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The Journal of Experimental Medicine
Year: 2009  |  Volume: 206  |  Issue: 6  |  Page No.: 1273 - 1289

Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection

J. F Salazar Gonzalez, M. G Salazar, B. F Keele, G. H Learn, E. E Giorgi, H Li, J. M Decker, S Wang, J Baalwa, M. H Kraus, N. F Parrish, K. S Shaw, M. B Guffey, K. J Bar, K. L Davis, C Ochsenbauer Jambor, J. C Kappes, M. S Saag, M. S Cohen, J Mulenga, C. A Derdeyn, S Allen, E Hunter, M Markowitz, P Hraber, A. S Perelson, T Bhattacharya, B. F Haynes, B. T Korber, B. H Hahn and G. M. Shaw    

Abstract:

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.

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