Genetic features of cerebrospinal fluid-derived subtype B HIV-1 tat

Abstract

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.

Fig. 1

Genetic signature associated with CSF sequences. Legend. The values in parentheses are the number of instances/number of incorrect classifications. Nucleotide position (5905) is based on HXB2 position and one-letter nucleotide codes are used. Position 5905 C was associated with blood and 5905T or Y CSF.

Fig. 2

Difference in Shannon entropy between CSF- and blood-derived tat sequences Legend: Position 5905 (circle) of HIV-1 tat had the greatest difference in Shannon entropy between CSF and blood. Y axis (Entropy difference) represents the entropy difference between CSF and blood.

Fig. 3

Secondary RNA structures for wild-type tat of HIV-1 subtype B(HXB2) (A) and mutant tat with the CSF-signature synonymous mutation (C5905T) (B)