A candidate gene study of intermediate histopathological phenotypes in HIV-associated neurocognitive disorders

Abstract

HIV-associated neurocognitive disorders (HAND) describe a spectrum of neuropsychological impairment caused by HIV-1 infection. While the sequence of cellular and physiological events that lead to HAND remains obscure, it likely involves chronic neuroinflammation. Host genetic markers that increase the risk for HAND have been reported, but replication of such studies is lacking, possibly due to inconsistent application of a behavioral phenotype across studies. In the current study, we used histopathologic phenotypes in order to validate putative risk alleles for HAND. The National NeuroAIDS Tissue Consortium, a longitudinal study of the neurologic manifestations of HIV. Data and specimens were obtained from 175 HIV-infected adults. After determining several potential covariates of neurocognitive functioning, we quantified levels of six histopathological markers in the frontal lobe in association with neurocognitive functioning: SYP, MAP 2, HLA-DR, Iba1, GFAP, and β-amyloid. We then determined alleles of 15 candidate genes for their associations with neurocognitive functioning and histopathological markers. Finally, we identified the most plausible causal pathway based on our data using a multi-stage linear regression-based mediation analysis approach. None of the genetic markers were associated with neurocognitive functioning. Of the histopathological markers, only MAP 2 and SYP were associated with neurocognitive functioning; however, MAP 2 and SYP did not vary as a function of genotype. Mediation analysis suggests a causal pathway in which presynaptic degeneration (SYP) leads to somatodendritic degeneration (MAP 2) and ultimately neurocognitive impairment. This study did not support the role of host genotype in the histopathology underlying HAND. The findings lend further support for synaptodendritic degeneration as the proximal underlying neuropathological substrate of HAND.

An exploratory pilot study on the involvement of APOE, HFE, C9ORF72 variants and comorbidities in neurocognitive and physical performance in a group of HIV-infected people

“…Our work has some strengths, to our knowledge it was one of the first studies that compares genetic polymorphisms, comorbidities, HIV-related values, and neurocognitive outcomes in HIV-infected patients. Previously, several authors studied the possible correlation between genetic polymorphisms, comorbidities or HIV-related values and neurocognitive outcomes in PWH (Foley et al 2010 ; Fogel et al 2015 ; Monroe et al, 2017; Callisaya et al 2019 ; Sun et al 2020 ; Buyo et al 2020 ; Levine et al, 2020 ; Ojeda-Juarez and Kaul, 2021 ; Xu et al 2021 ; Tahmi et al 2021 ). Notwithstanding, the combination of cognitive and physical functionality with genetic, comorbidities and HIV related values has never been assessed.…”