Fig 1.
Schematic representation of the studied populations at the time of study sampling.
Characteristics of PHIVAYA subgroups (NS-PHIVAYA, LS-PHIVAYA and ES-PHIVAYA) and healthy control group.
Table 1.
Characteristics of the studied populations at the time of study sampling.
Table 2.
Immunological and cellular aging biomarkers in Suppressed (S) and Not Suppressed (NS) PHIVAYA.
Fig 2.
Comparison of immune and cellular markers of aging among PHIVAYA subgroups.
Comparison of levels of activated CD4 (A), CD8 (B) and B (C) cells; senescent CD4 (D) and CD8 (E) cells; exhausted CD4 (F) and CD8 (G) cells; regulatory T (T-regs) (H), and B (B-regs) cells (I), relative telomere length (L), and thymic output (TREC) (M) among PHIVAYA subgroups; p-values were adjusted for age, time on ART and time of ART initiation.
Table 3.
Immunological and cellular aging biomarkers of Early Suppressed (ES)- and Late Suppressed (LS)-PHIVAYA.
Fig 3.
Comparison of HIV-DNA and cell-associated HIV-RNA levels among PHIVAYA subgroups.
Comparison of levels of total HIV-DNA (A), total cell-associated HIV-RNA (C), unspliced HIV-RNA (D) and between total and unspliced HIV-RNA (B) among PHIVAYA subgroups; p-values were adjusted for age, time on ART and time of ART initiation.
Fig 4.
Correlation plot between HIV reservoir and immune and cellular markers in PHIVAYA.
Colour scale represents Spearman’s correlation coefficient. Red and blue correspond to positive and negative coefficients, respectively. Asterisks * p< 0.05, ** p<0.01, *** p<0.001.
Fig 5.
Comparison of circulating biomarkers among PHIVAYA subgroups.
Circulating levels of 16S rDNA (PAMPs) (A), mtDNA (DAMPs) (B), and pro-inflammatory cytokines IL-6 (C), IL-8 (D) and TNF-α (E), and muscle wasting and denervation biomarkers, NCAM1 (F) and CAF (G) in PHIVAYA subgroups; p-values were adjusted for age, time on ART and time of ART initiation.
Fig 6.
Comparison of markers of aging among PHIVAYA groups and healthy controls.
Comparison of levels of immune senescent CD4 (A), CD8 (B), exhausted CD4 (C) and CD8 (D) cells, telomere length (E), and DAMPs (F) among PHIVAYA subgroups and healthy controls; p-values were adjusted for age.
Fig 7.
Schematic pathogenetic pathway of how persistent HIV reservoir may lead to premature aging and precocious onset of aging-related comorbidities.
ART does not eradicate the virus, which persists as proviral HIV-DNA and residual cell-associated HIV-RNA. This persistence, likely through the damage of the gut mucosa and the release of PAMPs and DAMPs into the circulation, leads to a chronic inflammatory/immune activated condition, which in turn causes cellular and immunological senescence, including increased immune senescence and exhaustion, decreased thymic output, shorter telomeres, and higher levels of muscle wasting and denervation biomarkers. This multifaceted premature aging profile adds new tools for the minimally invasive monitoring of premature/accelerated aging-associated status in people at high risk since they have been living with the virus for their entire lives. The Not Suppressed (NS)-PHIVAYA subgroup displayed the highest (red arrow) HIV reservoir size, degree of inflammation (measured as levels of PAMPs, DAMPs, and proinflammatory cytokines), highest immune senescence and exhaustion, lowest levels of TREC, shorter telomere length and highest levels of NCAM1 and CAF compared to Late Suppressed (LS) (orange arrow) and Early Suppressed (ES) (green arrow) PHIVAYA.