RESUMO
Since HIV-1 Tat has been associated with neurocognitive dysfunction, we investigated 60 HIV-1 subtype B-infected individuals who were characterized for neurocognitive functioning and had paired CSF and blood plasma samples available. To avoid issues with repeated sampling, we generated population-based HIV-1 tat sequences from each compartment and evaluated these data using a battery of phylogenetic, statistical, and machine learning tools. These analyses identified position HXB2 5905 within the cysteine-rich domain of tat as a signature of CSF-derived HIV-1, and a higher number of mixed bases in CSF, as measure of diversity, was associated with HIV-associated neurocognitive disorder. Since identified mutations were synonymous, we evaluated the predicted secondary RNA structures, which showed that this mutation altered secondary structure. As a measure of divergence, the genetic distance between the blood and CSF-derived tat was inversely correlated with current and nadir CD4+ T cell counts. These data suggest that specific HIV-1 features of tat influence neurotropism and neurocognitive impairment.
Assuntos
Complexo AIDS Demência/virologia , HIV-1/genética , RNA Viral/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Complexo AIDS Demência/sangue , Complexo AIDS Demência/líquido cefalorraquidiano , Adulto , Inteligência Artificial , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/patologia , Feminino , Heterogeneidade Genética , HIV-1/classificação , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Conformação de Ácido Nucleico , Estrutura Terciária de Proteína , RNA Viral/sangue , RNA Viral/líquido cefalorraquidiano , Análise de Sequência de DNA , Tropismo Viral , Produtos do Gene tat do Vírus da Imunodeficiência Humana/sangue , Produtos do Gene tat do Vírus da Imunodeficiência Humana/líquido cefalorraquidianoRESUMO
BACKGROUND: When antiretroviral therapy does not fully suppress HIV replication, suboptimal levels of antiretrovirals can select for antiretroviral resistant variants of HIV. These variants may exhibit reduced replication capacity and result in lower viral loads in blood. Our study evaluated whether antiretroviral resistance was associated with viral loads in the cerebrospinal fluid (CSF) and better neuropsychological (NP) performance. METHODS: We enrolled 94 participants and each participant underwent a comprehensive neuromedical evaluation that used structured clinical assessments of medical history, ART and other medication use, comprehensive NP testing, and neurological and general physical signs of disease. Blood was collected by venipuncture, and all participants were offered lumbar puncture. Univariate and multivariate statistical methods were used to analyze the relationship between antiretroviral resistance, blood and CSF HIV RNA levels, substance use, and NP performance. RESULTS: Antiretroviral resistance, detected in blood, was associated with lower CSF viral loads (p<0.01) and better NP performance (p=0.04) in multivariate analyses, independent of past and current ARV use and blood viral loads (model: p<0.01). However, HIV RNA levels in CSF did not independently correlate with NP performance. Low viral loads in the CSF limited our ability to investigate the relationship between antiretroviral resistance detected in CSF and NP performance. CONCLUSIONS: Even in the absence of ART, antiretroviral resistance-associated mutations correlate with better NP performance possibly because these mutations reflect reduced neurovirulence compared with wild-type HIV.