 |
|
|
on New Biological Treatments |
|
Interview by John S. James
ATN: What did you find most important at the IHV meeting? Dr. Gallo: My belief--and there is wide consensus on this--is that we need not only new drugs for HIV infection, but also new approaches, new biological approaches to therapy. The problems with treatment today were predicted long ago. As in cancer, these problems will increase the longer you have intensive combination chemotherapy. If you can't eradicate the virus and people have to keep taking the drugs, you will see rising resistance and drug toxicity among some of the patients. It may become a large majority in the next few years. Today the pharmaceutical companies are on a reasonable roll in creating new drugs. They see enough gain, and will continue to make new chemicals to target enzymes. But more is needed for the future. New biological therapies have come, and will continue to come, from research on HIV pathogenesis. I can't emphasize enough the importance of continuing these studies, while other research continues for developing a preventive vaccine. Pathogenesis research will help the vaccine efforts as well. ATN: What are some examples of new biological approaches to treatment? Dr. Gallo: Targeting the chemokine receptors [such as CXCR-4 and CCR-5] is one such example. At the meeting we heard from people studying modified chemokines as potential therapies. Pharmaceutical companies are also developing smaller molecules to target CCR-5, for example. Tat Toxoid
[The body partially controls Tat by producing antibodies against it, as the body produces antibodies against other foreign proteins. [Tat toxoid is a slightly modified form of Tat which is designed as a potential component of treatment, or of a preventive vaccine. It does not have the biological activity of Tat, so it does not stimulate HIV or poison the immune system, as Tat does. But it is close enough to Tat that when the body produces antibodies against the toxoid, these antibodies are effective against the Tat protein as well, reducing its level in the blood. Antibodies work based on the shape of the target molecule--and the Tat toxoid and Tat protein have almost the same shape.] We believe the Tat toxoid is important to pursue, both therapeutically and for a preventive vaccine. Led by my collaborator Daniel Zagury in Paris, we now have three years of clinical trials in 40 people demonstrating safety; and this Tat toxoid is strikingly immunogenic. But we do not expect it to be used alone, either for a therapy or a vaccine. For therapy, we believe that the Tat toxoid will work best when combined with another vaccine that Daniel Zagury initiated and I am working with, vaccinating against alpha interferon. The two synergize. Part (not all) of the harmful effects of Tat are mediated by its activation of alpha interferon. It has long been known that alpha interferon is overproduced in HIV-positive people, and we think we have found the mechanism (published in 1998 in the Proceedings of the National Academy of Sciences, USA). Combining the two therapeutically has stabilized CD4 counts in people without other therapy. It did not dramatically change the viral load, but it did stabilize the immune parameters that were evaluated. In studies of over 80 volunteers who were given the vaccine against alpha interferon, there were no opportunistic infections or deaths in the treatment group, compared to about 20 opportunistic infections and several deaths in the control group. But this approach has not yet been brought to the United States in large-scale clinical trials. To get credibility and get this project moving, we have to get it into the U.S. on a large scale. There are questions about whom to treat; it would be helpful to test this treatment in people who are not using antiretrovirals for one reason or another. Certainly, this approach would not be effective in end-stage disease. We believe it is important to use Tat which has been chemically modified, inactivated. Some researchers have argued for native, biologically active Tat--as if a chemically dead Tat wouldn't work. We have years of experience with this, and the Tat which is inactivated works just as well, and without the danger of the toxin being put into people, who may be immune suppressed already. Preventive and Treatment Vaccines
Some of the preventive vaccines being developed today might also be used as treatments, to stimulate the immune system when the virus is suppressed by HAART [highly active antiretroviral therapy]. Years ago, people tried to stimulate the immune system when the virus was high, and they didn't get very far. You can understand the reason, because the immune system was somewhat paralyzed by the HIV infection. A recent test in macaque monkeys, presented by Veffa Franchini at the [IHV] meeting, used the canarypox vaccine after antiretroviral treatment. The animals received antiretrovirals, then those drugs were stopped, and a little later the animals were vaccinated. They did well. There is now wide agreement that the well-known "faucet and drain" mathematical models--T-cells die, new ones replace them, and eventually there is immune exhaustion--are dead