Abstract
The Val158Met (rs4680) single-nucleotide polymorphism (SNP) of the catechol-O-methyltransferase gene (COMT) influences executive function and prefrontal function through its effect on dopamine (DA) metabolism. Both HIV and the Val allele of the Val158Met SNP are associated with compromised executive function and inefficient prefrontal function. The present study used behavioral and neuroimaging techniques to determine independent and interactive associations between HIV serostatus and COMT genotype on working memory and prefrontal function in women. For the behavioral study, 54 HIV-infected and 33 HIV-uninfected women completed the 0-, 1-, and 2-back conditions of the verbal N-back, a working memory test. For the imaging study, 36 women (23 HIV-infected, 13 HIV-uninfected) underwent functional magnetic resonance imaging (fMRI) assessments while completing the N-back task. HIV-infected women demonstrated significantly worse N-back performance compared with HIV-uninfected women (p < 0.05). A significant serostatus by genotype interaction (p < 0.01) revealed that, among Val/Val, but not Met allele carriers, HIV-infected women performed significantly worse than HIV-uninfected controls across N-back conditions (p < 0.01). Analogous to behavioral findings, a serostatus by genotype interaction revealed that HIV-infected Val/Val carriers showed significantly greater prefrontal activation compared with HIV-uninfected Val/Val carriers (p < 0.01). Conversely, HIV-uninfected Met allele carriers demonstrated significantly greater prefrontal activation compared with HIV-infected Met allele carriers. Findings suggest that the combination of HIV infection and the Val/Val COMT genotype leads to working memory deficits and altered prefrontal function in HIV-infected individuals.
Highlights
HIV targets the central nervous system within days after infection, which leads to neurological, behavioral, and cognitive complications (Brew et al, 1988; Grant et al, 1989; McArthur, 1994)
The same Met allele frequency difference was previously found in comparisons between HIV-infected and uninfected women in the general Women’s Interagency HIV Study (WIHS) population (Sundermann et al, 2013) demonstrating that this Met allele imbalance between serostatus groups generalizes to a population of multi-racial, low-income women and is not a sampling bias within this subsample
These findings occurred across N-back conditions, suggesting that, together, HIV serostatus and Val/Val genotype negatively affects attentional processes, short-term memory, and more complex updating and temporal indexing components of working memory
Summary
HIV targets the central nervous system within days after infection, which leads to neurological, behavioral, and cognitive complications (Brew et al, 1988; Grant et al, 1989; McArthur, 1994). The Val158Met (rs4680) single nucleotide polymorphism (SNP) of the COMT gene influences the activity and thermal stability of the COMT enzyme (Lachman et al, 1996), whereby Met/Met homozygotes have approximately one quarter of the enzyme activity compared to the Val/Val genotype (Bilder et al, 2004) This reduction in COMT activity results in slower DA breakdown and increased synaptic DA availability, in the PFC (Chen et al, 2004; Lotta et al, 1995). Healthy adults and individuals with schizophrenia, Val/Val participants demonstrate poorer performance on executive function tasks, including working memory (Egan et al, 2001; Goldberg et al, 2003; Minzenberg et al, 2006), suggesting that for those groups, the lower levels of prefrontal DA associated with the Val/Val genotype results in suboptimal levels that fall to the left of the peak. Based on the assumption that HIV-infected individuals with the Val/Val genotype have suboptimal DA levels that fall to the left of the peak, we hypothesized that the Val/Val genotype would compound the negative effect of HIV on working memory such that HIV-infected Val/Val carriers would show the worst accuracy and the greatest PFC activation overall
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