Genetic Characterization of HIV-1 tat Gene from Virologically Controlled Aging Individuals with HIV on Long-Term Antiretroviral Therapy.

Abstract

Despite advancements in antiretroviral therapy (ART) that reduces the viral load to undetectable levels and improve CD4 T cell counts, viral eradication has not been achieved due to HIV-1 persistence in resting CD4⁺ T-cells. We, therefore, characterized the tat gene, which is essential for HIV-1 replication and pathogenesis, from 20 virologically controlled aging individuals with HIV (HIV⁺) on long-term ART and improved CD4⁺ T-cell counts, with a particular focus on older individuals. Peripheral blood mononuclear cell genomic DNA from HIV⁺ were used to amplify tat gene by polymerase chain reaction followed by nucleotide sequencing and analysis. Phylogenetic analysis showed that each HIV⁺ tat sequences were confined to their own subtrees and well discriminated from other HIV⁺ sequences. Moreover, there was a low degree of viral heterogeneity and lower estimates of genetic diversity within these individuals' tat sequences, which decreased with increasing CD4 T counts in these HIV⁺. Most HIV⁺ Tat deduced amino acid sequences showed intact open reading frames and maintained the important functional domains for Tat functions, including transactivation, TAR binding, and nuclear localization. Furthermore, Tat-deduced amino acid sequences showed variation in previously characterized cytotoxic T lymphocytes (CTL) epitopes, suggesting escape mutants. In conclusion, a low degree of genetic variability and conservation of functional domains and variations in CTL epitopes were the features of tat sequences that may be contributing to viral persistence in these 20 aging individuals with HIV on long-term ART.