Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection.
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.
Salazar-Gonzalez, JF; Salazar, MG; Keele, BF; Learn, GH; Giorgi, EE; Li, H; Decker, JM; Wang, S; Baalwa, J; Kraus, MH; Parrish, NF; Shaw, KS; Guffey, MB; Bar, KJ; Davis, KL; Ochsenbauer-Jambor, C; Kappes, JC; Saag, MS; Cohen, MS; Mulenga, J; Derdeyn, CA; Allen, S; Hunter, E; Markowitz, M; Hraber, P; Perelson, AS; Bhattacharya, T; Haynes, BF; Korber, BT; Hahn, BH; Shaw, GM
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