UC San Diego

Since the 1980s, and arguably earlier, human immunodeficiency virus type-1 (HIV) has wreaked havoc on the lives of millions and devastated entire communities as a result of HIV-induced Acquired Immunodeficiency Syndrome (AIDS). Despite the advent of highly active antiretroviral therapy (HAART), HIV infection remains prevalent worldwide and is particularly threatening in the face of emerging drug-resistant HIV strains, against which there is limited treatment. Autophagy is an essential and ubiquitous catabolic cellular pathway, by which complex proteins and organelles are digested and recycled in this concerted process of self-preservation. Until recently the role of autophagy in modulating the immune-response has been under appreciated, but is now known to help fight against infectious diseases; increased autophagic activity of a cell results in increased pathogen recognition and subsequent inhibition. However, in the case of productive HIV infection, autophagy is down-regulated, thereby promoting viral replication and cell survival. NVP-BEZ235, a dual mammalian target of the rapamycin complex 1 (MTORC1)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) class I inhibitor, has been shown in cancer cell lines to induce autophagy and is examined here as a potential therapeutic agent against HIV infection. Using protein markers microtubule-associated protein 1 light chain 3 beta (LC3B) and sequestosome 1 (SQSTM1) to measure autophagic flux, I demonstrate that NVP-BEZ235 induces autophagy in primary human macrophages and CD4⁺ T cells while inhibiting HIV infection in an autophagy-dependent manner. These findings suggest that NVP-BEZ235 may be a useful adjunct to current antiretroviral therapy, and has the potential to be used in an HIV cure strategy