11th Conference on Retroviruses and Opportunistic Infections San Francisco, California - February 8 - 11, 2004

Conf Retrovir Opportunistic Infect 2004 Feb 8-11;11:abstract no. 22

S D W Frost¹, T Wrin², E Paxinos², C Chappey², J Galovich², J Beauchaine², C J Petropoulos², S J Little¹, and D D Richman^1,3
1Univ. of California, San Diego, USA; ²ViroLogic Inc., South San Francisco, CA, USA; and ³San Diego VA Healthcare System, CA, USA

BACKGROUND: Little is known about the relationship between the dynamics of autologous and heterologous neutralizing antibody responses and the evolution of viral envelope in patients with recent HIV infection.

METHODS: We assayed 14 patients with recent (30 to 65 days) HIV infection for autologous and heterologous neutralizing antibody responses (mean follow-up = 523 days) using a recombinant virus assay. Population sequences of the env gene were obtained at baseline and at a mean of 318 days of follow-up from 12 patients. Clonal sequences of env were obtained from 2 patients, 1 with strong (<1:1000 dilution for 50% neutralization) and 1 with weak neutralizing antibody responses (>1:100 dilution for 50% neutralization) to their baseline virus. Neutralizing antibody responses were analyzed using nonparametric random effects models to obtain estimates of the doubling time of neutralizing antibody responses for a given viral isolate for subsequent sera and the rate of viral escape, defined in terms of the half life of neutralizing antibody responses for a given serum for subsequent viral isolates. The rate of evolution between 2 sequences was calculated as the difference between the nonsynonymous and synonymous distances, divided by the time between samples.

RESULTS: Patients showed increases in neutralizing antibody responses to autologous baseline virus, which plateaued following 1 to 2 years of infection. Heterologous responses were weaker than autologous responses and continued to rise over time. Clonal analysis of env in 2 patients showed that non-synonymous (dN) and synonymous variation (dS) between env sequences at baseline and subsequent env samples rose linearly over time. In the patient with the strongest neutralizing antibody response, dN increased faster than dS (1.3% vs. 0.3%, p<0.01) per year, while in the patient with the weakest neutralizing antibody responses, dN and dS increased at the same rate (both 0.3% per year, p>0.1). Among 12 patients, there was a positive correlation between the rate of viral escape and the rate of evolution in env (Spearman's ρ = 0.6, p<0.05). There was no correlation between genetic distance and heterologous neutralization.

CONCLUSIONS: Our data suggest that the evolution of env is driven by neutralizing antibody responses. Viral escape may account for the plateauing of neutralizing antibody responses to baseline virus. Heterologous neutralizing antibody responses may be mediated differently than autologous neutralizing antibody responses, as shown by the lack of correlation between genetic distance and heterologous neutralization, and the continued increase of heterologous responses over time since infection.

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Copyright © 2004 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.