Genetic attributes of blood-derived subtype-C HIV-1 tat and env in India and neurocognitive function

Abstract

Genetic elements in HIV-1 subtype B tat and env are associated with neurotoxicity yet less is known about other subtypes. HIV-1 subtype C tat and env sequences were analyzed to determine viral genetic elements associated with neurocognitive impairment in a large Indian cohort. Population-based sequences of HIV-1 tat (exon 1) and env (C2-V3 coding region) were generated from blood plasma of HIV-infected patients in Pune, India. Participants were classified as cognitively normal or impaired based on neuropsychological assessment. Tests for signature residues, positive and negative selection, entropy, and ambiguous bases were performed using tools available through Los Alamos National Laboratory (http://www.hiv.lanl.gov) and Datamonkey (http://www.datamonkey.org). HIV-1 subtype C tat and env sequences were analyzed for 155 and 160 participants, of which 34-36% were impaired. Two signature residues were unique to impaired participants in exon 1 of tat at codons 29 (arginine) and 68 (proline). Positive selection was noted at codon 29 among normal participants and at codon 68 in both groups. The signature at codon 29 was also a signature for low CD4+ (<200 cells/mm(3)) counts but remained associated with impairment after exclusion of those with low CD4+ counts. No unique genetic signatures were noted in env. In conclusion, two signature residues were identified in exon 1 of HIV-1 subtype C tat that were associated with neurocognitive impairment in India and not completely accounted for by HIV disease progression. These signatures support a linkage between diversifying selection in HIV-1 subtype C tat and neurocognitive impairment.

Keywords: clade C; impairment; neuropsychological testing; residue; sequence; signature.

Fig. 1

Secondary RNA structures with lowest free energy generated from consensus sequences for subjects with normal performance on neuropsychological testing with either (a) arginine or (b) lysine at codon 29. Nucleotides 121–126 code for the dicysteine motif. Similar changes were demonstrated for the impaired group at this position, although amino acid differences at codon 68 did not result in significant changes in secondary RNA structure of this region. In these examples, the amino acid at codon 68 is leucine, which was the signature for normal subjects.

Fig. 2

a: Relative amino acid frequencies at codon 29: The percentages of subtype C HIV-1 tat sequences with arginine and other amino acids at residue 29 are shown for viral sequences obtained from sub-Saharan Africa, India, and the Pune study cohort. b: Relative amino acid frequencies at codon 68: the percentages of subtype C HIV-1 tat sequences with proline and other amino acids at residue 68 are shown for viral sequences obtained from sub-Saharan Africa, India, and the Pune study cohort.