Preservation of MHC-Ia protective allele suppression of SIVmac239 in aged rhesus macaques.

Major histocompatibility complex class Ia (MHC-Ia)-restricted CD8⁺ T cell responses play a central role in the host defense against HIV-1, with certain MHC-Ia alleles known to be associated with cytotoxic T lymphocyte responses having an increased potential for viral control. However, the impact of immune aging on the effectiveness of such protective alleles remains unclear. In this study, we assessed SIVmac239 replication in aged (17-23 yr old) rhesus macaques (RMs) exhibiting low frequencies of naïve T cells and expanded effector memory T cells, that were further stratified by the presence (MHC⁺) or absence (MHC-) of 3 known "protective MHC-Ia alleles" (Mamu-A*01, Mamu-B*08, or Mamu-B*17). All RMs were infected with SIVmac239 and viral dynamics monitored longitudinally. MHC⁺ RMs demonstrated significantly lower plasma viral loads (PVLs) through 70 d postinfection compared with MHC- RMs. At 70 d postinfection, half of the RMs from each group initiated suppressive triple antiretroviral therapy comprising dolutegravir, emtricitabine, and tenofovir disoproxil fumarate (TDF) for 15 wk, followed by suboptimal TDF monotherapy for an additional 21 wk. While antiretroviral therapy substantially reduced PVL in both groups, viral decline was accelerated in MHC⁺ RMs relative to MHC- RMs. Moreover, upon switching to TDF monotherapy, PVL rebounded by almost 3 logs in MHC- RMs, while MHC⁺ RMs maintained viral suppression. Collectively, these findings indicate that protective MHC-Ia alleles can mediate viral control in aged hosts, even under suboptimal treatment conditions, and highlight the potential role of optimized CD8+ T cell responses in strategies targeting viral persistence in aging populations.