March 14, 2011
Two types of T cells are critically important in HIV infection. Most discussion of these immune cells refers to the subset known as CD4+, which is the cell type counted during most patient visits to gauge when to start antiretroviral therapy and the success of such treatment over time. The other subset, known as CD8+ "killer" T cells, are also crucial because of their ability to control most viral infections. But even in the earliest stages of HIV infection the performance of CD8+ T cells, including their ability to fend off HIV and other viral infections, is suboptimal. And in the late stages of infection, CD8+ numbers decline. However, the reasons for these declines in the number of cells and their performance are not well understood.
Writing in the February issue of the journal Blood, amfAR fellow Dr. David Favre; amfAR grantees Drs. Joseph McCune, Steven Deeks, and Frederick Hecht; and colleagues at Genentech and the Montreal-based National Immune Monitoring Laboratory have begun to explore mechanisms that may explain these declines in CD8+ T-cell number and function. Their identification of a defect in a special type of CD8+ cell, known as "naive CD8-low," should point the way to "future maneuvers to sustain immune responses in HIV-infected patients."
Researchers have previously noted that chronic immune activation is routinely seen in HIV infection, in which T cells, especially CD8+ T cells, are inappropriately "on" or active in terms of the immune hormones they secrete. Clinically, chronic immune activation contributes to premature aging effects such as heart disease, osteoporosis, and diabetes, all of which complicate the treatment of HIV. In mice that have been genetically engineered to be susceptible to HIV, previous studies have demonstrated a chain of events in which HIV infection of the thymus, the birthplace of all T cells, results in the production of the immune hormone interferon-alpha, leading to an increase in MHC-I (a marker of infected cells) and naive CD8-low cells. Instead of responding actively to the infection as CD8+ cells typically do, these cells respond poorly to the presence of HIV.
Following those leads, Dr. Favre and associates report that in HIV-infected humans, HIV progression and associated immune activation are closely linked to the presence of naive CD8-low type cells. When HIV infection progresses toward AIDS, MHC-I increases as well as CD8-low T cells (similar to what has been described in mice). Because of the similarities between these results and those observed in mice, the researchers conclude that interferon-alpha may play a central role in "crippling the host immune response against HIV." It is hoped that manipulation of interferon-alpha pathways might improve immune function and inflammation status in HIV disease and perhaps related viral infections linked to impaired CD8 function, such as hepatitis C.
Dr. Laurence is amfAR's senior scientific consultant and Dr. Johnston is vice president and director of research.