In vivoeffectsof α4β7 blockade on size of viral reservoirs in SIV-infected rhesus macaques

Abstract

Abstract Cellular viral reservoirs are rapidly established upon HIV/SIV infection, which persist throughout viral infection, even under long-term antiretroviral therapy (ART). Recent studies report α4β7 blockade in vivo could preserve mucosal CD4+ T cells, and control persistent viral infection in SIV-infected macaques. In this study, we investigated the effects of early administration with α4β7 antagonist (antibody against α4β7 or small-molecule dual inhibitor TR-14035) for the prevention of infection, and for reducing cellular reservoirs in systemic and lymphoid tissues post SIV infection. Rhesus macaques (Macaca mulatta, RMs) were intravenously (i.v.) inoculated with 100 TCID50 SIVmac251, then administrated a single i.v. dose of anti-α4β7mAb one week prior to SIV inoculation and another 3 weeks post SIV inoculation, or orally treated with TR-14035 for two weeks beginning on the day of SIV inoculation. Our results indicated that early α4β7 blockade did not result in viral containment or reduction of the reservoir size post SIV infection. Plasma viral loads and cell-associated SIV DNA/RNA levels in blood and lymphoid tissues in treated animals were similar to untreated cohorts. Interestingly, TR-14035, a dual inhibitor for α4β7 and α4β1, resulted in persistently higher viremia throughout infection, and more rapid disease progression when administrated in the acute stage of SIV infection. Conclusions These findings suggest that α4β7 blockade alone may not effectively control viral infection, replication, and dissemination and reservoir establishment in HIV/SIV infection. Its usage for potential preventive or/and therapeutic strategies in combined with ART requires further investigation.