An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

Abstract

With increasing survival of patients infected with human immunodeficiency virus type 1 (HIV-1), the manifestation of heterogeneous neurological complications is also increasing alarmingly in these patients. Currently, more than 30% of about 40 million HIV-1 infected people worldwide develop central nervous system (CNS)-associated dysfunction, including dementia, sensory, and motor neuropathy. Furthermore, the highly effective antiretroviral therapy has been shown to increase the prevalence of mild cognitive functions while reducing other HIV-1-associated neurological complications. On the contrary, the presence of neurological disorder frequently affects the outcome of conventional HIV-1 therapy. Although, both the children and adults suffer from the post-HIV treatment-associated cognitive impairment, adults, especially depending on the age of disease onset, are more prone to CNS dysfunction. Thus, addressing neurological complications in an HIV-1-infected patient is a delicate balance of several factors and requires characterization of the molecular signature of associated CNS disorders involving intricate cross-talk with HIV-1-derived neurotoxins and other cellular factors. In this review, we summarize some of the current data supporting both the direct and indirect mechanisms, including neuro-inflammation and genome instability in association with aging, leading to CNS dysfunction after HIV-1 infection, and discuss the potential strategies addressing the treatment or prevention of HIV-1-mediated neurotoxicity.

Keywords: AIDS; cognitive dysfunction; dementia; genome instability; human immunodeficiency virus type 1; neurodegeneration.

Figures

Fig. 1.

Schematic overview of HIV-1 effects in CNS. The figure illustrates the mechanisms by which HIV-1, HIV-1 proteins, and cART mediate neurotoxicity; act on endothelial cells to decrease the expression of tight junction proteins; act on microglia to promote the release of various inflammatory factors and increasing phagocytic inclusions; act on monocyte derived macrophages and astrocytes to promote the release of various cytokines that act on neurons directly. HIV-1 infected astrocytes also promote neurotoxicity by decreasing the production of growth factors and altering the glutamate homeostasis. HIV-1 viral proteins (HIV-1 Tat and gp120) and cART promote the formation of Aβ by decreasing AβPP uptake or increasing the activity of BACE or decreasing the activity of NEP and IDE. HIV-1 viral proteins are indicated in blue boxes and various antiretroviral drugs are indicated in light pink boxes. Also included are cART, combination antiretroviral therapy; MMP, matrix metalloproteinase; ROS, reactive oxygen species; ZO, zona occludens; RhoA, Ras homolog gene family, member A; ROCK, Rho-associated protein kinase; IL, interleukin; TNF, tumor necrosis factor; MCP-1, monocyte chemotactic protein 1; AβPP, amyloid-β protein precursor; LRP1, low density lipoprotein receptor-related protein 1; Aβ, amyloid-β; IFN, interferon; HSPGs, heparan sulfate proteoglycans; BACE, beta-site amyloid precursor protein cleaving enzyme; ER, endoplasmic reticulum; EFV, Efavirenz; RTV, Ritonavir; SQV, Saquinavir; 3TC, Lamivudine; IDV, Indinavir; ABC, Abacavir; NFV, Nelfinavir; NEP, Neprilysin; IDE, Insulin degrading enzyme.

Fig.2.

Schematicpresentation of HIV-associatedCNSdysfunction via genome damage. The major CNS cell populations, neurons, astrocytes and microglia, are differentially affected by HIV factors, but may involve genome damage signaling. HIV-secreted Vpr protein can cause DNA strand breaks by directly binding to the chromosome along with other endonuclease partners. Vpr can also lead to constitutive DDR (p53 and ATM) activation through SLX4, which leads to NF-kB-activation, leading to neuroinflammation and which could contribute to neuronal dysfunction and apoptosis. Another HIV protein Integrase also causes neural loss by apoptosis viaitsinteractionwithNBS1andATM.Furthermore,Vprinterferes with cell cycle in replicating pool of brain cells including neural stem cells and cycling glia arresting them at G2-phase of cell cycle, finally leading to cell death by ATR/Chk1 activation in the infected brain cells.