Innate Immune Dysfunction and Persistent Activation in South African HIV Elite Controllers

Christina Thobakgale^1*Asisipo Mohamed¹Yenzekile Zungu¹Sharon Shalekoff²Osman Ebrahim¹Ziyaad Waja³Neil Martinson³Caroline T Tiemessen²

• ¹University of the Witwatersrand, Johannesburg, South Africa
• ²Centre for HIV & Sexually Transmitted Infections, National Institute of Communicable Diseases, Johannesburg, Gauteng, South Africa
• ³Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Soweto, South Africa

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 (PWHEC), 20 HIV progressors (PWHPROG), and 19 individuals suppressed on ART (PWHART). Eighteen individuals without HIV infection (PWOHHIV-) 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 analysed 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 PWHEC (p=0.04) compared to PWOHHIV-. A reduced frequency of the classical monocyte (CD14+CD16) subset in PWHEC (p=0.02) and PWHPROG (p=0.05) compared to PWOHHIV-. TNF-α and IL-1β production was lower in monocytes and mDCs of PWHEC compared to PWOHHIV-poststimulation with TLR4, and TLR7/8 (all p<0.05). Increased sCD14 levels in PWHEC compared to PWOHHIV-(p=0.01) indicate persistent immune activation, whereas increased D-dimer levels in PWHPROG compared to PWHART (p=0.01) and PWHEC (p=0.04) suggest higher inflammation in PWHPROG. Conclusion: PWHEC exhibits similar immune responses as other PWH including PWHPROG, 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 PWHEC. Furthermore, it expands our understanding of complex innate immune cell responses in PWHEC.