HIV and SIV infected CD4+ T cells localize primarily to mucosal and lymphoid tissues (LT), which are also a major site for maintenance and subsequent recrudescence of the long-term HIV reservoir. Cytotoxic CD8+ T cells are critical for control of HIV and SIV viremia but the most potent peripheral blood cytotoxic CD8+ T cells are rarely found in LT, indicating that they seldom have the opportunity to interact with infected CD4+ T cells. Here, we assessed the impact of LT CD8+ T cells on SIV immunopathogenesis by inhibiting cell egress from LT in viremic rhesus macaques (RM) using the lymphocyte migration inhibitor FTY720. We hypothesized that the retention of recirculating CD8+ T cells in LT may enable local differentiation into cytotoxic effector cells with a subsequent impact on plasma viral load.
Four RM were infected intravenously with SIVmac239, and treated with FTY720 daily from day 7 or 28 until day 90 post-infection. Separately, fourteen acutely infected RM were treated with antiretrovirals (since day 14 post infection) for 6 months followed by treatment interruption while seven of them were receiving FTY720. Peripheral blood and lymph node (LN) samples were collected for flow cytometry analyses and viral load quantification.
We observed near complete redistribution of circulating T cells into tissues within 28 days of FTY720 treatment (436±346 vs 75±62 CD8+ T cells/µl; and 610±462 vs 4±3 CD4+ T cells/µl). Despite the FTY720-induced retention of CD8+ T cells in LT, no beneficial effect was observed on peak viremia or set point during acute infection, nor time or degree of viral rebound after antiretroviral treatment interruption. FTY720-enforced tissue retention promoted an increase in the frequency of SIV-specific CD8+ T cells in LN of FTY720-treated RM after antiretroviral treatment interruption (p=0.035, vs control RM). However, the frequency of perforin+ granzyme B+ cells within LN SIV-specific CD8+ T cells remained low (1±1% vs 2±2%, pre vs post FTY720). Furthermore, FTY720 treatment did not increase the frequency of follicular homing CXCR5+ SIV-specific CD8 T cells.
These data indicate that simply increasing the number of CD8+ T cells in LT is insufficient to enable viral control in the SIV model. Moreover, enforced retention of CD8+ T cells in viremic tissues does not enable the acquisition of cytotoxic properties, suggesting that secondary signals not present in LT may be necessary to promote or maintain cytotoxic CD8+ T cell differentiation.