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Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics.

ABSTRACT: Neurocognitive impairments associated with human immunodeficiency virus (HIV) infection remain a considerable health issue for almost half the people living with HIV, despite progress in HIV treatment through combination antiretroviral therapy (cART). The pathogenesis and risk factors of HIV-associated neurocognitive disorder (HAND) are still incompletely understood. This is partly due to the complexity of HAND diagnostics, as phenotypes present with high variability and change over time. Our current understanding is that HIV enters the central nervous system (CNS) during infection, persisting and replicating in resident immune and supporting cells, with the subsequent host immune response and inflammation likely adding to the development of HAND. Differences in host (human) genetics determine, in part, the effectiveness of the immune response and other factors that increase the vulnerability to HAND. This review describes findings from studies investigating the role of human host genetics in the pathogenesis of HAND, including potential risk factors for developing HAND. The similarities and differences between HAND and Alzheimer's disease are also discussed. While some specific variations in host genes regulating immune responses and neurotransmission have been associated with protection or risk of HAND development, the effects are generally small and findings poorly replicated. Nevertheless, a few specific gene variants appear to affect the risk for developing HAND and aid our understanding of HAND pathogenesis.

SUBMITTER: Olivier IS

PROVIDER: S-EPMC6274730 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics.

Olivier Ian Simon IS Cacabelos Ramón R Naidoo Vinogran V

International journal of molecular sciences 20181114 11

Neurocognitive impairments associated with human immunodeficiency virus (HIV) infection remain a considerable health issue for almost half the people living with HIV, despite progress in HIV treatment through combination antiretroviral therapy (cART). The pathogenesis and risk factors of HIV-associated neurocognitive disorder (HAND) are still incompletely understood. This is partly due to the complexity of HAND diagnostics, as phenotypes present with high variability and change over time. Our cu ...[more]

PMID: 30441796

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Project description:Human cytomegalovirus (HCMV) is a ubiquitous herpes virus (human herpes virus 5) with the highest morbidity and mortality rates compared to other herpes viruses. Risk groups include very young, elderly, transplant recipient, and immunocompromised individuals. HCMV may cause retinitis, encephalitis, hepatitis, esophagitis, colitis, pneumonia, neonatal infection sequelae, inflammatory, and age-related diseases. With an arsenal of genes in its large genome dedicated to host immune evasion, HCMV can block intrinsic cellular defenses and interfere with cellular immune responses. HCMV also encodes chemokines, chemokine receptors, and cytokines. Therefore, genes involved in human viral defense mechanisms and those encoding proteins targeted by the CMV proteins are candidates for host control of CMV infection and reactivation. Although still few in number, host genetic studies are producing valuable insights into biological processes involved in HCMV pathogenesis and HCMV-related diseases. For example, genetic variants in the immunoglobulin GM light chain can influence the antibody responsiveness to CMV glycoprotein B and modify risk of HCMV-related diseases. Moreover, CMV infection following organ transplantation has been associated with variants in genes encoding toll-like receptors (TLRs), programmed death-1 (PD-1), and interleukin-12p40 (IL-12B). A KIR haplotype (2DS4+) is proposed to be protective for CMV activation among hematopoietic stem cell transplant patients. Polymorphisms in the interferon lambda 3/4 (IFNL3/4) region are shown to influence susceptibility to CMV replication among solid organ transplant patients. Interestingly, the IFNL3/4 region is also associated with AIDS-related CMV retinitis susceptibility in HIV-infected patients. Likewise, interleukin-10 receptor 1 (IL-10R1) variants are shown to influence CMV retinitis development in patients with AIDS. Results from genome-wide association studies suggest a possible role for microtubule network and retinol metabolism in anti-CMV antibody response. Nevertheless, further genetic epidemiological studies with large cohorts, functional studies on the numerous HCMV genes, and immune response to chronic and latent states of infection that contribute to HCMV persistence are clearly necessary to elucidate the genetic mechanisms of CMV infection, reactivation, and pathogenesis.

Dataset Information

Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics.

Publications

Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics.

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