The Bay Area Reporter - February 16, 1998
Jeff Gustavson, ACT UP/Golden Gate Writers Pool

Cleveland rocks

Dr. Michael Lederman, from Case Western Reserve University Medical Center in Cleveland, chairman of the Immunology Research Agenda Committee of the AIDS Clinical Trial Group (ACTG), discussed several areas of research. "It is important to conduct pathogenesis-based investigation to understand the nature of immune dysfunction in HIV disease, and this can be accomplished in two ways," he says. "First, by looking at immune reconstitution, after successful antiretroviral therapy, we can gain insight into the mechanisms of immune decline.

"Second, we need to gain a better understanding of immunity against host [human] pathogens."

Lederman continues, "We need to explore the basis of host-directed immunity. We're not sure yet if HAART is useful against the pool of latently infected memory CD4 [Helper T] cells. We need some novel strategies to attack that pool. Additionally, we need the means to augment cellular reconstitution. While we have seen increases in numbers of CD4 cells, and some increase in function, nonetheless, the magnitude of this change is unclear. The changes we have seen are modest, at best, and it will be years before normalization.

"On the exploratory side of things, the role of immune activation is being examined. An activated cell is more permissive, if you will, towards infection. Some markers of immune activation [CD8+/CD38+/HLA-DR+] have been shown by Janis Giorgi at UCLA School of Medicine to be predictors of poor outcome."

The question remains as to whether modulation will have some beneficial effect. The AIDS Clinical Trial Group (ACTG) is currently looking at immune suppression in three different trials. ACTG 349 is looking at corticosteroid (anti-inflammatory) suppression in people with CD4 counts above 200. Diego Morales at Duke University is conducting a small pilot study (ACTG 380), looking at administering cytoreductive therapy (chemotherapy) for HIV.

Block, block, blocking enhancer's door

ACTG 334 is using low dose cyclosporin A to suppress immune activation. This drug is usually given post-transplantation to prevent rejection of organs and works at the intracellular level by binding to an immunophilin called cyclophilin and blocking the phosphotase (dephosphorylation) activity of calcineuerin on NFAT (Nuclear Factor Activating Transcription). In this form, NFAT is unable to cross the nuclear membrane and bind to the enhancer region for the gene which codes for Interleukin 2 (IL-2). Additionally, due to a negative pharmacokinetic interaction, people taking protease inhibitors are excluded from this trial.

Bob Grant, M.D., M.P.H., of Gladstone Institute of Virology and Immunology at UCSF, emphasizes that "334 is a Phase I trial, and as such it is to determine safety. Obviously, this is moving into the realm of wildly speculative theory; however, given the history of AIDS research, one realizes that conventional wisdom can't dictate the directions for research." Citing the initial reluctance to use steroids for PWAs with active PCP infection, and the subsequent success with prednisone, Grant waxes enthusiastic. "Ideas must be explored," he says. "Relatively short-term immune suppressive therapy may be of benefit - and who knows, may induce remission."

Slow down, you move too fast

Grant goes on to discuss other concerns about inappropriate activation: "Activation may cause innocent bystander destruction - in the lymph nodes, thymus [the organ from which T cells derive their name], and in the bone marrow. Also, CD4 cells that are active are more susceptible to HIV infection. So, ironically, those cells which are specific for HIV are more easily infected and may either apoptose or burst from HIV production, thereby blunting a person's ability to fight the infection."

Taking a U-turn, like any good scientist, Grant argues the merits of a seemingly opposite tactic. "Stimulating infected cells under cover of HAART with agents like IL-2 may be a way to provoke latently infected cells into exposing themselves. However," he cautions, "activating latently infected cells at the same time target cells [for infection] are most susceptible may not be a good thing."

Aware of the apparent ambiguity, Grant elucidates, "The main point I am trying to make is that clinical trials are needed. The possible risks and/or benefits of cytoreductive therapy or immune stimulation are difficult to predict based on the available information. Given evidence of an inducible reservoir of HIV-1 infected cells ... we need clinical trials to evaluate novel therapies targeting that reservoir."

Totally, dude

Another interesting approach being undertaken at Gladstone is Total Lymphocyte Irradiation (TLI) with thymic shielding, a harsher sounding therapy than it really is. Krishna Komanduri, M.D., one of the researchers involved, explains, "The basic rationale stems from certain situations in which thymic rebound was noted, for example Hodgkin's disease where chemotherapy had been used. In those persons where thymic mass returned after the depletion of lymphocytes (white blood cells), people speculated some feedback might be given to the thymus causing it to hypertrophy [grow]."

The youthful Krishna continues, "We observed greater than expected thymic index [bigger organ] in young [less than 39 years old] HIV-1 infected adults with mildly depressed CD4+ counts (300-500), and in all older HIV-1 infected adults. We thought we could possibly drive down viral burden in the lymph tissue while simultaneously induce a signal to the thymus to hypertrophy." Komanduri echoes Grant in stressing that these are Phase I trials, meant to assess toxicity, but he is clearly animated by the potential.

"Ultimately," he says, "we would like to know how much function can be regained, whether thymic persistence [beyond adolescence] and function predict reconstitution, and can we find better ways to drive that?"

Studies like these can only further our understanding.

ACTion UPdate: Managed care - or is it?

Dr. Stephen Becker of Brown & Toland Medical Group will be at ACT UP/Golden Gate's next treatment issues meeting for a discussion on Managed Care and HIV. The meeting will begin at 7:30 p.m. next Thursday, February 26 at 590 Castro Street.
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