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

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).

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.

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 p<0.05). 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.

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.