Neuroimmune Cross Talk and HIV-Associated Neurocognitive Disorders

Abstract

Human immunodeficiency virus (HIV) infection is a global and devastating epidemic effecting the health, well-being, and social fabric of many of the world’s populations. UNAIDS estimates that 34 million people are infected with HIV with 2.7 million new infections yearly. The majority of infections are in sub-Saharan Africa (http://www.who.int/hiv/data/en/). Viral infection is persistent despite vigorous host immune responses [1–6]. HIV enters its CD4+ T lymphocyte, and mononuclear phagocyte (MP; dendritic cells, monocytes, macrophages, and microglial cells) targets through cell surface interaction of its envelope protein, gp120, with its CD4 and chemokine receptor/co-receptors, CCR5 and CXCR4 [7–11]. Following cell entry, HIV RNA is reverse transcribed and integrated into the host cell’s genome. Transcription of viral genes is controlled by interactions between HIV-1 regulatory proteins and host cell transcription factors such as nuclear factor kappa beta (NF-κB) [12–15]. Viral assembly proceeds at the cell surface or in subcellular organelles and the viral RNA encapsulated by interactions with Gag, GagPol, and envelope proteins, with subsequent viral budding and release of mature virions [16–23]. Ongoing HIV infection results in profound CD4+ T cell losses with consequent immune impairments resulting in a range of opportunistic infections, metabolic disorders, and malignancies [3, 5, 24–26]. Less appreciated are primary manifestations of viral replication that include its effects on the central nervous system (CNS) [27–29]. Indeed, although HIV primarily affects immune function and integrity [3, 24–26], virus-associated effects on the nervous system are a significant cause of comorbidity during the course of disease [27, 29, 30]. Prior to the introduction of combination antiretroviral therapy (cART), opportunistic infections (OIs) and advanced cognitive, motor, and behavioral abnormalities commonly occurred as HIV disease advanced and was associated with virus-induced progressive immunosuppression. While cART has reduced the prevalence of OIs along with severity of virus-induced nervous system disorders, both remain active albeit less severe [27].