gating strategy.
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FSC-A
Count
SSC-A
Comp-PE-cy7-A :: HLA-DR PE-Cy7-A
FSC-A