HIV-macrophage Interactions:  Role in viral persistence

Mario Stevenson, University of Massachusetts Medical School (USA)

HIV-1 replication, as measured by steady-state levels of plasma viral RNA, is a result of the cumulative virus output from a variety of cellular reservoirs.  Most of our understanding on the dynamics of viral replication and factors which regulate viral replication are based on studies with T-cells.  Activated lymphocytes support efficient virus reproduction and the life-span of the infected cell is truncated as a consequence of viral replication.  At the opposite end of the spectrum, quiescent lymphocytes support a latent infection and long-term virus persistence.  Between these two extremes, other cells including macrophages, dendritic cells and minimally activated T-cells contribute to the ability of the virus to persist within the infected individual.  However our understanding of the roles these cells play in viral replication and persistence is unclear.  Our research focuses primarily on the role played by tissue macrophages in viral replication, persistence and pathogenicity.  We have evidence that HIV-1 alters the physiology of macrophages in a way that enhances conditions for viral replication and dissemination.  Some of the viral accessory gene products, namely Nef and Vpr, have functions that operate specifically in macrophage-lineage cells.  These accessory proteins play an important role not only in the ability of the virus to replicate within macrophages, but also help to forge connections between macrophages and T-cells that promote viral dissemination.  We also have evidence that several aspects of viral replication in macrophages are distinct to that in T-cells.  In contrast to T-cells, virions bud at intracellular endosomal membranes and accumulate within endosomal compartments.  These intracellular virions retain infectivity for prolonged periods and can be transmitted to T-cells in trans.  This represents a non-conventional reservoir for viral persistence that may promote the ability of the virus to escape immune surveillance and therapeutic intervention.