HIV associated immune aging among people living with HIV: implications for long-term antiretroviral therapy and potential HIV cure interventions in sub-Saharan Africa.

BACKGROUND: Clinical and biological consequences of accelerated immune aging are substantial, with growing evidence of increased risk of non-communicable diseases (NCD) among people living with HIV (PLHIV). However, there is limited understanding of reliable biomarkers of immune aging, singly or in combination, that can be used for monitoring HIV treatment in large longitudinal cohorts in sub-Saharan Africa (SSA). This review describes candidate biomarkers of immune aging during HIV treatment and their potential clinical application in monitoring immune aging, immune function recovery and risk of NCD complications among adults aging with HIV and ART. METHODS: On April 1, 2026, we searched PubMed using a broad Boolean strategy that combined MeSH terms and title/abstract keywords for HIV-related concepts with MeSH terms and title/abstract keywords for immunosenescence-related concepts. The HIV block included terms such as HIV, HIV infections, HIV seropositivity, HIV-1, HIV-2, AIDS, and descriptors for people living with HIV, while the immunosenescence block included immunosenescence, T cell senescence, cellular senescence, immune aging/ageing, inflammaging, age-associated immune changes, and accelerated or premature immune aging. RESULTS: Key findings reveal that CD4/CD8 ratio inversion, T-cell senescence markers including CD28 and CD57+ expression on CD4/CD8 T-cells and Natural Killers cells, PD-1 expression, as well as selected inflammatory cytokine panels and proteomic signatures of immune aging are promising biomarkers that could contribute to monitoring immune aging during long-term ART. In addition, there is evidence to suggest association of immune aging with HIV reservoir characteristics during ART. However, validation of immune aging markers remains incomplete in SSA populations with chronic HIV infections, host genetic diversity, HIV viral non-B sub-type diversity, variable ART access and multiple endemic co-infections. CONCLUSION: This systematic review underscores the need for evidence to develop HIV-associated immune aging biomarker panels during long-term HIV treatment in SSA; to guide the development of predictive, diagnostic and/or monitoring biomarker panels for HIV-associated immune aging and its complications among PLHIV in SSA. We recommend well-characterized human studies to inform the adoption of context-specific HIV cure innovations in consideration of the heterogeneous host immune aging phenotypes, HIV-1 viral sub-types and endemic co-infections in SSA.