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

PLoS Pathogens

Robert W. Doms¹  Feng Gao²  Shilpa S. Iyer³  Craig B. Wilen³  Jesus F. Salazar-Gonzalez³  Julie M. Decker³  Tatenda Mahlokozera³  Anna Berg⁴  Michael P. Busch⁴  George M. Shaw⁴  Jennifer Hopper⁴  Bhavna Hora⁴  Michael R. Betts⁴  Amit Kumar⁵  Erica H. Parrish⁵  Beatrice H. Hahn⁵  Jennifer M. Pfaff⁵  Lauren B. Banks⁵  Maria G. Salazar⁵  Nicholas F. Parrish⁵  John C. Tilton⁵  Barton F. Haynes⁶  Sallie R. Permar⁷  John C. Kappes⁷  Haitao Ding⁸  David Montefiori⁸  Christina Ochsenbauer⁸  Sally Yuan⁸  Marion Vermeulen⁸  Charl Coleman⁸ 

[1] Blood Systems Research Institute, San Francisco, California, United States of America;Department of General Medical Sciences, Center for Proteomics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America;Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America;Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, United States of America;Donation Testing Department, South African National Blood Service, Roodepoort, Gauteng, South Africa;Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America

关键词: T cells;    Viral replication;    HIV-1;    Viral transmission;    infection;    Antibodies;    Cloning;    Integrins;    HIV;   

DOI  :  10.1371/journal.ppat.1002686

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY