Background
Major histocompatibility complex class Ia (MHC-Ia)-restricted CD8⁺ T cell responses are commonly associated with limiting viral replication in the absence of antiretroviral therapy (ART). However, their role in the establishment and persistence of viral reservoirs during ART remains unclear. In this study, we contrasted SIV-infected rhesus macaques (RM) receiving ART with and without known protective MHC-Ia alleles (Mamu–A*01, -B0*8, -B*17) to assess the impact of protective alleles on cell-associated viral loads (CAVL) in blood and lymphoid tissues during treatment.
Methods
Male RM with protective MHC-Ia alleles (pMHC+, n=11) and without (pMHC-, n=13) were inoculated intravenously with SIVmac239M (5000 IU). Daily ART (TDF, FTC, DTG) was initiated 9 days post-infection (dpi) and continued through 72 weeks pi (wpi). SIV in blood and tissues was assayed by ddPCR and cellular immune dynamics by flow cytometry.
Results
By 12-dpi (3 days post-ART initiation), plasma viral loads (PVL) were significantly lower in pMHC+ RM compared to pMHC- RM (mean log10 6.7 vs 7.2; p=0.003) and pMHC+ RM achieved PVL suppression (15 copies/ml) more rapidly than pMHC- RM (median 6 wpi vs 15 wpi, p=0.002). pMHC+ RM had significantly lower levels of SIV RNA in peripheral blood mononuclear cells (PBMC; p=0.02), peripheral lymph nodes (PLN; p=0.004), bone marrow (BM; p=0.01), duodenum (p=0.01) and spleen (p=0.01) by 12 dpi. These lower SIV RNA levels in pMHC+ RM persisted in PBMC (p=0.007) and spleen (p=0.02) at 21 wpi. Importantly, the elevated SIV RNA expression in pMHC- RM was not associated with increased reservoir seeding, as assessed by SIV DNA levels, which did not significantly differ between groups across tissues. While magnitudes of SIV-specific CD8⁺ T cell responses in PBMC were not significantly different in pMHC+ RM (p=0.08), they did have higher frequencies of central and transitional memory CD8⁺ T cells (p=0.003 and 0.0001, respectively), and lower levels of effector memory CD8⁺ T cells (p=0.004) in the blood at 21 wpi. This suggests an expansion of more terminally differentiated CD8⁺ T cells in pMHC- RM.
Conclusions
These data demonstrate that MHC-Ia-restricted CD8⁺ T cell responses can significantly influence the dynamics of CAVL in SIVmac239M-infected RM on long-term ART. Notably, their capacity to suppress SIV RNA expression across multiple lymphoid tissue compartments underscores the potential of optimized CD8⁺ T cell-based strategies to support reservoir reduction in HIV cure efforts.
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