Host and Viral Factors Influencing Interplay between the Macrophage and HIV-1

HIV-1 persists in cellular reservoirs that cannot be eliminated by antiretroviral therapy (ART). The major reservoir in infected individuals on effective ART is composed of resting memory CD4+ T cells that harbor proviral cDNA, and undergo a state of latency in which viral gene expression is minimal to absent. The CD4+ T cell reservoir has been extensively characterized. However, other HIV-1-permissive cells may contribute to HIV-1 persistence. Lentiviruses have a long recognized association with macrophages. However, the role, if any, played by macrophages in HIV-1 persistence is not well understood. Macrophages are resistant to cell death upon HIV-1 infection, and can survive for long periods of time, making them ideal host cells in which the virus might persist. Studying macrophages is challenging, as these cells reside in nearly all tissues. Moreover, detecting viral DNA or RNA in macrophages does not necessarily indicate that these cells will produce replication-competent viral particles. Currently, the gold standard assay to detect cellular reservoirs is the ex vivo quantitative viral outgrowth assay (QVOA), which requires a patient blood draw. However, macrophages reside deep within tissues that are inaccessible in living subjects, such as the central nervous system (CNS). Therefore, tools other than QVOA must be developed to identify cellular reservoirs that reside in the tissues. In this review, we will focus on the main aspects involved in HIV-1 persistence, including the molecular mechanisms of viral evasion, the main cell types responsible for harboring persistent HIV-1 and the tissue compartments that are likely to be reservoirs for HIV-1.