Therapeutic CD8+T cell tissue retention and immunomodulation during ART interruption fails to prevent SIV rebound
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
A primary obstacle for HIV elimination is the long-term viral reservoir in lymphoid tissues (LT) that can cause rebound viremia if therapy is stopped. Cytotoxic CD8+ T cells are critical for control of HIV and SIV viremia; however, CD8+ T cells that migrate to LT are primarily non-cytotoxic, calling into question whether these cells could reduce the viral reservoir on ART or control viral replication when therapy is halted. To determine if CD8+ T cells can inhibit viral replication when retained in lymphoid tissues, we inhibited lymphocyte egress from LTs in antiretroviral therapy (ART)-treated SIV-infected rhesus macaques (RM) during analytic treatment interruption (ATI) using the S1PR modulator FTY720 alone or in combination with anti-PD1 and the IL-15 receptor superagonist N-803 to increase cytolytic function. FTY720 retained migrating CD4+ and CD8+ T cells in LT, whereas cytotoxic CD8+ T cells remained in the vasculature. After ATI and viral rebound, activated SIV-specific CD8+ T cells increased in frequency in LT of FTY720-treated RM but failed to become cytotoxic or control plasma viremia compared to controls, even when combined with anti-PD1 and N-803. These findings indicate that LT-localized CD8+ T cells alone are insufficient to delay or prevent plasma viral rebound during ATI.
Significance Statement
HIV therapeutic and cure strategies have all operated under the assumption that CD8+ T cells can become cytotoxic in lymph nodes to eliminate infected cells from reservoir repositories. Using FTY720 to prevent lymphocyte egress from lymph nodes, we demonstrated that lymphoid tissue-restricted CD8+ T cells are insufficient to prevent SIV rebound during antiretroviral treatment interruption, even in the presence of immunomodulators such as IL-15 receptor superagonist and PD-1 blockade. These findings call into question the ability of lymph node CD8+ T cells to control or eliminate SIV/HIV infection from lymphoid tissues without substantial immunomodulation, a notion contrary to current efforts to engage CD8+ T cells for therapeutic elimination of HIV viral reservoirs during ART.
