Host hindrance to HIV-1 replication in monocytes and macrophages

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.

Figure 1

Schematic representation of host restriction factors in human Mos and Mφ. On the left, low levels of CD4 and CCR5 may limit viral entry in monocytes. Low expression of thymidine phosphorylase associated with a limited stock of dTTP reduces RT rate. APOBEC3A and 3G may interfere with HIV-1 RT in Mos. HIV-2/SIV Vpx antagonizes the restriction of HIV-1 in Mos and Mφ by counteracting an unidentified host factor. Cellular miRNAs have been proposed to target the 3'UTR of HIV-1 transcripts. miR-198 may repress CycT1 expression that contributes to Tat transactivation. On the right, the CCR5Δ32 mutation restricts viral entry of R5 HIV-1 in Mφ. LPS targets the early phases of the HIV-1 cycle in Mφ, through the down-regulation of CCR5 expression and the LTR-driven transcription by IL-10/IFN-β-induced expression of 16 kDa C/EBPβ. p21^Waf1 interferes with both RT and integration and is induced by FcγR engagement. CTIP2 and TRIM22 have been implicated in the inhibition of HIV-1 transcription. Urokinase-type plasminogen activator (uPA) blocks the release of viral particles from intracellular vacuoles.

Figure 2

Schematic model of infection of monocytes and macrophages. A) Hypothetical ways to infect monocytes. Mo precursors may be infected before leaving the bone marrow (1) and then migrate to peripheral tissues where they differentiate into Mφ (2). Viral replication will then be reactivated leading to viral production and infection of neighboring cells (3). Alternatively, Mo subsets may become permissive to infection after being activated in the bone marrow or in the blood, owing to the inflammatory environment (4). Mos may be infected after encountering the virus or infected cells in inflamed tissues (5), where they then differentiate to Mφ. However, infected Mos might also transmigrate back to the blood (6). A Mo subset expressing CD16 that displays pro-inflammatory characteristics appears to be preferentially infected by HIV-1. B) Dissemination and control of HIV-1 infection in tissue macrophages. Infected Mos migrate to peripheral tissues such as brain, lungs and gastrointestinal tract where they differentiate and disseminate infection to resident microglial cells, alveolar Mφ or mucosal Mφ. The CD16+ subset has an enhanced capacity to transmigrate into tissues. Various factors that may control HIV-1 replication are present in peripheral compartments. Mφ from the mucosa of the gastrointestinal tract, where exposure to LPS is frequent, do not express CCR5 and are resistant to HIV-1 infection. An increased expression of the inhibitory C/EBPβ may suppress viral transcription in Mφ in brain and lungs, contributing to viral latency. Transcriptional silencing of the HIV-1 LTR by CTIP2 may contribute to HIV-1 latency in the CNS. uPA is also involved in the control of HIV-1 replication in the CNS and is sequestered by the soluble receptor suPAR in CNS disease.