GMHC Treatment Issues, Volume 10, Number 1 - January 1996
Theo Smart

Dr. Levy found that activated CD8 cells from HIV-negative donors, and SIV-infected primates, also halted the growth of HIV in cell cultures. This activity was not due to CD8 cells directly killing HIV-infected cells, as one might expect considering their commonly accepted antiviral role. Rather, something that these cells produced, which Dr. Levy referred to as the cell antiviral factor (CAF), was keeping the virus in check.

Since proportionally more CD8 cells are required to block the virus in cultures derived from patients with advanced HIV disease, Dr. Levy concluded that these CD8 cells were not producing as much CAF. He reported that CAF could be what is responsible both for the long period of clinical latency that most people with HIV experience and for the continued health of many long-term survivors. He also believes that production of CAF ebbs before CD4 cells become depleted and people develop symptoms.

CAF's exact chemical identity proved to be extremely elusive. Dr. Levy could isolate no one substance secreted by CD8 cells that could affect this dramatic suppression of HIV. His work languished, garnering little interest or support from the National Institutes of Health.

Last month, Dr. Levy's discovery regained the spotlight, when two groups separately claimed to have identified CAF. Researchers from the Paul Ehrlich Institute in Langen, Germany reported in a letter to Nature (December 7, 1995, page 563) that a cytokine called lymphocyte chemoattractant factor, or IL-16, has a strong suppressive effect on HIV. The other team, led by Drs. Paulo Lusso and Robert Gallo, formerly of the National Cancer Institute, argued that CAF was not one, but three different substances acting in concert to keep the virus in check (see Science, Dec. 15, 1995, pages 1811-5). Dr. Levy, though, does not believe that CAF has truly been identified by either group.

IL-16

Dr. Paul Reinhard Kurth and the other German investigators have been working with a factor isolated from the CD8 cells of African green monkeys that suppresses SIV, the monkey virus similar to HIV. The Germans found that this factor is virtually identical to human IL-16. However, the observed HIV-suppressive activity of pure IL-16 was not as dramatic as that of the crude material extracted from the CD8 cell cultures.

In a review accompanying the Nature letter, Anthony Fauci, M.D., director of the National Institute of Allergy Infectious Diseases, suggested that IL-16 may be working together with other suppressive factors. How IL-16 works is unknown, but it does bind to the CD4 receptor and may inhibit CD4 cell activation. At the doses that Dr. Kurth's group used, IL-16 was not toxic to cells and so perhaps has some therapeutic potential.

Chemokines

Dr. Gallo's team took a CD8 cell line that was particularly effective at suppressing HIV, removed the actual cells and separated the remaining substances in the culture. They found three proteins, previously dubbed RANTES, MIP-1a and MIP-1b, that had potent anti-HIV activity at nontoxic levels in cell culture. These proteins belonged to the chemokine family, which heretofore were known to direct lymphocytes to the site of infection or inflammation.

The researchers then added antibodies that inactivate the individual chemokines to the cultures to see which chemokine was primarily responsible for the CAF activity. Only the antibody to RANTES seemed to partially reverse some of the suppressive effect. Yet when antibodies to all three chemokines were added, all of the anti-HIV activity was eliminated. The scientists observed the same result when the antibodies were added to cell cultures taken from people with HIV and concluded that all three of the chemokines are required to keep the virus under control.

Dr. Gallo's group is currently running the chemokines through various in vitro assays to determine which aspect of the viral life cycle is disturbed by the chemokines. They may act at an early phase in the viral life cycle, but Dr. Gallo says, "there may be more than one mechanism of action."

Natural History

Dr. Gallo's paper concluded with the suggestion that the people with HIV should be studied to see whether those who produce higher levels of these chemokines have a slower rate of disease progression. Does production ebb as people progress? (Dr. Gallo says other factors may emerge that reduce the chemokines' effect in people with progressive disease.)

Another area to look at is whether vaccine-induced higher levels correlate with protection against SIV infection in monkeys. At present, there is little natural history data on the secretion of chemokines (or IL-16) in people with HIV disease.

High production of chemo-kines has been noted in a large number of autoimmune disorders, such as rheumatoid arthritis and lupus. This observation raises the question of whether people with a history of such conditions are less likely to become HIV infected, or, if they do become infected, whether they progress more slowly.

Researchers have noted that it is extremely unusual to find HIV and these other conditions together, but there are a few case studies in the literature. Rather than a slower progression of HIV disease, a remission of the autoimmune disorders was observed.

William Blattner, M.D., Deputy Director of the University of Maryland institute that Dr. Gallo now directs, says, "The first thing to do is get a better understanding of the way in which these [chemokines] occur in these different populations. A single marker may not tell the whole story -- ratios or combinations may be important. It is possible that there are some suitable populations for case control studies. Our first approach will be to look at levels of these markers in patients at different stages of HIV infection, and whether these markers correlate with protection in HIV-negative people with continued high-risk exposures. But again, the initial focus is standardizing the assays."

Therapeutic Potential

The extent to which any of these findings will lead to the development of new therapeutic agents remains to be seen. IL- 16 may suffer from the same fate as other cytokines that have shown anti-HIV activity in the lab. Some of these compounds also concurrently stimulate the production of inflammatory cytokines such as TNF-a when administered in people, undermining whatever direct anti-HIV activity they might have had in the test tube. And generally, administration of the HIV-suppressor cytokines have been associated with severe side effects.

The systemic administration of chemokines poses certain problems. The most established purpose of chemokines is to direct white blood cells to the sight of the infection. If administered systemically, immune cells might wander aimlessly, confused by conflicting signals and be less likely to respond when secondary infections do occur.

Administering MIPs alternatively might make common infections life-threatening by magnifying the amount of inflammation present. In the lungs, excessive MIP-induced inflammation during pulmonary infection can lead to suffocation. Added RANTES, meanwhile, could cause side effects similar to arthritis.

Nevertheless, the chemokine levels effective in cell culture "are not showing toxic effects in the animal [rodent] toxicology studies," says Dr. Gallo. He hopes to administer the chemokines to green monkeys (the SIV model) within several weeks (although he notes that delays in the construction of his new institute make it difficult for him to say for certain).

Dr. Gallo also believes there may be some way to trigger the local secretion of chemokines. Presently, Dr. Sergio Romanagni, in Florence, is conducting experiments to determine how CD8 cells produce these chemokines, and what factors might stimulate their secretion.

Dr. Gallo's team also is manipulating the molecular structures of the chemokines to determine which subunits are responsible for the antiviral activity. Altered molecules might be developed that suppress HIV but do not have the potential side effects of the whole chemokine molecule.

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