Exploring How HIV Kills Cells of the Immune System
by Jeffrey Laurence, M.D.
June 19, 2006—HIV infection ultimately leads to a diverse range of opportunistic infections and cancers which we refer to, collectively, as AIDS. It does so by suppressing our immune system, killing cells, particularly CD4+ T cells, responsible for guarding against development of infections and cancers. Recent studies by amfAR grantee Dr. Ramesh Ganju, working at the Beth Israel Deaconess Medical Center of Harvard University, are helping to define one of the mechanisms by which HIV-directed cell death occurs. His work has the potential, in the author's words, to “suggest new avenues for therapeutic intervention.”
Writing in a recent issue of the Journal of Biological Chemistry, Dr. Ganju and colleague Dr. Appakkudal Anand did not focus on the direct killing of T cells. This occurs within 2-3 weeks after initial infection, but prior to the development of a positive HIV test for antibody, when the majority of people do not yet know they have been infected. During this acute infection period, HIV is able to replicate rapidly and grow to very high levels. The virus destroys a large proportion of tissue in the intestines, tissue that is otherwise capable of forming critical types of CD4+ T cells. Instead, these researchers examined the period of chronic infection when, in the absence of effective antiretroviral treatment, T cells continue to die while the body struggles to replace them. At this point very few T cells carry replicating HIV, yet many die anyway. How does this happen, and what might be done about it?
One hallmark of this period of chronic infection is immune activation. The immune system is revved up—or "activated" —in an attempt to control HIV. And the immune system is able to check the growth of HIV at least to some extent as evidenced by a long latency period —an average of 10-12 years—before AIDS-defining illnesses begin to emerge. Unfortunately, although activated cells can kill the virus, they are also programmed to die prematurely. This “activation-induced cell death” is one thing that must be countered, and is an area of research for many scientists.
The second major mechanism of T cell death in the chronic phase is closely related to the first. It involves gp120, the sugar-protein on the outer coat of HIV. gp120 can become detached from the virus and float free in the blood of an infected individual. If it lands on a healthy T cell—an "innocent bystander"—gp120 sets in motion a series of molecular events, leading to death of the cell by a process known as apoptosis, or programmed cell death.
Dr. Ganju's group found that this cell killing required two proteins: one co-receptor for HIV infection, CXCR4, and a cell signaling protein, CD45. Drugs to inhibit CXCR4 are already in clinical trials. Methods of interfering with the activity of CD45 may represent another potential means to suppress killing of T cells in HIV infection. Attacking either target has the potential to prevent or slow the inexorable loss of T cells that is the hallmark of HIV/AIDS.
Dr. Laurence is senior scientific consultant for programs at amfAR.