Viral determinants of HIV-1 macrophage tropism

Abstract

Macrophages are important target cells for HIV-1 infection that play significant roles in the maintenance of viral reservoirs and other aspects of pathogenesis. Understanding the determinants of HIV-1 tropism for macrophages will inform HIV-1 control and eradication strategies. Tropism for macrophages is both qualitative (infection or not) and quantitative (replication capacity). For example many R5 HIV-1 isolates cannot infect macrophages, but for those that can the macrophage replication capacity can vary by up to 1000-fold. Some X4 viruses are also capable of replication in macrophages, indicating that cellular tropism is partially independent of co-receptor preference. Preliminary data obtained with a small number of transmitted/founder viruses indicate inefficient macrophage infection, whereas isolates from later in disease are more frequently tropic for macrophages. Thus tropism may evolve over time, and more macrophage tropic viruses may be implicated in the pathogenesis of advanced HIV-1 infection. Compartmentalization of macrophage-tropic brain-derived envelope glycoproteins (Envs), and non-macrophage tropic non-neural tissue-derived Envs points to adaptation of HIV-1 quasi-species in distinct tissue microenvironments. Mutations within and adjacent to the Env-CD4 binding site have been identified that determine macrophage tropism at the entry level, but post-entry molecular determinants of macrophage replication capacity involving HIV-1 accessory proteins need further definition.

Keywords: HIV-1; evolution; macrophage; monocyte; transmitted/founder virus; tropism.

Figure 1.

Determinants of macrophage tropism (mac-tropism) and macrophage replication capacity (MRC). Theoretical schematic representation of the interacting spectrum of HIV permissiveness between different tissues (from low to high on y-axis), and tropism of isolates from various stages of infection (from low to high on the x-axis), in determining mac-tropism and macrophage replication capacity (MRC) of isolates from various tissues. A linear relationship is entirely speculative, as indicated by the dotted line. The key molecular determinants of mac-tropism concern receptor-binding efficiency (both CD4 and chemokine co-receptor), whilst post-entry the accessory proteins (e.g., Vif, Nef, Vpu, etc.) mediate MRC. AIDS = acquired immunodeficiency syndrome.