Genetic variation and HIV-associated neurologic disease

Abstract

HIV-associated neurologic disease continues to be a significant complication in the era of highly active antiretroviral therapy. A substantial subset of the HIV-infected population shows impaired neuropsychological performance as a result of HIV-mediated neuroinflammation and eventual central nervous system (CNS) injury. CNS compartmentalization of HIV, coupled with the evolution of genetically isolated populations in the CNS, is responsible for poor prognosis in patients with AIDS, warranting further investigation and possible additions to the current therapeutic strategy. This chapter reviews key advances in the field of neuropathogenesis and studies that have highlighted how molecular diversity within the HIV genome may impact HIV-associated neurologic disease. We also discuss the possible functional implications of genetic variation within the viral promoter and possibly other regions of the viral genome, especially in the cells of monocyte-macrophage lineage, which are arguably key cellular players in HIV-associated CNS disease.

Figure 6.1

Model of HIV trafficking across the BBB and its impact on the CNS. (1) Infected, activated monocytes transport HIV across the BBB through a “Trojan Horse” model, where they differentiate into perivascular macrophages. Infected perivascular macrophages then result in production of HIV within the CNS. (2) To a lesser extent, infected CD4⁺T cells also serve to carry HIV across the BBB and may also contribute to HIV pools within the CNS. (3) HIV produced in the CNS can result in infection of resident microglial cells. (4) The presence of multinucleate giant cells is an important feature of HIV-related brain pathology; these are produced as a result of cell-to-cell fusion. (5) Astrocytes are known to harbor HIV, but it is well established that they do not result in a productive infection. (6) The viral evolution and adaptation within the CNS adversely affect the physiology of neurons via a variety of mediators including ROS, nitrous oxide (NO), MMPs, and viral proteins that exhibit neurotoxic properties resulting in compromised neurologic functions.

Figure 6.2

Potential pathways and mediators of CNS damage. Subsequent to neuroinvasion, HIV-1-infected perivascular macrophages and brain microglial cells are likely to be the major producers of infectious virus and neurotoxic cellular and viral proteins such as gp120, Tat, and Nef. The extent of CNS dysfunction observed during HIV-1 infection is likely due to both host and viral factors. CNS damage may occur through increased viral replication within the CNS, production of viral neurotoxic proteins, and release of toxins including NO, TNF-α, and quinolinic acid, all of which target neurons, astrocytes, endothelial cells, and oligodendrocytes (not shown).

Figure 6.3

The dynamic interplay of multiple viral and host factors contributes to both the onset and severity of HIV-1-associated neurocognitive impairment. An individual’s HAART (highly active antiretroviral drug) and/or drugs of abuse status, as well as the presence of comorbidities resulting from opportunistic pathogens, greatly influence overall disease course and the establishment of central nervous system (CNS) pathology. One major complicating factor with respect to HIV-1-induced neurodegeneration is the ability of HIV-1 to adapt and evolve specific genetic variants in response to host immune pressures and subsequently to increase in its capacity to replicate within specific tissue compartments such as the CNS. This ability of HIV to evolve within the CNS eventually manifests as a variety of neurologic symptoms including asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia.