Monocyte/macrophages and their role in HIV neuropathogenesis

Abstract

Neurological sequelae of human immunodeficiency virus (HIV) infection have been and remain a significant problem. Monocytes and macrophages in humans and monkeys are susceptible to infection by HIV and simian immunodeficiency virus (SIV), and are considered to be a main mechanism by which the central nervous system (CNS) is infected. Within the infected CNS, perivascular macrophages and, in some cases, parenchymal microglia are infected as are multinucleated giant cells when present. While neurons are not themselves directly infected, neuronal damage occurs within the infected CNS. Despite the success of antiretroviral therapy (ART) in limiting virus in plasma to non-detectable levels, neurological deficits persist. This review discusses the continued neurological dysfunctions that persist in the era of ART, focusing on the roles of monocyte and macrophage as targets of continued viral infection and as agents of pathogenesis in what appears to be emergent macrophage-mediated disease resulting from long-term HIV infection of the host. Data discussed include the biology of monocyte/macrophage activation with HIV and SIV infection, traffic of cells into and out of the CNS with infection, macrophage-associated biomarkers of CNS and cardiac disease, the role of antiretroviral therapy on these cells and CNS disease, as well as the need for effective adjunctive therapies targeting monocytes and macrophages.

Fig. 1. Pathways and mechanisms of expanded monocyte/macrophage activation, turnover and accumulation in parenchymal tissues with HIV infection

1) Monocyte egress from bone marrow in response to elevated LPS, macrophage death in tissues (lymph node and parenchymal), and systemic immune activation. 2) Markers and signaling molecules involved in augmented monocyte activation and turnover, including viral proteins, acute phase proteins, immune complexes, sCD163 and signaling through LPS/CD14/TLR4 and macrophage scavenger receptor (SR-A), and expression of tissue factor (TF) and CD163. 3) Correlates of neuronal damage in the central nervous system include: activated and infected macrophages and parenchymal microglia, M1 (MAC387)/M2 (CD163) ratio, monocyte/macrophage (MΦ) accumulation, and perivascular (PV) cuffs. MNGC= multi-nucleated giant cell. 4) Pathways of cardiac pathogenesis including development of foam cells, macrophage accumulation in the intima, reduced reversed cholesterol transport, thickening of the intima-media. 5) sCD163 is a marker of HIV activity, plasma marker of non-calcified (vulnerable) cardiac plaques, and neurocognitive impairment. sCD163 has immune-suppressive functions in vitro, is elevated in macrophage mediated diseases, has a long half-life, and is therefore a stable biomarker.