Shocking HIV out of hiding: Where are we with clinical trials of latency reversing agents?

Purpose of review: To provide an overview of the initial experiences with the use of latency-reversing agents (LRAs) in clinical trials in HIV and to discuss and contrast results arising from these studies. Recent findings: Although the clinical administration of histone deacetylase inhibitors (HDACis) and disulfiram to HIVinfected individuals on antiretroviral therapy significantly increased cell-associated HIV RNA in CD4⁺ T cells and in some cases plasma HIV RNA, this did not reduce the frequency of latently infected cells in blood. Potential reasons for this include insufficient potency in latency reversal, lack of virus or immunemediated cytolysis of virus-expressing cells and/or a high frequency of immune escape mutations in the recently activated virus. Analyses of HIV-specific T-cell responses in vivo did not demonstrate that HDACis impair immune cell effector functions. Summary: More effective latency-reversing interventions and additional strategies to eliminate virus-expressing cells are needed. Key challenges include testing combinations of LRAs and/or LRAs with immune modulation to optimize potency in the absence of adverse events. A better understanding of the mechanisms of action of LRAs as well as strategies to enhance potency and penetration in tissue are key challenges for future studies.