Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection.
The precise identification of the HIV-1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV-1 transmission and in designing effective vaccines. Here, we developed a mathematical model of random viral evolution and, together with phylogenetic tree construction, used it to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection. Viral env genes evolving from individual transmitted or founder viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence at or near the estimated time of virus transmission. Overall, 78 of 102 subjects had evidence of productive clinical infection by a single virus, and 24 others had evidence of productive clinical infection by a minimum of two to five viruses. Phenotypic analysis of transmitted or early founder Envs revealed a consistent pattern of CCR5 dependence, masking of coreceptor binding regions, and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and broadly neutralizing antibodies compared with Envs from chronically infected subjects. Low multiplicity infection and limited viral evolution preceding peak viremia suggest a finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.
Keele
Brandon F
BF
Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, AL 35223, USA.
Giorgi
Elena E
EE
Salazar-Gonzalez
Jesus F
JF
Decker
Julie M
JM
Pham
Kimmy T
KT
Salazar
Maria G
MG
Sun
Chuanxi
C
Grayson
Truman
T
Wang
Shuyi
S
Li
Hui
H
Wei
Xiping
X
Jiang
Chunlai
C
Kirchherr
Jennifer L
JL
Gao
Feng
F
Anderson
Jeffery A
JA
Ping
Li-Hua
LH
Swanstrom
Ronald
R
Tomaras
Georgia D
GD
Blattner
William A
WA
Goepfert
Paul A
PA
Kilby
J Michael
JM
Saag
Michael S
MS
Delwart
Eric L
EL
Busch
Michael P
MP
Cohen
Myron S
MS
Montefiori
David C
DC
Haynes
Barton F
BF
Gaschen
Brian
B
Athreya
Gayathri S
GS
Lee
Ha Y
HY
Wood
Natasha
N
Seoighe
Cathal
C
Perelson
Alan S
AS
Bhattacharya
Tanmoy
T
Korber
Bette T
BT
Hahn
Beatrice H
BH
Shaw
George M
GM
D016915:AIDS Vaccines / Q000276:immunology; D001483:Base Sequence; D018562:Disease Transmission, Infectious; D019143:Evolution, Molecular; D014644:Genetic Variation; D015483:HIV Antibodies / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000635:transmission* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D019713:Receptors, CCR5 / Q000378:metabolism; D017423:Sequence Analysis, RNA; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology
D016915:AIDS Vaccines; D015483:HIV Antibodies; D012367:RNA, Viral; D019713:Receptors, CCR5; D054299:env Gene Products, Human Immunodeficiency Virus