The persistence of HIV infection under anti-retroviral therapy (ART) is due to a reservoir of latently-infected cells harboring integrated replication-competent virus which cause rebound viremia after analytic treatment interruption (ATI). However, whether these latently infected cells are formed directly after integration or following a phase of productive infection remains unclear. In this study, we addressed this question in SIV-infected rhesus macaques (RM) by performing experimental CD8+ depletion either prior to infection or prior to ART initiation (day-12 post-infection).
A total of 21 RM were infected with a barcoded SIVmac239 and ART was initiated 2 weeks post-infection. 8 RM received the CD8?-depleting antibody MT-807R1 before SIV infection, 8 RM were CD8 depleted just prior to ART initiation, and 5 SIV-infected ART treated RM served as the control group. After 50 weeks on ART, all RM underwent ATI and were followed for 12 weeks. SIV expression was monitored by plasma viral load, as well as cell-associated (CA)-RNA in peripheral blood (PB) and lymph node (LN). The viral reservoir size was assessed by total SIV CA-DNA in PB and LN. Mathematical modeling was used to assess the decay kinetics of virus expression.
As expected, we found that CD8+ depletion resulted in slower decline of plasma viremia, corresponding to a slower decline in SIV CA-RNA frequency and higher barcode diversity in plasma, therefore indicating that CTLs reduce the average lifespan of productively infected cells during the acute phase of SIV infection. In addition, we observed an increased ratio of viral CA-RNA:CA-DNA in CD8+ depleted animals. Significantly, CD8+ depletion did not change the size of the virus reservoir measured either directly, as total CA-DNA, or indirectly, as kinetics of virus rebound after ART interruption.
Together, these data support the role of CD8+ T cells, presumably through cytotoxic T lymphocyte function, in decreasing the average lifespan of short-lived productively infected cells during acute infection. By contrast, long-lived infected cells were not significantly impacted by the presence of CD8+ T cells, supporting the hypothesis that long-lived infected cells establish the persistent reservoir independent of cytolytic T cell control. These data highlight the importance of understanding the mechanisms by which cytolytic and non-cytolytic CD8+ T cell functions impact the establishment and maintenance of the virus reservoir under ART.