title: Phenotypic and immunologic comparison of clade B transmitted/founder and chronic HIV-1 envelope glycoproteins.
abstract: Sexual transmission of human immunodeficiency virus type 1 (HIV-1) across mucosal barriers is responsible for the vast majority of new infections. This relatively inefficient process results in the transmission of a single transmitted/founder (T/F) virus, from a diverse viral swarm in the donor, in approximately 80% of cases. Here we compared the biological activities of 24 clade B T/F envelopes (Envs) with those from 17 chronic controls to determine whether the genetic bottleneck that occurs during transmission is linked to a particular Env phenotype. To maximize the likelihood of an intact mucosal barrier in the recipients and to enhance the sensitivity of detecting phenotypic differences, only T/F Envs from individuals infected with a single T/F variant were selected. Using pseudotyping to assess Env function in single-round infectivity assays, we compared coreceptor tropism, CCR5 utilization efficiencies, primary CD4(+) T cell subset tropism, dendritic cell trans-infections, fusion kinetics, and neutralization sensitivities. T/F and chronic Envs were phenotypically equivalent in most assays; however, T/F Envs were modestly more sensitive to CD4 binding site antibodies b12 and VRC01, as well as pooled human HIV Ig. This finding was independently validated with a panel of 14 additional chronic HIV-1 Env controls. Moreover, the enhanced neutralization sensitivity was associated with more efficient binding of b12 and VRC01 to T/F Env trimers. These data suggest that there are subtle but significant structural differences between T/F and chronic clade B Envs that may have implications for HIV-1 transmission and the design of effective vaccines.
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Wilen
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Parrish
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Pfaff
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Henning
authors.forename: Hillel
authors.initials: H
authors.lastname: Haim
authors.forename: Josiah E
authors.initials: JE
authors.lastname: Petersen
authors.forename: Jason A
authors.initials: JA
authors.lastname: Wojcechowskyj
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: John C
authors.initials: JC
authors.lastname: Tilton
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Robert W
authors.initials: RW
authors.lastname: Doms
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D003713:Dendritic Cells / Q000821:virology; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000276:immunology* / Q000302:isolation & purification / Q000472:pathogenicity*; D006801:Humans; D008297:Male; D056189:Viral Tropism; D053586:Virus Internalization; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology* / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus