Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection

doi:10.1073/pnas.0802203105

Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection

Departments of ^aMedicine and
^mMicrobiology, University of Alabama at Birmingham, Birmingham, AL 35223;
^bTheoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545;
^cDepartment of Mathematics and Statistics, University of Massachusetts, Amherst, MA 01002;
Departments of ^dMedicine and
^gSurgery, Duke University Medical Center, Durham, NC 27710;
Departments of ^eMedicine and
^fBiochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599;
^hDepartment of Epidemiology, University of Maryland, College Park, MD 20742;
ⁱBlood Systems Research Institute and Department of Laboratory Medicine, University of California, San Francisco, CA 94118;
^jDepartment of Biostatistics and Computational Biology, University of Rochester, Rochester, NY 14642;
^kInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa; and
^lSanta Fe Institute, Santa Fe, NM 87501

Communicated by Robert C. Gallo, University of Maryland, Baltimore, MD, March 5, 2008 (received for review December 20, 2007)

Abstract

The precise identification of the HIV-1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV-1 transmission and in designing effective vaccines. Here, we developed a mathematical model of random viral evolution and, together with phylogenetic tree construction, used it to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection. Viral env genes evolving from individual transmitted or founder viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence at or near the estimated time of virus transmission. Overall, 78 of 102 subjects had evidence of productive clinical infection by a single virus, and 24 others had evidence of productive clinical infection by a minimum of two to five viruses. Phenotypic analysis of transmitted or early founder Envs revealed a consistent pattern of CCR5 dependence, masking of coreceptor binding regions, and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and broadly neutralizing antibodies compared with Envs from chronically infected subjects. Low multiplicity infection and limited viral evolution preceding peak viremia suggest a finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.

Footnotes

ⁿTo whom correspondence should be addressed. E-mail: gshaw{at}uab.edu
Author contributions: B.F.K. and E.E.G. contributed equally to this work; B.F.K., J.F.S.-G., J.M.D., K.T.P., M.G.S., C. Sun, T.G., S.W., H.L., X.W., C.J., J.L.K., F.G., J.A.A., L.-H.P., R.S., G.D.T., W.A.B., P.A.G., J.M.K., M.S.S., E.L.D., M.P.B., M.S.C., D.C.M., B.F.H., B.H.H., and G.M.S. performed research; E.E.G., B.G., G.S.A., H.Y.L., N.W., C. Seoighe, A.S.P., T.B., and B.T.K. contributed new reagents/analytic tools; and B.F.K., E.E.G., R.S., B.F.H., C. Seoighe, A.S.P., T.B., B.T.K., B.H.H., and G.M.S. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. EU574937–EU579293).
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