Project

Determining the Role of Integrins in HIV Transmission Across the Mucosa

Council researchers are studying the role of integrin alpha-4 beta-7, a molecule expressed on immune cells in mucosal tissues, in vaginal and rectal HIV infection.

The Issue

HIV transmission during sexual intercourse is incompletely understood. However, several factors are known to facilitate infection, including viral load (the level of HIV in an infected person’s blood), inflammation caused by sexually transmitted diseases, and breaks in the vaginal epithelium.

But what are the factors in otherwise healthy people that make them more susceptible to infection?

The discovery of a cell surface receptor called integrin alpha-4 beta-7 may provide one answer. Integrin alpha-4 beta-7 is a receptor on the surface of immune cells that is necessary for the movement of immune cells to the gut. HIV may bind to this receptor and exploit it so it can be transported rapidly from the vaginal and rectal tissues to the lymph nodes and gut, where HIV can replicate quickly and disseminate.

The Progress

Researchers at the Council’s Center for Biomedical Research are exploring the role of integrin alpha-4 beta-7 in HIV sexual transmission. Researchers are using macaque models of HIV transmission to:

  • Examine factors that may increase the amount of integrin alpha-4 beta-7 in rectal and vaginal tissues and thus increase susceptibility to infection;
  • Develop strategies or interventions that prevent HIV from attaching to integrin alpha-4 beta-7 and alpha-4 beta-7-expressing immune cells from going to the gut and lymph nodes and determine whether susceptibility to infection is thereby decreased; and
  • Compare the ability of different strains of HIV to bind to integrin alpha-4 beta-7 and test their ability to infect the vaginal and rectal mucosa.

While investigating why infection with herpes simplex virus 2 (HSV-2) increases susceptibility to HIV infection in the absence of breaks in the vaginal epithelium and inflammation, Council researchers have found that animals rectally infected with HSV-2 have more alpha-4 beta-7-expressing immune cells in the rectum and blood than animals who are not infected with HSV-2. Research is determining whether the same hypothesis holds true for immune cells in the vagina of HSV-2 vaginally infected macaques and in vaginal tissues infected with HSV-2 ex vivo (i.e., relatively intact body tissues studied in an external environment).

Researchers are testing the ability of certain drugs to block HIV from binding to integrin alpha-4 beta-7 and to inhibit alpha-4 beta-7-expressing immune cells from going to the gut to determine whether susceptibility to infection is decreased. The drugs being tested are similar to those used to treat inflammatory bowel diseases. If the drugs successfully block HIV’s pathway to the gut, then the major insult to the immune system will be prevented, and HIV may be stopped from spreading systemically.

Future studies include investigating strains of the simian version of HIV that bind more effectively to integrin alpha-4 beta-7 and comparing them with strains of the virus that bind less effectively to determine which strains have a better chance of causing infection. Presumably, HIV that binds more effectively to the receptor will result in increased infection.

The Impact

Results from this basic research may lead to the development of innovative strategies to prevent HIV infection that could be less toxic than current antiretrovirals.

Experts (4)

  • Melissa Robbiani Senior Scientist and Director, Biomedical HIV Research, Center for Biomedical Research
  • Thomas Zydowsky Senior Scientist, Head of Pharmaceutical Development, HIV and AIDS, Center for Biomedical Research
  • Elena Martinelli Scientist, Center for Biomedical Research
  • Kyle Kleinbeck Senior Research Investigator, Center for Biomedical Research