Dialing Down the T Cell
By Jeffrey Laurence, M.D.
June 16, 2008—Immune system activation appears to be a key determinant of the virulence of both HIV and its monkey counterpart, SIV. One feature distinguishing a deadly SIV infection in a rhesus monkey from a benign infection in a sooty mangabey is the degree to which SIV switches on, or activates, the T cells of its host.
Similar differences separate the long-term HIV survivor from a person rapidly succumbing to infection. amfAR grantee Dr. Steven Deeks of the University of California, San Francisco, writing in the May issue of the Journal of Immunology, studied molecular differences underlying T-cell activation in HIV-positive, long-term non-progressors versus disease progressors, and the impact of treatment on these differences.
Dr. Deeks and colleagues found that in progressors, several critical “messenger” molecules were in a heightened state of activation. These included cell proteins responsible for translating a signal received by an immune cell on its surface into a course of action to be carried out by internal components. This activated state, seen in all types of CD4+ “helper” and CD8+ “killer” T cells, was identified chemically as an increase in levels of phosphate attached to the messenger molecules. These cells, which should have been at rest and awaiting a call to action by a foreign invader, for example, were instead already switched on and therefore in no state to respond further when they were really needed.
Dr. Deeks noted that this defect helps to explain why decreases in T-cell numbers alone cannot explain disease progression. Some people with near-normal numbers of T cells still succumb to AIDS-defining infections and cancers.
The good news is that effective antiretroviral treatment returned the phosphate levels of cells from HIV progressors to normal, at the same time renewing their ability to respond to signals on the cell surface. The authors ended their paper with a call to investigate additional ways to restore normal signaling in T cells, in a novel approach to the goal of reconstituting a normal immune system for all people living with HIV/AIDS.
Dr. Laurence is amfAR’s senior scientific consultant.