TreatmentUpdate43: Vol. 4, No. 3, July, 1993
Sean Hosein

For much of the past decade of the AIDS epidemic most researchers assumed that everyone exposed to HIV would eventually develop AIDS. In part this is because HIV infection results in a huge loss of "CD4+ T-helper cells" (also called T4+ cells) which makes patients prone to certain infections and cancers. Even the prospect of protecting uninfected people with a vaccine seemed dismal as HIV mutates rapidly.

Immunosuppression or Immune Dysfunction?

There are some aspects of HIV infection that are confusing. For instance, the number of CD4+ cells declines over time. On the other hand the activity of antibody-producing B-cells increases. Even when the CD4+ count is over 500 cells, the performance of these T-helper cells is below normal. Recently, some researchers have been reporting that there are people whose immune systems have apparently encountered HIV and yet remained intact.

Successful Defense Against HIV

Scientists at the NCI's Experimental Immunology Branch (National Cancer Institute, Bethesda, Maryland) have been studying large numbers of people who have been exposed to HIV on several occasions and yet have remained healthy and HIV antibody-negative (that is, they did not produce anti-HIV antibodies). The NCI researchers have been conducting extensive and sophisticated experiments on the cells of the immune system from these people to find out how and why they managed to remain healthy. For comparison, similar work was done on blood samples from people with HIV infection at different stages of illness. What these researchers have found is a way to assess the decline in the "performance" of T-helper cells.

What These Tests Mean

The researchers tested over 600 HIV-infected but symptom-free subjects to see how their T-helper cells would respond. As well, the researchers monitored the subjects to see how their health declined. Compared to subjects who responded to all the tests, the researchers found that subjects whose T-helper cells did not react to one or more of the tests were more likely to have:

* a steep decline in their CD4 ' cell counts * more life-threatening infections (in HIV-infected children) * a higher chance of developing life-threatening infections and/or cancers * higher levels of Beta2-microglobulin in their CSF (cerebrospinal fluid in which the brain and spinal cord float)

They noticed that when improvements in T-helper cell activity happened patients remained relatively free of infections. Increases in the CD4+ cell counts did not have the same effect. Thus "loss or recovery of [T-helper] cell function can occur...independently of changes in the CD4+ count.

Why Does The Performance of T-Helper Cell Activity Decline?

The precise cause of this loss of T-helper cell activity is not yet clear but there are a number of possibilities, including:

* toxicity from anti-virals, antibiotics and other drugs * loss of "memory" T-cells * a defect in one of the immune system's key defenses (described by researchers as APCs; antigen presenting cells) * the production of antibodies which impair the functioning of APCs * the presence of immunosuppressive chemicals; either parts of HIV or * products from HIV-infected cells * chemicals produced by the immune system which derail attempts to contain HIV infection

Antibodies

In order to explain several ideas about the immune system we will describe them in a highly simplified way. There are two basic parts in the immune system. The part that is involved with antibody production is called humoral immunity. In cases of the common cold, nu and certain bacterial infections, producing antibodies can be useful as they attack individual microorganisms that are lurking outside cells of the body. However, most of the serious infections people with AIDS get involve microorganisms that get inside cells. In such cases antibodies are of little use.

CMI

The other arm of the immune system is called CMI (cell-mediated immunity). The cells that perform this function include NK (natural killer) cells, activated macrophages and CD8+ cells. These cells can destroy HIV-infected cells and do not produce antibodies. In HIV/AIDS, for reasons mentioned before, CMI is dysfunctional and this allows certain infections/tumors to get out of control.

Two Types of CD4+ Cells:

The following passage is reprinted with the kind permission of the author, B. Goldberg.

"There are two types of CD4+ cells. The first type or Th 1 [starts the process] of delayed hypersensitivity which [activates] CMI. The CD8+ cells that are activated by Th 1 are known as Tl. The second type of CD4+ cells [triggers] the antibody response and is known as Th2. The CD8+ cells in this Th2 response suppress CMI and are known as T2. What is critical is that the opportunistic infections and HIV in AIDS are in the cells and can only be controlled by cellular immunity (Th1/T1)." By themselves counting CD4+ cells is not a sophisticated way to go about finding out what condition the immune system is in. This is because some CD4+ cells "can be Th1 (good) or Th2 (bad). The absolute CD8+ cell count is probably more useful in predicting the [appearance of, and the body's response] to opportunistic infections."

The Immune System Shifts Gears

Researchers at the NCI have found that people with HIV infection undergo a shift in their immune response. That is, from a CMI (Th1) response to a more humoral (Th2) response. This happens gradually so that by the time AIDS develops the shift has largely happened. In the next section we explain how some researchers think this shift happens.

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Copyright © 1993 - TreatmentUpdate. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Canadian AIDS Treatment Information Exchange, 555 Richmond St. West, Suite 505, Box 1104, Toronto, ON, M5V 3B1 • Phone: 416-203-7122 • Toll Free: 1-800-263-1638 • Fax: 416-203-8284  http://www.catie.ca