Eradication of HIV-1 from CNS reservoirs: current strategies and future priorities.

Abstract

Eradication of HIV-1 and achieving a sterilizing or functional cure has become a priority area in the AIDS field. Large investments have been made by funding agencies, particularly NIH, in understanding the mechanisms of HIV persistence and approaches to target and eradicate latent reservoirs. The majority of the work that is ongoing has focused on studying resting CD4+ T cell reservoirs and developing strategies for reactivation and purging HIV from this cell type. However, it is becoming increasingly clear that other sites of HIV persistence exist including anatomic reservoirs such as the brain and gut. Also, myeloid cells residing in these anatomic compartments may harbor persistent HIV-1 that could potentially be a source of rebounding virus upon cessation of therapy. The brain is unique in terms of its immune privileged status and the presence of the blood-brain barrier which restricts entry of anti-retrovirals. HIV-1 seeds the brain early in infection and may reside in long-lived cells such as microglia and astrocytes and thus serve as a site of viral persistence. At an NIMH-sponsored meeting entitled “Eradication of HIV-CNS Reservoirs—Current and Future Strategies” held in Washington DC in conjunction with the 12th International Symposium on NeuroVirology (October 2013), many of the challenges in targeting brain HIV-1 reservoirs and the need to better understand the mechanisms of establishment of latency in this unique anatomic compartment were discussed. At that meeting, it was felt that the field would greatly benefit by the publication of a special issue of the Journal of NeuroVirology devoted to HIV-1 CNS reservoirs that would address the challenges and current knowledge in this area. This special issue represents work presented by many of the speakers at the NIMH-sponsored symposium. In addition, several other authors have contributed in order to provide a comprehensive review of the state of the field. The articles presented discuss current challenges in targeting CNS reservoirs as well as mechanisms of establishing persistence in CNS-derived cell populations such as microglia, macrophages, and astrocytes. Current approaches to target myeloid reservoirs as well as some novel gene editing strategies that may aid in HIV-1 eradication strategies are also discussed. I have provided below, for the reader of this special issue, a brief summary of each of the papers published in order to capture the flavor of the topic area covered. The summaries are by no means comprehensive but are illustrative of the research areas that these papers represent. An overview of the translational challenges in targeting latent HIV infection and the CNS reservoir problem was highlighted by Dr. David Margolis. Some of the challenges include the need for reliable, validated cell-based and animal model systems to test latency-reversing agents. He cautions that of several potential anatomic reservoirs, the central J. Joseph (*) Division of AIDS Research, National Institute of Mental Health, Room 9G20, MSC 9831 5601 Fishers Lane, Bethesda, MD 20892-9830, USA e-mail: jjeymoha@mail.nih.gov