Transmitted/founder and chronic subtype C HIV-1 use CD4 and CCR5 receptors with equal efficiency and are not inhibited by blocking the integrin α4β7.
Sexual transmission of human immunodeficiency virus type 1 (HIV-1) most often results from productive infection by a single transmitted/founder (T/F) virus, indicating a stringent mucosal bottleneck. Understanding the viral traits that overcome this bottleneck could have important implications for HIV-1 vaccine design and other prevention strategies. Most T/F viruses use CCR5 to infect target cells and some encode envelope glycoproteins (Envs) that contain fewer potential N-linked glycosylation sites and shorter V1/V2 variable loops than Envs from chronic viruses. Moreover, it has been reported that the gp120 subunits of certain transmitted Envs bind to the gut-homing integrin α4β7, possibly enhancing virus entry and cell-to-cell spread. Here we sought to determine whether subtype C T/F viruses, which are responsible for the majority of new HIV-1 infections worldwide, share biological properties that increase their transmission fitness, including preferential α4β7 engagement. Using single genome amplification, we generated panels of both T/F (n = 20) and chronic (n = 20) Env constructs as well as full-length T/F (n = 6) and chronic (n = 4) infectious molecular clones (IMCs). We found that T/F and chronic control Envs were indistinguishable in the efficiency with which they used CD4 and CCR5. Both groups of Envs also exhibited the same CD4+ T cell subset tropism and showed similar sensitivity to neutralization by CD4 binding site (CD4bs) antibodies. Finally, saturating concentrations of anti-α4β7 antibodies failed to inhibit infection and replication of T/F as well as chronic control viruses, although the growth of the tissue culture-adapted strain SF162 was modestly impaired. These results indicate that the population bottleneck associated with mucosal HIV-1 acquisition is not due to the selection of T/F viruses that use α4β7, CD4 or CCR5 more efficiently.
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Nicholas F
NF
Parrish
Craig B
CB
Wilen
Lauren B
LB
Banks
Shilpa S
SS
Iyer
Jennifer M
JM
Pfaff
Jesus F
JF
Salazar-Gonzalez
Maria G
MG
Salazar
Julie M
JM
Decker
Erica H
EH
Parrish
Anna
A
Berg
Jennifer
J
Hopper
Bhavna
B
Hora
Amit
A
Kumar
Tatenda
T
Mahlokozera
Sally
S
Yuan
Charl
C
Coleman
Marion
M
Vermeulen
Haitao
H
Ding
Christina
C
Ochsenbauer
John C
JC
Tilton
Sallie R
SR
Permar
John C
JC
Kappes
Michael R
MR
Betts
Michael P
MP
Busch
Feng
F
Gao
David
D
Montefiori
Barton F
BF
Haynes
George M
GM
Shaw
Beatrice H
BH
Hahn
Robert W
RW
Doms
D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism / Q000635:transmission*; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D009092:Mucous Membrane / Q000821:virology; D009500:Neutralization Tests; D019713:Receptors, CCR5 / Q000378:metabolism*; D056189:Viral Tropism; D053586:Virus Internalization; D014779:Virus Replication
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D016023:Integrins; D019713:Receptors, CCR5; C514793:gp120 protein, Human immunodeficiency virus 1; C071777:integrin alpha4beta7