Background.

HIV infection of humans and SIV or SHIV infection of macaques results in massive CD4 T cell depletion in the gut, translocation of bacterial products across the gut and subsequent high levels of immune activation and exhaustion. Immune activation plays a significant role in the progression to AIDS and death, even with effective HIV drug treatments. MAIT cells appear to decline in the blood of HIV infected humans but the variable and unknown levels of MAIT cells pre-infection has made it difficult to definitively show a role for MAIT cell depletion or dysfunction in HIV immunopathogenesis. Macaque models of AIDS using SIV or chimeric SHIV viruses, along with MR1 tetramers, allow a more precise dissection of MAIT cell numbers and function following infection.

Methods

Pigtailed macaques (M. nemestrina) were infected with SIVmac251, SHIVsf162p3 (both CCR5-tropic viruses) or SHIVmn229 (a CXCR4-tropic virus) and serial PBMC samples studied for MAIT cell numbers and activation status by flow cytometry. Gut biopsy and necropsy specimens were also analysed.

Results

MAIT cells were readily detectable in macaque blood and gut samples using MR1 tetramers, with virtually all cells being CD8+, Va7.2+ and CCR6+. There was an initial ~2-fold rise is MAIT cell numbers in blood during first few week following S/HIV followed by a substantial depletion to <20% of pre-infection levels. HLA-DR and CD38 expression rose on the remaining MAIT cells after S/HIV infection, showing MAIT cell activation. Gut biopsies also had very low levels of MAIT cells detectable after S/HIV infection.

Conclusions

HIV infection in macaque models results in activation and depletion of MAIT cells. This likely contributes to ongoing bacterial translocation across the damaged gut, generalized immune activation and HIV-related morbidity and mortality. Strategies to restore MAIT cell numbers and function during HIV infection could improve HIV disease outcomes.