HIV-1 latency in monocytes/macrophages

Abstract

Human immunodeficiency virus type 1 (HIV-1) targets CD4+ T cells and cells of the monocyte/macrophage lineage. HIV pathogenesis is characterized by the depletion of T lymphocytes and by the presence of a population of cells in which latency has been established called the HIV-1 reservoir. Highly active antiretroviral therapy (HAART) has significantly improved the life of HIV-1 infected patients. However, complete eradication of HIV-1 from infected individuals is not possible without targeting latent sources of infection. HIV-1 establishes latent infection in resting CD4+ T cells and findings indicate that latency can also be established in the cells of monocyte/macrophage lineage. Monocyte/macrophage lineage includes among others, monocytes, macrophages and brain resident macrophages. These cells are relatively more resistant to apoptosis induced by HIV-1, thus are important stable hideouts of the virus. Much effort has been made in the direction of eliminating HIV-1 resting CD4+ T-cell reservoirs. However, it is impossible to achieve a cure for HIV-1 without considering these neglected latent reservoirs, the cells of monocyte/macrophage lineage. In this review we will describe our current understanding of the mechanism of latency in monocyte/macrophage lineage and how such cells can be specifically eliminated from the infected host.

Figure 1

Model of pre-integration and post-integration latency in HIV-1 infected monocytes/macrophages. Pre-integration latency is governed by interplay of host restriction factors including APOBEC3, SAMHD1 and MX2. Such form of latency is more relevant in the cells of monocyte/macrophage lineage. On the other hand, post-integration latency is manifested by several mechanisms that include chromatin remodeling, epigenetic mechanisms and host-encoded miRNAs. Furthermore, Tat mediated reactivation has been also shown. PIC: Pre-Integration Complex.

Figure 2

Role of cells of monocyte/macrophage lineage in HIV-1 pathogenesis. Cells of monocyte/macrophage lineage are susceptible to HIV-1 infection. Infected monocytes are an important short-lived viral pool that upon entering tissues differentiated into macrophages. Infected macrophages can transfer virus to the uninfected cells via virological synapses (VS). In addition, infected macrophages release chemokines and cytokines (MIP-1α, MIP-1β, MCP-1 and CCL-5) that attract immune cells (T cells and monocytes) for further infection. Macrophages can induce an anti-apoptotic state in infected CD4⁺ T cells, thereby increasing the viral reservoir. The role of macrophages in inducing latency in CD4⁺ T cells is also postulated. Furthermore, infected macrophages induce the apoptosis of uninfected bystander cells (CD4⁺ and CD8⁺ T cells) further contributing to the HIV-1 pathogenesis. Intestinal macrophages fuel HIV pathogenesis by disseminating the virus to CD4⁺ T cells. Of note, CNS resident macrophages represent an important anatomical viral sanctuary and a difficult target for HIV-1 therapy.