Adaptive regulatory T cells suppress killing of persistently infected cells

Scientists report that they have identified a cellular mechanism that prevents the immune system from destroying chronic, incurable viral infections such as herpes, hepatitis and human immunodeficiency virus (HIV). The research, published in the March issue of Immunity, explains why critical immune cells fail to act against the viral infection and demonstrates a successful intervention that facilitates elimination of the virus. The results open up exciting new avenues for design of future antiviral therapeutics.

Many human viruses are able to evade the immune system during acute infection and establish long-term persistent infections that are extremely difficult to eliminate. Most of the time, proliferation of the virus is balanced by antiviral immunity and the host experiences little to no damage. However, persistent infections with viruses such as HIV or hepatitis lead to life threatening diseases that currently have no cure.

Immune cells called CD8+ T cells are critical for recovery from viral infections and persistent viral infections are associated with a malfunction of these cells that is not well understood. Dr. Kim J. Hasenkrug from the Rocky Mountain Laboratories, part of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, and colleagues investigated persistent infection of mice with Friend virus (FV) to look at the specific mechanisms that contribute to CD8+ T cell dysfunction. The researchers found that although the CD8+ T cells could recognize their appropriate targets they could not destroy them. The key finding was that regulatory CD4+ T cells suppress the normal function of the CD8+ T cells in the persistently infected mice. Importantly, suppressing the activity of the regulatory CD4+ cells could prevent dysfunction of CD8+ T cells.

The researchers conclude that CD4+ T cells contribute to viral persistence by suppressing the host CD8+ T cell response and that influencing the activity of CD4+ T cells can reduce this suppression. “A practical intervention that could reduce virus loads during chronic HIV infection would likely be an invaluable tool in postponing the onset of AIDS. While it remains to be seen whether an intervention such as described in our study would work in HIV infections, our experiments open new possibilities of therapy for treating persistence, one of the most refractory elements of retroviral infections,” explains Dr.Hasenkrug.

Ulf Dittmer, Hong He, Ronald J. Messer, Simone Schimmer, Anke R.M. Olbrich, Claes Ohlen, Philip D. Greenberg, Ingunn M. Stromnes, Michihiro Iwashiro, Shimon Sakaguchi, Leonard H. Evans, Karin E. Peterson, Guojun Yang, and Kim J. Hasenkrug: “Functional Impairment of CD8+ T Cells by Regulatory T Cells during Persistent Retroviral Infection”

Published in Immunity, Volume 20, Number 3, March 2004, pages 293-304.