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|Publication Abstract Display|
|Title: Viral signatures in HIV-1 subtype C tat are associated with neurocognitive impairment in an Indian cohort.|
|Authors: Tilghman MW, Deshpande S, Battacharya J, Ghate M, Marcotte T, Smith D, Mehendale S|
|Abstract:Background: Genetic elements within the HIV-1 subtype B tat and env coding regions are associated with neurotropism and neurotoxicity, yet less is known about other subtypes. We analyzed HIV-1 subtype C tat and env sequences to determine viral genetic elements associated with neurocognitive impairment in a large well-characterized (n=171) Indian cohort.
Methods: Population-based sequences of HIV-1 tat exon 1 and the C2-V3 coding region of env were generated from blood plasma of HIV-infected patients in Pune, India. Sequences were screened for infecting HIV-1 subtype and contamination (http://www.hiv.lanl.gov). Subjects underwent detailed neuropsychological (NP) assessment that was validated in the Marathi-speaking population of Pune. Subjects were classified as cognitively normal or impaired based upon demographically-adjusted NP test norms. Tests for signature residues, positive and negative selection, site-specific variability as measured by Shannon entropy, N-glycosylation sites, and ambiguous bases were performed using tools available through LANL and Datamonkey (http://www.datamonkey.org). Fisher’s exact test or chi square analysis and independent t-tests or Mann-Whitney U tests were used for comparison of categorical and continuous variables between groups, adjusted for repeat testing.
Results: HIV-1 subtype C tat and env sequences were analyzed for 163 and 171 subjects respectively, of which 33% were NP impaired. Current CD4 counts of NP normal subjects were on average 68 cells/μL higher than those of impaired subjects (p<0.05); otherwise, clinical and demographic variables were similar between groups. Two signature residues were unique to impaired subjects in exon 1 of tat at codons 29 (arginine) and 68 (proline). Positive selection was noted at codon 29 among normal subjects, primarily for amino acids other than arginine. At codon 68, positive selection for and against proline occurred at equal rates in both groups. These signatures were not associated with CD4 counts or viral loads. No significant viral sequence differences were noted in env between normal and impaired subjects.
Conclusions: In this large sample, two signature residues were identified in exon 1 of HIV-1 subtype C tat that were associated with neurocognitive impairment in India and unrelated to HIV disease progression. No signature was found in env. These signatures support a role for HIV-1 tat in neurotoxicity of HIV-1 subtype C.|
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