CD8+ lymphocytes do not impact SIV reservoir establishment under ART

Abstract

Persistence of the human immunodeficiency virus type-1 (HIV-1) latent reservoir in infected individuals remains a problem despite fully suppressive antiretroviral therapy (ART). While reservoir formation begins during acute infection, the mechanisms responsible for its establishment remain unclear. CD8+ T cells are important during the initial control of viral replication. Here we examined the effect of CD8+ T cells on formation of the latent reservoir in simian immunodeficiency virus (SIV)-infected macaques by performing experimental CD8+ depletion either before infection or before early (that is, day 14 post-infection) ART initiation. We found that CD8+ depletion resulted in slower decline of viremia, indicating that CD8+ lymphocytes reduce the average lifespan of productively infected cells during acute infection and early ART, presumably through SIV-specific cytotoxic T lymphocyte (CTL) activity. However, CD8+ depletion did not change the frequency of infected CD4+ T cells in the blood or lymph node as measured by the total cell-associated viral DNA or intact provirus DNA assay. In addition, the size of the persistent reservoir remained the same when measuring the kinetics of virus rebound after ART interruption. These data indicate that during early SIV infection, the viral reservoir that persists under ART is established largely independent of CTL control.

CD8+ cells and small viral reservoirs facilitate post-ART control of SIV in Mauritian cynomolgus macaques

“…It would be interesting to directly compare MCMs to RMs in an ART interruption study. While acute CD8+ T cells do not impact reservoir establishment in RMs 18 , it is possible that CD8+ T cells impair reservoir establishment in MCMs. Depletion of CD8+ T cells during acute SIV infection in MCMs could help determine if CD8+ T cells are required for reservoir formation, virus suppression under ART, and later PTC.…”

“…4a). In contrast, RMs initiated on ART in similar timeframes consistently rebound within two weeks of ART interruption with peak rebound viremia of ~4-7 log 10 ceq/mL 18,26,47,55 . Thus, even when MCMs exhibit viral rebound, viremia is delayed and of a smaller magnitude compared to RMs.…”

“…Depletion of CD8+ T cells during acute SIV infection in MCMs could help determine if CD8+ T cells are required for reservoir formation, virus suppression under ART, and later PTC. Even though similar depletion studies were performed in RMs 18 , acute depletion studies in this novel MCM model of PTC may identify key features of immune-mediated virus suppression that were otherwise confounded by the larger viral reservoir and rapid viral rebound in RMs. CD4+ T cells in RMs may also be more susceptible to SIV infection than CD4+ T cells in MCMs, which would affect reservoir formation and size.…”

“…Most RM ART interruption studies identify zero PTCs 18,26,47,55,60 . While the definition of PTC varies dramatically between studies 10 , many definitions of PTC (e.g., maintain plasma viremia <10 4 copies/mL 27 ) are lenient enough to include at least nine of the 14 MCMs described here.…”

“…We used IPDAs to compare the number of intact and total vDNA copies per 1x10 6 cell equivalents between MCMs at the time of ART initiation, and a separate cohort of RMs infected with SIVmac239M by the same dose and route 35 . RMs initiated on ART ~one to four weeks post SIV exhibit prompt viral rebound after ART interruption 18,26,47,55,60 , but it is unknown if differences in reservoir sizes between RMs and MCMs account for the different rebound kinetics after ART withdrawal.…”