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

Academic Article

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.
  • Published In

    Keywords

  • CD4-Positive T-Lymphocytes, Evolution, Molecular, Female, Genome, Viral, HIV Infections, HIV-1, Humans, Likelihood Functions, Macrophages, Male, Models, Theoretical, Mutation, Phenotype, Phylogeny, Receptors, CCR5, Virion, Virus Replication
  • Digital Object Identifier (doi)

    Author List

  • Salazar-Gonzalez JF; Salazar MG; Keele BF; Learn GH; Giorgi EE; Li H; Decker JM; Wang S; Baalwa J; Kraus MH
  • Start Page

  • 1273
  • End Page

  • 1289
  • Volume

  • 206
  • Issue

  • 6