Integrated Assessment of Viral Transcription, Antigen Presentation, and CD8<sup>+</sup>T Cell Function Reveals Multiple Limitations of Class I-Selective Histone Deacetylase Inhibitors during HIV-1 Latency Reversal
Talia M. Mota, Chase D. McCann, Ali Danesh, Szu-Han Huang, Dean Magat, Yanqin Ren, Louise Leyre, Tracy D. Bui, Thomas Rohwetter, Colin Kovacs, Erika Benko, Lynsay MacLaren, Avery Wimpelberg, Christopher Cannon, William D. Hardy, Jeffrey T. Safrit, R. Brad Jones
Abstract
Antiretroviral (ARV) drug regimens suppress HIV-1 replication but are unable to cure infection. This leaves people living with HIV-1 burdened by a lifelong commitment to expensive daily medication. Furthermore, it has become clear that ARV therapy does not fully restore health, leaving individuals at elevated risk for cardiovascular disease, certain types of cancers, and neurocognitive disorders, as well as leaving them exposed to stigma. Efforts are therefore under way to develop therapies capable of curing infection. A key focus of these efforts has been on a class of drugs called histone deacetylase inhibitors (HDACi), which have the potential of exposing hidden reservoirs of HIV-1 to elimination by the immune system. Unfortunately, clinical trial results with HDACi have thus far been disappointing. In the current study, we integrate a number of experimental approaches to build a model that provides insights into the limited activity of HDACi in clinical trials and offers direction for future approaches.