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Human immunodeficiency virus (HIV)-mediated cardiac fibrosis: implication of cellular immunomodulation and cytokine profile alterations
Thesis (PhD)--Stellenbosch University, 2026.
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Stellenbosch : Stellenbosch University
2026
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| _version_ | 1867614133658058752 |
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| access_status_str | Open Access |
| author | Mukonowenzou, Nyasha Charity |
| author2 | Essop, Faadiel |
| author_browse | Essop, Faadiel Mukonowenzou, Nyasha Charity |
| author_facet | Essop, Faadiel Mukonowenzou, Nyasha Charity |
| author_sort | Mukonowenzou, Nyasha Charity |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2026. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/136131 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:47:10.728Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2026 |
| publishDateRange | 2026 |
| publishDateSort | 2026 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/136131 Human immunodeficiency virus (HIV)-mediated cardiac fibrosis: implication of cellular immunomodulation and cytokine profile alterations Mukonowenzou, Nyasha Charity Essop, Faadiel Sishi, Balindiwe Joseph, Danzil Teer, Eman Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences. Thesis (PhD)--Stellenbosch University, 2026. Mukonowenzou, N. C. 2026. Human immunodeficiency virus (HIV)-mediated cardiac fibrosis: implication of cellular immunomodulation and cytokine profile alterations. Unpublished doctoral dissertation. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/f72a24d9-9ba7-44f0-a1de-b6515322777d The advent of antiretroviral therapy (ART) has significantly increased the lifespan of people living with human immunodeficiency virus (HIV, PLWIH). Cardiovascular disease (CVD), however, has become a leading global health concern among this population. Cardiac fibrosis, a contributor to both CVD onset and progression, varies by region, with non-ischemic cardiomyopathy predominant in sub-Saharan Africa (SSA) and ischemic cardiomyopathy prevalent in high-income countries. Few mechanistic studies, however, have been conducted in SSA. This study hypothesized that HIV infection drives persistent immune activation and chronic inflammation, which in turn disrupt cellular immunomodulation and increase susceptibility to cardiac fibrosis. To test this hypothesis, we evaluated changes in T-cell subsets (T-helper cell 1 (Th1) and T-helper cell 2 (Th2)), monocyte/macrophage subsets (macrophage type 1 (M1) and macrophage type 2 (M2)) and circulating fibrocyte subsets (CD34+, collagen 1 [COL1+]). We further examined how these immune and profibrotic parameters relate to (i) classical markers of HIV progression (CD4 count, viral load, immune activation); (ii) cardiometabolic indices (blood pressure, heart rate, body mass index, fasting lipids, glucose and glycated hemoglobin) (iii) hematological changes and (iv) circulating cytokines with pro-and anti-inflammatory or profibrotic roles. We conducted a main (cross-sectional) study (n=37; 29 PLWIH, 8 people living without HIV; PLWOH) and a sub-study (longitudinal) (n=90; 69 PLWIH, 21 PLWOH). In both studies, participants aged 18-55 years were recruited from People’s Healthcare clinic in Worcester, South Africa. All participants completed a comprehensive and validated questionnaire. Cardiometabolic measurements were taken, and blood samples were collected and processed for analysis. The samples were either used immediately or stored for later use at -80°C. The analyses included flow cytometry determination of T-cell, monocyte/macrophage and circulating fibrocyte subsets. For T-cells, the activation marker (CD8+CD38+), co-stimulation marker (CD4+CD28+), Th1 marker on T-cells (CD183), and Th2 marker on T-cells (CD194) were assessed. For the monocyte/macrophage subset, non-classical monocytes (CD14+CD16+), M1 marker on macrophages (CD86) and M2 marker on macrophages (CD163) were evaluated. The markers CD34+, COL1+ and CD34+COL1+ were used to assess the circulating fibrocytes subset. In addition, blood samples were also used to evaluate HIV markers of progression (viral load; CD4 count), plasma biomarkers (tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), IL-4, IL-6, IL-10, IL-13, transforming growth factor-beta (TGF-β), osteopontin and hematological tests. The major findings from the main study demonstrated a coordinated pro-fibrotic immune profile in PLWIH, particularly those with severe immunosuppression (CD4 <200 cells/mm³). Key findings were i) increased immune activation in PLWIH shown by the expansion CD8+38+ (p < 0.0009), ii) T-cell depletion and exhaustion shown by the reduction of the co-stimulation marker CD4+CD28+ (p < 0.0001), iii) upregulation of circulating fibrocytes demonstrated by increased COL1+ (p = 0.04), iv) relative eosinophilia in PLWIH (p = 0.04) and a robust positive association with circulating fibrocytes (p = 0.009, r = 0.52), v) cellular immunomodulation of M1 to M2 (p < 0.0001), and a skewing from Th1 to a Th2-like response (p = 0.06). IL-10 was significantly elevated in PLWIH (CD4 counts < 200 cells/mm3 and CD4 count < 500 cells/mm3) compared to PLWOH (p < 0.05). Multivariate analysis revealed that viral load, not HIV status, independently predicted IL-10 levels (p = 0.04). No other significant differences were noted in the cytokine concentrations (p > 0.05). Associations were observed between IL-1β and IL-6 with profibrotic cytokines (IL-4, IL-10, osteopontin) and circulating fibrocytes (CD34+COL1+, COL1+). These associations suggest that sustained inflammation and immune dysfunction promote a profibrotic environment. In the sub-study, PLWOH exhibited a distinct risk profile characterized by traditional CVD risk factors. The risk factors included higher BMI (p = 0.02), elevated systolic and diastolic blood pressure and subclinical dyslipidemia. The sub-study confirmed relative stability in immune and virological factors over 18 months in PLWIH. In contrast, PLWOH showed a significant increase in systolic blood pressure (p = 0.02). This study highlights that persistent immune activation and chronic inflammation in HIV infection promote coordinated cellular immunomodulation. This coordinated immunomodulation is characterized by Th2/M2 polarization, circulating fibrocyte mobilization and eosinophil-fibrocyte interactions. Resultantly, these interactions create a pro-fibrotic environment distinct from the traditional metabolic risk profile evident in PLWOH. These findings suggest different routes to cardiac fibrosis in PLWIH versus PLWOH. Doctoral 2026-04-23T07:49:43Z 2026-04-23T07:49:43Z 2026-03 Thesis https://scholar.sun.ac.za/handle/10019.1/136131 en Stellenbosch University 207 pages application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Mukonowenzou, Nyasha Charity Human immunodeficiency virus (HIV)-mediated cardiac fibrosis: implication of cellular immunomodulation and cytokine profile alterations |
| title | Human immunodeficiency virus (HIV)-mediated cardiac fibrosis: implication of cellular immunomodulation and cytokine profile alterations |
| title_full | Human immunodeficiency virus (HIV)-mediated cardiac fibrosis: implication of cellular immunomodulation and cytokine profile alterations |
| title_fullStr | Human immunodeficiency virus (HIV)-mediated cardiac fibrosis: implication of cellular immunomodulation and cytokine profile alterations |
| title_full_unstemmed | Human immunodeficiency virus (HIV)-mediated cardiac fibrosis: implication of cellular immunomodulation and cytokine profile alterations |
| title_short | Human immunodeficiency virus (HIV)-mediated cardiac fibrosis: implication of cellular immunomodulation and cytokine profile alterations |
| title_sort | human immunodeficiency virus hiv mediated cardiac fibrosis implication of cellular immunomodulation and cytokine profile alterations |
| url | https://scholar.sun.ac.za/handle/10019.1/136131 |
| work_keys_str_mv | AT mukonowenzounyashacharity humanimmunodeficiencyvirushivmediatedcardiacfibrosisimplicationofcellularimmunomodulationandcytokineprofilealterations |