Role of Myeloid Cells in Persistence and Eradication of HIV-1 Reservoirs from the Brain
Jeymohan Joseph, Ph.D.
Division of AIDS Research, NIMH
The goal of this initiative is to stimulate research on mechanisms of HIV persistence in myeloid cells and develop strategies to target this reservoir in the central nervous system (CNS).
Eradicating latent reservoirs of HIV-1 within the body and achieving a sterilizing or functional cure have become priority areas in the AIDS field and NIH AIDS programs across many Institutes and Centers, including NIMH. The majority of ongoing work in the HIV eradication field has focused on studying resting memory CD4+ T cell reservoirs and developing strategies for reactivating and purging HIV from this cell type. Resting memory CD4+ T cells in the blood are the major and best-characterized cellular reservoir in a host. The presence of latent proviral HIV-1 DNA in this cell population has been well established. However, there are other sites of HIV persistence in the body. For example, phylogenetic analysis has shown that during rebound viremia (following the cessation of highly active antiretroviral therapy [HAART]), the virus could be detected from a reservoir other than the CD4+ T cells. Anatomic and tissue compartments such as brain, gut, lung, and lymphoid tissue may also be contributing to the HIV reservoir. In addition, 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 access of anti-retroviral medications. HIV-1 is found in the brain early in infection, likely through transmigration of infected monocytes, and may reside in long-lived myeloid cells such as macrophages, microglia, and astrocytes, and thus serve as a site of viral persistence. The perivascular macrophages and the microglial cells, the main targets for HIV-1 in the CNS, have a low turnover (i.e., 2-3 months for the perivascular macrophages and several years for the microglial cells). Viral DNA can also be isolated from these cells suggesting the role for myeloid cells as potential reservoirs for HIV-1. Furthermore, persistently infected myeloid cells could produce partial HIV transcripts, proteins, or soluble factors that could affect the size of the latent reservoir or the sensitivity of latently infected cells to reactivation.
The mechanisms of HIV-1 latency in resting memory CD4+ T cells has been well studied and could result from: (1) repression of HIV-1 proviral DNA integrated into host cell chromosomes by neighboring cis-acting sequences; (2) non-permissive host-cell environment for transcription of HIV genome; and, (3) post-transcriptional restriction mechanisms, such as impaired HIV mRNA nuclear export and the expression of host or viral micro-RNAs. While much has been learned about the mechanisms of HIV-1 latency and persistence in resting memory CD4+ T cells, there is a very limited understanding of how HIV-1 persists in monocytes, macrophages, and other cells of myeloid origin. Further studies also warranted to better comprehend how this cell population contributes to HIV persistence and/or viral rebound following interruption of HAART.
This initiative will encourage research in the following areas:
- Understanding the mechanisms of HIV-persistence in cells of the myeloid lineage;
- Determining if myeloid cells are a source of rebound virus upon cessation of anti-retroviral therapy;
- Characterizing functional changes in persistently infected myeloid cells that could impact the total HIV reservoir or viral rebound;
- Developing animal models and physiologically relevant primary cell models to study myeloid cell reservoirs in the context of viral suppression with HAART;
- Developing strategies for targeting persisting HIV in the myeloid cells with optimal drug penetration profiles; and,
- Studying the impact of latent and persistent myeloid reservoirs on neuronal function in the absence of active viral replication.