Abstract
Monocytes and macrophages are targets of HIV-1 infection and play critical roles in multiple aspects of viral pathogenesis. HIV-1 can replicate in blood monocytes, although only a minor proportion of circulating monocytes harbor viral DNA. Resident macrophages in tissues can be infected and function as viral reservoirs. However, their susceptibility to infection, and their capacity to actively replicate the virus, varies greatly depending on the tissue localization and cytokine environment. The susceptibility of monocytes to HIV-1 infection in vitro depends on their differentiation status. Monocytes are refractory to infection and become permissive upon differentiation into macrophages. In addition, the capacity of monocyte-derived macrophages to sustain viral replication varies between individuals. Host determinants regulate HIV-1 replication in monocytes and macrophages, limiting several steps of the viral life-cycle, from viral entry to virus release. Some host factors responsible for HIV-1 restriction are shared with T lymphocytes, but several anti-viral mechanisms are specific to either monocytes or macrophages. Whilst a number of these mechanisms have been identified in monocytes or in monocyte-derived macrophages in vitro, some of them have also been implicated in the regulation of HIV-1 infection in vivo, in particular in the brain and the lung where macrophages are the main cell type infected by HIV-1. This review focuses on cellular factors that have been reported to interfere with HIV-1 infection in monocytes and macrophages, and examines the evidences supporting their role in vivo, highlighting unique aspects of HIV-1 restriction in these two cell types.
Highlights
Bone marrow-derived monocytes (Mos) are released into the blood where they circulate for a few days before subsequent extravasation into the lungs, gastrointestinal tract, kidney, primary and secondary lymphoid organs and the central nervous system (CNS)
HIV-1 replication is restricted at different steps
Evidence for the relevance of some of these mechanisms in vivo is coming from studies concerning HIV-1 infected individuals and from the SIV/ macaque model, as reviewed above for the IFNβ/CCAAT enhancer binding protein β (C/EBPβ) or Urokinase-type plasminogen activator (uPA)/uPAR pathways
Summary
Bone marrow-derived monocytes (Mos) are released into the blood where they circulate for a few days (the half-life of circulating Mos in normal healthy individuals is 71 h [1]) before subsequent extravasation into the lungs, gastrointestinal tract, kidney, primary and secondary lymphoid organs and the central nervous system (CNS). We showed that HIV-1 entry and post-integration steps of the viral replication are not affected in ICactivated MDM, whereas levels of reverse transcription products and integrated proviruses are strongly decreased [110] Other lentiviruses, such as HIV-2, SIVmac and SIVagm, are affected by FcγR engagement, suggesting that the restriction targets either a protein conserved among these viruses or a common function. Mφ from the vaginal mucosa display a similar phenotypic profile to that of blood Mos, and express CD4 and CCR5, whereas Mφ from the jejunum intestinal mucosa express a distinct phenotype, with very low levels of CD4 and virtually no CCR5 [8,171,172] The latter cells could resist HIV-1 infection by restricting viral entry due to a lack of the CCR5 co-receptor or to an inappropriate CCR5/CD4 stochiometry [28,173] (Fig. 2B). The excess suPAR in the CSF would bind most of the extracellular uPA, preventing its binding to cell surface uPAR and its signaling-induced inhibition of HIV-replication [193]
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