Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection

doi:10.1073/pnas.0504658102

Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection

^*Departments of Pathology and Medicine, University of California at San Diego, La Jolla, CA 92093-0679; ^‡Monogram Biosciences, Inc., 345 Oyster Point Boulevard, South San Francisco, CA 94080; and ^§Veterans Affairs San Diego Healthcare System, San Diego, CA 92161

Edited by Malcolm A. Martin, National Institute of Allergy and Infectious Diseases, Bethesda, MD (received for review June 17, 2005)

Abstract

HIV type 1 (HIV-1) can rapidly escape from neutralizing antibody responses. The genetic basis of this escape in vivo is poorly understood. We compared the pattern of evolution of the HIV-1 env gene between individuals with recent HIV infection whose virus exhibited either a low or a high rate of escape from neutralizing antibody responses. We demonstrate that the rate of viral escape at a phenotypic level is highly variable among individuals, and is strongly correlated with the rate of amino acid substitutions. We show that dramatic escape from neutralizing antibodies can occur in the relative absence of changes in glycosylation or insertions and deletions (“indels”) in the envelope; conversely, changes in glycosylation and indels occur even in the absence of neutralizing antibody responses. Comparison of our data with the predictions of a mathematical model support a mechanism in which escape from neutralizing antibodies occurs via many amino acid substitutions, with low cross-neutralization between closely related viral strains. Our results suggest that autologous neutralizing antibody responses may play a pivotal role in the diversification of HIV-1 envelope during the early stages of infection.

Footnotes

↵ † To whom correspondence should be addressed. E-mail: sdfrost{at}ucsd.edu.
Author contributions: S.D.W.F., C.J.P., S.J.L., and D.D.R. designed research; S.D.W.F., T.W., D.M.S., S.L.K.P., Y.L., E.P., C.C., J.G., and J.B. performed research; S.D.W.F., T.W., S.L.K.P., and C.C. contributed new reagents/analytic tools; S.D.W.F., E.P., and C.C. analyzed data; and S.D.W.F. wrote the paper.
This work was presented in part at the 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, February 8–11, 2004.
Conflict of interest statement: D.D.R. is on the Scientific Advisory Board of Monogram Biosciences, Inc., who performed the neutralization assays and sequencing, and S.D.W.F. is a consultant for Monogram Biosciences, Inc.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: PNGS, potential N-linked glycosylation sites; nAb, neutralization antibody.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. DQ296677–DQ297052).
Freely available online through the PNAS open access option.