Host Restriction Factors Modulating HIV Latency and Replication in Macrophages

Abstract

In addition to CD4⁺ T lymphocytes, myeloid cells and, particularly, differentiated macrophages are targets of human immunodeficiency virus type-1 (HIV-1) infection via the interaction of gp120Env with CD4 and CCR5 or CXCR4. Both T cells and macrophages support virus replication, although with substantial differences. In contrast to activated CD4⁺ T lymphocytes, HIV-1 replication in macrophages occurs in nondividing cells and it is characterized by the virtual absence of cytopathicity both in vitro and in vivo. These general features should be considered in evaluating the role of cell-associated restriction factors aiming at preventing or curtailing virus replication in macrophages and T cells, particularly in the context of designing strategies to tackle the viral reservoir in infected individuals receiving combination antiretroviral therapy. In this regard, we will here also discuss a model of reversible HIV-1 latency in primary human macrophages and the role of host factors determining the restriction or reactivation of virus replication in these cells.

Keywords: HIV; MDM; macrophage polarization; macrophages; restriction factors; transcription factors.

Figure 1

Restriction factors interfering with HIV-1 infection of macrophages. PIC: Pre-Integration Complex. See Table 2 for details.

Figure 2

M1-MDM: a model of HIV-1 restriction suitable to be exploited as model of reversible HIV-1 latency. (A) Differentiation of circulating monocytes into MDM leads to their productive infection by HIV-1 (“permissive phenotype”), whereas their polarization into M1 cells induces a significant reduction in virus replication (“restricted phenotype”). Further stimulation of M1-MDM by different proinflammatory signals leads to an even greater reduction in their capacity to support virus replication approaching a state of proviral latency. (B) Incubation of restimulated M1-MDM with either T cell blasts, T regulatory cells or with selected pharmacological agents leads to reversal of proviral latency in MDM and viral spreading.