[26] HIV-1 ENVELOPE GENE EVOLUTION IS DRIVEN BY STRONG NEUTRALIZING ANTIBODY SELECTION

2nd International AIDS Society Conference on HIV Pathogenesis and Treatment

Paris, France - July 13 - 16, 2003

[TITLE:] HIV-1 ENVELOPE GENE EVOLUTION IS DRIVEN BY STRONG NEUTRALIZING ANTIBODY SELECTION

[AUTHOR(S):] EE Paxinos¹, T Wrin¹, J Galovich¹, J Beauchaine¹, S Little², DD Richman² and CJ Petropoulos¹
¹ ViroLogic Inc., South San Francisco, CA, USA; and ² VA San Diego Healthcare System and UC San Diego, San Diego, CA, USA

IAS Conf HIV Pathog Treat 2003 Jul 13-16;2nd: Abstract No. 26
Antiviral Therapy 2003; 8(Suppl. 1):S191

[ABSTRACT:] Background: Recently, we reported strong neutralizing antibody (NA) responses in subjects presenting with recent HIV-1 infection (Richman et al., PNAS 2003, 7:4144–4149). A longitudinal evaluation of plasma virus revealed the continuous emergence of neutralization resistant variants consistent with strong selective pressure. We concluded that NA responses drive extensive variation in the envelope (env) gene following primary HIV infection. In the current study, we compare env gene evolution in response to strong and weak NA pressure.

Study Design: Subjects were diagnosed with recent HIV infection (AEIDRP). Sequential virus populations were selected for analysis based on NA titers directed at the autologous virus. Subject TN-1 mounted strong NA responses [IC₅₀(1:3000)] whereas the NA responses in subject TN-2 were weak or absent (IC₅₀<100). env nucleotide sequences were determined for 72 TN-1 virus clones representing 8 timepoints (>2 years) and 133 TN-2 virus clones representing 13 timepoints (>3 years). env (gp160) sequences were determined using GeneSeq [HIV (ViroLogic)].

Results: TN-1 virus populations were largely monophyletic. env clone sequences (terminal taxa) from individual timepoints shared a common ancestor, suggesting successive virus populations were derived from a subset of the previous virus population. The pattern was consistent with a small effective population size. TN-1 env sequences from sequential timepoints diverged rapidly from the ancestral sequence in a temporally linear fashion, implying that selection was strong and relatively constant through time. In contrast, TN-2 env clones from multiple timepoints clustered and shared ancestry across sampling dates. TN-2 env clones from distinct timepoints were intercalated throughout the phylogeny and the genetic diversity of the pool was maintained through time, suggesting a large effective population size and little or no selection or drift.

Conclusions: These findings support our hypothesis that rapid evolution of the HIV env gene following primary infection occurs in response to strong NA selective pressure and that env sequence divergence over time reflects the continual emergence of NA resistant escape variants.

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