HIV-1 neuroimmunity in the era of antiretroviral therapy

Abstract

Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) can affect up to 50% of infected people during the disease course. While antiretroviral therapies have substantively increased the quality of life and reduced HIV-1-associated dementia, less severe minor cognitive and motor deficits continue. Trafficking of HIV-1 into the central nervous system (CNS), peripheral immune activation, dysregulated glial immunity, and diminished homeostatic responses are the disease-linked pathobiologic events. Monocyte-macrophage passage into the CNS remains an underlying force for disease severity. Monocyte phenotypes may change at an early stage of cell maturation and immune activation of hematopoietic stem cells. Activated monocytes are pulled into the brain in response to chemokines made as a result of glial inflammatory processes, which in turn, cause secondary functional deficits in neurons. Current therapeutic approaches are focused on adjunctive and brain-penetrating antiretroviral therapies. These may attenuate virus-associated neuroinflammatory activities thereby decreasing the severity and frequency of HAND.

Figure 1

Immune competent peripheral blood monocytes derived from CD34+ hematopoietic stem cells show enhanced proliferation rates in response to HIV-1 infection and a pro-inflammatory environment. Cells are pushed into the CNS in response to activation signals. Simultaneously, infected monocytes are drawn into areas of the brain viral infection by the presence of chemokines and pro-inflammatory factors elicited as a result of HIV-1 infection and ongoing neuroinflammatory responses. Once in the brain, HIV-1 infected perivascular macrophages and microglia elicit neurotoxic effects on surrounding neurons and affect astrocyte immunity resulting in amplifications of ongoing inflammatory responses from endothelial cells, resident microglia and infiltrating blood borne monocyte-macrophages. Adaptive immunity serves in regulatory and effector functions (including HIV-1 specific CTL) in curtailing ongoing inflammatory responses and in anti-HIV-1 surveillance, respectively.