The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20082831
The Journal of Experimental Medicine, Vol. 206, No. 5, 1117-1134
The Rockefeller University Press, 0022-1007 $30.00
© Keele et al.
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ARTICLE

 Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1

Brandon F. Keele1, Hui Li1, Gerald H. Learn1, Peter Hraber2, Elena E. Giorgi2,3, Truman Grayson1, Chuanxi Sun1, Yalu Chen1, Wendy W. Yeh4, Norman L. Letvin4,5, John R. Mascola5, Gary J. Nabel5, Barton F. Haynes6, Tanmoy Bhattacharya2,7, Alan S. Perelson2, Bette T. Korber2,7, Beatrice H. Hahn1, and George M. Shaw1

1 University of Alabama at Birmingham, Birmingham, AL 35223
2 Los Alamos National Laboratory, Los Alamos, NM 87545
3 University of Massachusetts, Amherst, MA 01002
4 Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115
5 Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Heath, Bethesda, MD 20892
6 Duke University Medical Center, Durham, NC 27710
7 Santa Fe Institute, Santa Fe, NM 87501

CORRESPONDENCE George M. Shaw: gshaw{at}uab.edu

We recently developed a novel strategy to identify transmitted HIV-1 genomes in acutely infected humans using single-genome amplification and a model of random virus evolution. Here, we used this approach to determine the molecular features of simian immunodeficiency virus (SIV) transmission in 18 experimentally infected Indian rhesus macaques. Animals were inoculated intrarectally (i.r.) or intravenously (i.v.) with stocks of SIVmac251 or SIVsmE660 that exhibited sequence diversity typical of early-chronic HIV-1 infection. 987 full-length SIV env sequences (median of 48 per animal) were determined from plasma virion RNA 1–5 wk after infection. i.r. inoculation was followed by productive infection by one or a few viruses (median 1; range 1–5) that diversified randomly with near starlike phylogeny and a Poisson distribution of mutations. Consensus viral sequences from ramp-up and peak viremia were identical to viruses found in the inocula or differed from them by only one or a few nucleotides, providing direct evidence that early plasma viral sequences coalesce to transmitted/founder viruses. i.v. infection was >2,000-fold more efficient than i.r. infection, and viruses transmitted by either route represented the full genetic spectra of the inocula. These findings identify key similarities in mucosal transmission and early diversification between SIV and HIV-1, and thus validate the SIV–macaque mucosal infection model for HIV-1 vaccine and microbicide research.

Abbreviations used: CI, confidence interval; HD, Hamming distance; i.r., intrarectally; MRCA, most recent common ancestor; NJ, neighbor-joining; SGA, single-genome amplification; SIV, simian immunodeficiency virus; vRNA, viral RNA.

© 2009 Keele et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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