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¹ University of Alabama at Birmingham, Birmingham, AL 35294
² Los Alamos National Laboratory, Los Alamos, NM 87545
³ University of Massachusetts, Amherst, MA 01002
⁴ The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
⁵ Zambia-Emory HIV Research Project, Lusaka, Zambia
⁶ Emory University, Atlanta, GA 30329
⁷ Aaron Diamond AIDS Research Center, New York, NY 10016
⁸ The Rockefeller University, New York, NY 10065
⁹ Santa Fe Institute, Santa Fe, NM 87501
¹⁰ Duke University Medical Center, Durham, NC 27710

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

Identification of full-length transmitted HIV-1 genomes could be instrumental in HIV-1 pathogenesis, microbicide, and vaccine research by enabling the direct analysis of those viruses actually responsible for productive clinical infection. We show in 12 acutely infected subjects (9 clade B and 3 clade C) that complete HIV-1 genomes of transmitted/founder viruses can be inferred by single genome amplification and sequencing of plasma virion RNA. This allowed for the molecular cloning and biological analysis of transmitted/founder viruses and a comprehensive genome-wide assessment of the genetic imprint left on the evolving virus quasispecies by a composite of host selection pressures. Transmitted viruses encoded intact canonical genes (gag-pol-vif-vpr-tat-rev-vpu-env-nef) and replicated efficiently in primary human CD4⁺ T lymphocytes but much less so in monocyte-derived macrophages. Transmitted viruses were CD4 and CCR5 tropic and demonstrated concealment of coreceptor binding surfaces of the envelope bridging sheet and variable loop 3. 2 mo after infection, transmitted/founder viruses in three subjects were nearly completely replaced by viruses differing at two to five highly selected genomic loci; by 12–20 mo, viruses exhibited concentrated mutations at 17–34 discrete locations. These findings reveal viral properties associated with mucosal HIV-1 transmission and a limited set of rapidly evolving adaptive mutations driven primarily, but not exclusively, by early cytotoxic T cell responses.

Abbreviations used: C.I., confidence interval; HD, Hamming distance; LTR, long terminal repeat; MRCA, most recent common ancestor; p_n, nonsynonymous divergence; p_s, synonymous divergence; sCD4, soluble CD4; SGA, single genome amplification; SIV, simian immunodeficiency virus.

© 2009 Salazar-Gonzalez et al.
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The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection

Nilu Goonetilleke, Michael K.P. Liu, Jesus F. Salazar-Gonzalez, Guido Ferrari, Elena Giorgi, Vitaly V. Ganusov, Brandon F. Keele, Gerald H. Learn, Emma L. Turnbull, Maria G. Salazar, Kent J. Weinhold, Stephen Moore, CHAVI Clinical Core B, Norman Letvin, Barton F. Haynes, Myron S. Cohen, Peter Hraber, Tanmoy Bhattacharya, Persephone Borrow, Alan S. Perelson, Beatrice H. Hahn, George M. Shaw, Bette T. Korber, and Andrew J. McMichael
J. Exp. Med. 2009 206: 1253-1272. [Abstract] [Full Text] [PDF]

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