The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Victorian Infectious Diseases Service, The Royal Melbourne Hospital and Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia
Despite the great success of antiviral therapy (ART), treatment is life long for the majority of people living with HIV (PLWH). Antiviral treatment is simple and relatively cheap and close to 60% of PLWH have access to treatment. However, ART is still not available or secure for many, drug resistance is common globally and there are emerging toxicities from some of the most potent antivirals. The main reason ART is unable to cure HIV infection is the persistence of long lived proliferating latently infected cells and impaired clearance of HIV-infected cells.
Immune checkpoint blockers may provide a potential strategy to eliminate HIV infected cells through latency reversal and/or enhancement of immune mediated clearance of infected cells. We and others have previously demonstrated that in people living with HIV (PLWH) on antiretroviral therapy (ART), HIV is enriched in CD4+ T-cells from blood that express immune checkpoint markers including programmed death (PD)-1, LAG3 and TIGIT. We recently evaluated the effects of antibodies to PD-1 either alone or in combination with anti-CTLA-4 in two large prospective clinical trials and identified that anti-PD1 can reverse latency, enhance the capacity to induce virus expression and when used in combination with anti-CTLA-4 can reduce the reservoir in some individuals.
Anti-PD1 alone and in combination with other immune checkpoint blockers can also enhance control of viral replication. We administered rhesusized nivolumab to SIV-infected rhesus macaques (RM) starting prior to cessation of ART, with low antigen exposure, or at time of cessation of ART with high antigen exposure and compared viral rebound kinetics to a control group who received an isotype control antibody. We found no difference of time to viral rebound in all groups but observed a ~2 log reduction of SIV RNA in both nivolumab treatment groups relative to isotype controls (2.5 logs and 2.6 logs vs. 4.5 logs, respectively). We are now investigating the role of next generation immune checkpoint blockers - anti-TIM3, anti-TIGIT and anti LAG3 – as they have reduced toxicity and when used in combination can significantly enhance function of HIV-specific T-cells.
Immune checkpoint blockers can perturb HIV latency and also enhance HIV-specific T-cell function. Further work is needed to minimise immune related adverse events to safely integrate these antibodies as part of a cure strategy.