Crucial Role of Central Nervous System as a Viral Anatomical Compartment for HIV-1 Infection

Abstract

The chronic infection established by the human immunodeficiency virus 1 (HIV-1) produces serious CD4+ T cell immunodeficiency despite the decrease in HIV-1 ribonucleic acid (RNA) levels and the raised life expectancy of people living with HIV-1 (PLWH) through treatment with combined antiretroviral therapies (cART). HIV-1 enters the central nervous system (CNS), where perivascular macrophages and microglia are infected. Serious neurodegenerative symptoms related to HIV-associated neurocognitive disorders (HAND) are produced by infection of the CNS. Despite advances in the treatment of this infection, HAND significantly contribute to morbidity and mortality globally. The pathogenesis and the role of inflammation in HAND are still incompletely understood. Principally, growing evidence shows that the CNS is an anatomical reservoir for viral infection and replication, and that its compartmentalization can trigger the evolution of neurological damage and thus make virus eradication more difficult. In this review, important concepts for understanding HAND and neuropathogenesis as well as the viral proteins involved in the CNS as an anatomical reservoir for HIV infection are discussed. In addition, an overview of the recent advancements towards therapeutic strategies for the treatment of HAND is presented. Further neurological research is needed to address neurodegenerative difficulties in people living with HIV, specifically regarding CNS viral reservoirs and their effects on eradication.

Keywords: HAND; central nervous system; human immunodeficiency virus; reservoir.

Figure 1

The mechanisms of HIV infection within the CNS. (A, B, C) HIV-1 enters the CNS through diverse pathways: (A) the Trojan horse process through which HIV-1-infected monocytes pass across the BBB and differentiate into perivascular macrophages; (B) the transfer into the CNS of HIV-1-infected CD4+ T cells; (C) entry into brain is possible in a direct way provided their is raised permeability, owing to dysfunctions and/or modified tissue. (D) Microglia, neurons, and astrocytes are the CNS-resident cells vulnerable to HIV-1 infection. Cell activation plays an important role in the release of proinflammatory cytokines and can increase changes in and the permeability of the BBB, thus helping the development of neuro-invasion of HIV and other viruses.

Figure 2

Infections, acute and chronic, by T-tropic CCR5-using (R5) viruses proceed in the systemic circulation. Populations of macrophage (M)-tropic HIV-1, which do not need high CD4 levels to infect cells and can proliferate within the brain in macrophages and other cells, are the second and more pathogenic type of compartmentalized infection related to HAD. Independent evolution happens at the systemic level with the development of CXCR4-using (X4) viruses; this is related to low blood CD4 cells and rapid advancement and may be shown in CSF.