Evaluation of HIV-1 Ambiguous Nucleotide Frequency During Antiretroviral Treatment Interruption

Abstract

Nucleotide mixtures in HIV-1 population sequences reflect sequence diversity. We evaluated gag and pol ambiguous nucleotide frequencies during an analytic treatment interruption (ATI) in an HIV-1 therapeutic vaccine study. The proportion of ambiguous nucleotides was significantly higher at ATI week 16 than at either the time of first detectable viremia (P<0.001 gag and P=0.03 RT) or pre-antiretroviral therapy (P=0.007 gag). No significant differences were observed in the proportion of ambiguous nucleotides between those receiving vaccine and placebo. Increased HIV diversity during the ATI may represent a potentially higher barrier to success for a therapeutic as compared to a preventative vaccine targeting cell-mediated immunity.

HIV-1 evolution in patients undergoing immunotherapy with Tat, Rev, and Nef expressing dendritic cells followed by treatment interruption

“…The general picture, however, was that therapeutic vaccination did not result in positive selection increasing viral diversity, similar to what others reported [3,7]. Although Li et al [7] observed an increase in ambiguous bases resulting in increased epitope diversity after therapeutic vaccination, this was also found in placebo controls. Hoffmann et al…”

“…Indeed, in one DC-TRN participant studied in detail, immune escape from Rev-specific immune pressure was observed in a newly defined CTL epitope [32]. The general picture, however, was that therapeutic vaccination did not result in positive selection increasing viral diversity, similar to what others reported [3,7]. Although Li et al [7] observed an increase in ambiguous bases resulting in increased epitope diversity after therapeutic vaccination, this was also found in placebo controls.…”

“…In contrast, others reported that immunotherapy with MVA-nef was associated with a decrease in nef variability compared with control genes and patients [6]. In contrast, in a rAd5-gag immunotherapy trial, viral diversity in gag was greater during treatment interruption than pretreatment [7].…”

“…Clinical parameters such as plasma viral load, kinetics of CD4 þ T-cell counts, and time remaining off cART were not affected by vaccination, suggesting limited efficacy of the vaccine. However, immunogenic vaccines not associated with improved clinical outcome may also result in increased viral sequence divergence [7]. Immunogenicity of therapeutic vaccines is influenced by the impaired function and number of T cells in chronically HIV-infected patients [38].…”

More efficacious drugs lead to harder selective sweeps in the evolution of drug resistance in HIV-1

“…Genetic diversity may result in ambiguous calls (also referred to as mixtures) in the reported sequence, so that a signal of within-patient genetic diversity is retained even though there is only a single sequence per patient. We use the ambiguous calls to quantify within-patient genetic diversity (see Figure 1BE, grey box), following several other studies [17][18][19][20]. Although ambiguous calls are an imperfect measure of diversity, it has been shown that the signal from ambiguous calls can be reproduced between laboratories [21].…”