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
Jesus F
JF
University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Salazar
Maria G
MG
Keele
Brandon F
BF
Learn
Gerald H
GH
Giorgi
Elena E
EE
Li
Hui
H
Decker
Julie M
JM
Wang
Shuyi
S
Baalwa
Joshua
J
Kraus
Matthias H
MH
Parrish
Nicholas F
NF
Shaw
Katharina S
KS
Guffey
M Brad
MB
Bar
Katharine J
KJ
Davis
Katie L
KL
Ochsenbauer-Jambor
Christina
C
Kappes
John C
JC
Saag
Michael S
MS
Cohen
Myron S
MS
Mulenga
Joseph
J
Derdeyn
Cynthia A
CA
Allen
Susan
S
Hunter
Eric
E
Markowitz
Martin
M
Hraber
Peter
P
Perelson
Alan S
AS
Bhattacharya
Tanmoy
T
Haynes
Barton F
BF
Korber
Bette T
BT
Hahn
Beatrice H
BH
Shaw
George M
GM
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D019143:Evolution, Molecular; D005260:Female; D016679:Genome, Viral; D015658:HIV Infections / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D016013:Likelihood Functions; D008264:Macrophages / Q000276:immunology / Q000821:virology; D008297:Male; D008962:Models, Theoretical; D009154:Mutation; D010641:Phenotype; D010802:Phylogeny; D019713:Receptors, CCR5 / Q000276:immunology; D014771:Virion / Q000235:genetics; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
D019713:Receptors, CCR5