Innate immune dysfunction and persistent activation in South African HIV elite controllers

Background Elite controllers can spontaneously control HIV-1 infection without antiretroviral treatment but remain at risk of developing non-AIDS-related conditions. The adaptive immune system is key in mediating spontaneous viral control; however, the innate immune response remains understudied. We assessed the quality of the innate immune responses by evaluating the phenotype and function of antigen-presenting cells (APCs) in South African adults living with HIV (PWH). Methodology A total of 73 black South Africans were included in this study. Of these, 55 were living with HIV and included 16 individuals with spontaneous viral control (PWH EC ), 20 HIV progressors (PWH PROG ), and 19 individuals suppressed on ART (PWH ART ). Eighteen individuals without HIV infection (PWOH HIV- ) served as the control group. Monocyte subsets, T cell and monocyte activation and the production of tumour necrosis factor-alpha (TNF-α), interferon-alpha (IFN-α), and interleukin-1 beta (IL-1β) by monocytes, myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells were analyzed using multicolour flow cytometry following stimulation with toll-like receptor (TLR)4 (LPS), TLR7/8 (CL097), and TLR9 (CpG-ODN2216) ligands. Plasma biomarkers, soluble CD14 (sCD14), and D-dimer were assessed using enzyme-linked immunosorbent assay. Results Our findings show a reduced expression of CD86 on monocytes of PWH EC (p=0.04) compared to PWOH HIV- . A reduced frequency of the classical monocyte (CD14+CD16) subset in PWH EC (p=0.02) and PWH PROG (p=0.05) compared to PWOH HIV- . TNF-α and IL-1β production was lower in monocytes and mDCs of PWH EC compared to PWOH HIV- post-stimulation with TLR4, and TLR7/8 (all p0.05). Increased sCD14 levels in PWH EC compared to PWOH HIV- (p=0.01) indicate persistent immune activation, whereas increased D-dimer levels in PWH PROG compared to PWH ART (p=0.01) and PWH EC (p=0.04) suggest higher inflammation in PWH PROG . Conclusion PWH EC exhibits similar immune responses as other PWH including PWH PROG , their innate immune profiles are characterized by lower levels of monocyte activation, reduced levels of classical monocytes, reduced capacity to produce pro-inflammatory cytokines, and elevated biomarkers associated with unfavourable disease outcomes. These findings highlight the need for continuous monitoring and potential therapeutic interventions to mitigate chronic inflammation in PWH EC . Furthermore, it expands our understanding of complex innate immune cell responses in PWH EC .