New Challenges of HIV-1 Infection: How HIV-1 Attacks and Resides in the Central Nervous System

Abstract

Acquired immunodeficiency syndrome (AIDS) has become one of the most devastating pandemics in recorded history. The main causal agent of AIDS is the human immunodeficiency virus (HIV), which infects various cell types of the immune system that express the CD4 receptor on their surfaces. Today, combined antiretroviral therapy (cART) is the standard treatment for all people with HIV; although it has improved the quality of life of people living with HIV (PLWH), it cannot eliminate the latent reservoir of the virus. Therefore HIV/AIDS has turned from a fatal disease to a chronic disease requiring lifelong treatment. Despite significant viral load suppression, it has been observed that at least half of patients under cART present HIV-associated neurocognitive disorders (HAND), which have been related to HIV-1 infection and replication in the central nervous system (CNS). Several studies have focused on elucidating the mechanism by which HIV-1 can invade the CNS and how it can generate the effects seen in HAND. This review summarizes the research on HIV-1 and its interaction with the CNS with an emphasis on the generation of HAND, how the virus enters the CNS, the relationship between HIV-1 and cells of the CNS, and the effect of cART on these cells.

Keywords: AIDS; CNS; CNS cells; HAND; HIV-1; cART.

Figure 1

Entry of human immunodeficiency virus (HIV)-1 into the central nervous system and its effects on cells that lead to damage and death of neurons. (1) HIV-1 can enter through monocytes or infected T cells that migrate from the bloodstream to the central nervous system (CNS) (Trojan horse theory). (2) The increase in pro-inflammatory cytokines and viral proteins can alter the permeability of the epithelial cells of the blood–brain barrier, making virus entry easier. In addition, the virus can use infected epithelial cells and reach the other side through transcytosis. (3) Reactive astrocytes can induce epithelial cell apoptosis, contributing to the modification of the permeability of the blood–brain barrier through the release of viral proteins such as Tat. (4) The viral protein Tat has a direct effect on oligodendrocytes and neurons, which produce increased damage and neuronal death. Chronic activation of activated (5) microglia and (6) macrophages generates an increase in the levels of proinflammatory cytokines, neurotoxins, reactive oxygen species (ROS), and reactive nitrogen species (RNS) (created with BioRender).