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 Pathog. 2012;8(5):e1002686. doi: 10.1371/journal.ppat.1002686. Epub 2012 May 31.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology
  • CD4 Antigens / metabolism*
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology
  • Cells, Cultured
  • Cloning, Molecular
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / immunology
  • HIV Envelope Protein gp120 / metabolism
  • HIV Infections / metabolism
  • HIV Infections / transmission*
  • HIV-1 / immunology
  • HIV-1 / metabolism
  • HIV-1 / pathogenicity*
  • Host-Pathogen Interactions
  • Humans
  • Integrins / immunology
  • Integrins / metabolism*
  • Mucous Membrane / virology
  • Neutralization Tests
  • Receptors, CCR5 / metabolism*
  • Viral Tropism
  • Virus Internalization
  • Virus Replication

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • CD4 Antigens
  • HIV Envelope Protein gp120
  • Integrins
  • Receptors, CCR5
  • gp120 protein, Human immunodeficiency virus 1
  • integrin alpha4beta7