Transcriptomic and Genetic Profiling of HIV-Associated Neurocognitive Disorders

Abstract

Early in the HIV pandemic, it became evident that people living with HIV (PLWH) develop a wide range of neurological and neurocognitive complications. Even after the introduction of combination antiretroviral therapy (cART), which dramatically improved survival of PLWH, the overall number of people living with some form of HIV-associated neurocognitive disorders (HAND) seemed to remain unchanged, although the incidence of dementia declined and questions about the incidence and diagnosis of the mildest form of HAND arose. To better understand this complex disease, several transcriptomic analyses have been conducted in autopsy samples, as well as in non-human primates and small animal rodent models. However, genetic studies in the HIV field have mostly focused on the genetic makeup of the immune system. Much less is known about the genetic underpinnings of HAND. Here, we provide a summary of reported transcriptomic and epigenetic changes in HAND, as well as some of the potential genetic underpinnings that have been linked to HAND, and discuss future directions with hurdles to overcome and angles that remain to be explored.

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.…”

Discovery of long non-coding RNAs in naïve CD4+ T cells in response to initiating antiretroviral therapy at acute or chronic phase of HIV-1 infection

“…Notably, three major KEGG pathways were significantly enriched, namely, axon guidance (p-value = 0.0139), PI3K-Akt signaling pathway (p-value = 0.0398), and MAPK signaling pathway (p-value = 0.0066). Previous studies have linked impairment of host axon guidance and these signaling pathways to neurological manifestations in HIV-1 patients (Zhou et al, 2012;Scutari et al, 2017;Ojeda-Juárez and Kaul, 2021). In addition, our analysis identified terms linked to signaling pathways related to neurodegenerative diseases, including the MAPK signaling pathway, axon guidance pathway, and phosphorylative mechanism/signaling pathway.…”

Genomic Factors and Therapeutic Approaches in HIV-Associated Neurocognitive Disorders: A Comprehensive Review

“…Furthermore, genetic variants of several dopaminergic genes involved in dopamine pathways also appear to be implicated in different ways in the neurocognitive function of people living with HIV-1. Interestingly, an improvement in executive functioning in HIV-1-infected individuals is predicted by methamphetamine (Met/Met) genotype at the catechol-O-methyltransferase locus (rs4680), which is attenuated by methamphetamine abuse [ 40 ]. Moreover, DRD3 (rs6280) was associated with neurocognitive illness only among people who abuse methamphetamine [ 40 ].…”

“…Interestingly, an improvement in executive functioning in HIV-1-infected individuals is predicted by methamphetamine (Met/Met) genotype at the catechol-O-methyltransferase locus (rs4680), which is attenuated by methamphetamine abuse [ 40 ]. Moreover, DRD3 (rs6280) was associated with neurocognitive illness only among people who abuse methamphetamine [ 40 ]. However, significant main and interaction effects for DRD1 and DRD2 have also been seen in cases of substance abuse for the ‘motor domain’ of neuropsychological performance in Caucasian populations and in nearly every neuropsychological domain in Afro-American patients [ 40 ].…”

“…Moreover, DRD3 (rs6280) was associated with neurocognitive illness only among people who abuse methamphetamine [ 40 ]. However, significant main and interaction effects for DRD1 and DRD2 have also been seen in cases of substance abuse for the ‘motor domain’ of neuropsychological performance in Caucasian populations and in nearly every neuropsychological domain in Afro-American patients [ 40 ]. Nonetheless, the GWAS conducted in the longitudinal Multicentre AIDS Cohort Study found no associations with DRD2 or DRD3, although this work did not address interactions with substance or stimulant abuse.…”