as explanations of HIV disease. It is clear that the uninfected T-cells are also impaired--so we need to find out why, which is what got us into Tat research to begin with. Some soluble factors must be suppressing the normal function of some of the remaining T-cells. Lowering the virus with antiretrovirals makes it more rational to do gross, unspecific stimulation with HIV antigens. Today the Remune trials [using the Salk HIV immunogen] can be re-evaluated--along with the canarypox approach and other vaccines people want to use. What if you vaccinated against Tat and alpha interferon, and did not succeed in lowering the viral load, but in time did help restore the capacity of T-cells to respond, or at least it did not get any worse. Would a vaccine like Remune or the canarypox preparation do anything? I don't know, but it makes some theoretical sense to try this and find out. No one spoke about the envelope-only vaccine which is now going into widespread preventive trials [AIDSVAX], but most scientists believe it is not a likely candidate. I hope it does not hurt the vaccine field if it turns out not to work, as virtually everyone expects. Other Biological Approaches Next year's meeting will highlight everything we know about the new pregnancy-urine peptide that we have described in impure form, before it was identified (see "New Approaches to HIV Treatment; Interview with Robert Gallo, M.D.," AIDS Treatment News #285, December 19, 1997). Now we have identified it, and the Institute will probably be reporting that before next year's meeting. I would be very disappointed if this potential treatment does not get into clinical trials properly. When we have learned how to use it--what route, what dose, what frequency of administration--I would be very surprised and extremely disappointed if it does not help people. Alonzo Heredia presented data on resveratrol a natural substance found in grapes and red wine, which might potentiate ddI and perhaps some other antiretrovirals; he is working with Robert Redfield at our Institute. We are working with pharmaceutical companies and will be starting two clinical trials. This research follows up on our concept of targeting cellular factors that the virus may need more than the cell does, thus widening our therapeutic targets. We (with my then co-worker Franco Lori and collaborator, Dr. Gao) first chose hydroxyurea because of speed, simplicity, availability, low cost, and so on; about six years later, it went into clinical trials for HIV. But there may be drugs better than hydroxyurea for this purpose. Resveratrol with ddI may be one such approach. Frank F. Weichold, from our institute, presented evidence that some the benefit of the protease inhibitor ritonavir may be from direct immune modulation, independent of its antiretroviral effect. He suspects that the major therapeutic benefit of this drug may be the inhibition of certain chemicals (cellular proteases) which lead to abnormal apoptosis (programmed cell death) of a large number of cells, including uninfected CD8 T-cells that fight HIV. If this theory is confirmed, then new drugs might be developed specifically for this purpose. Peter S. Kim spoke on the structure of gp 41 and details of viral fusion and entry--a truly elegant piece of work. This technology may identify lead compounds which could be developed into small-molecule fusion inhibitors.
On pathogenesis, Klara Tenner-Racz presented evidence of oral transmission of SIV when a relatively large amount of this virus was applied to the tonsils of macaques [suggesting a biological basis for transmission of HIV through unprotected oral sex]. Part of the meeting was devoted to cancer biology, tumor immunology, and cancer vaccines. There were many important overlaps with HIV and AIDS, opportunities to apply lessons learned from one to the other. In cancer vaccines they have some of the same issues as in HIV; there should be more interchange there. ATN: Are cancer vaccines primarily preventive, or therapeutic? Dr. Gallo: Most of the cancer vaccines, and all those discussed at the meeting, were therapeutic. About 15% of cancers have a known viral-necessary role, however, and for these there might be a place for preventive vaccines, especially in parts of the world where these cancers are common. For More Information: The abstracts of this meeting--over 200 of them--are published in the Journal of Human Virology, July/August 1999, volume 2, number 4. Some copies are available from the Institute of Human Virology; email your mailing address to schorr@umbi.umd.edu. Later the abstracts may also be placed on the Institute's Web site, http://www.ihv.org . AIDS Treatment News Published twice monthly Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number Fax: 415/255-4659 E-mail: aidsnews@aidsnews.org
Editor and Publisher: John S. James Associate Editor: Tadd T. Tobias Reader Services: Tom Fontaine and Denny Smith Operations Manager: Danalan Richard Copeland Statement of Purpose: AIDS Treatment News reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $270/year. Includes early delivery of an extra copy by email. Nonprofit organizations: $135/year. Includes early delivery of an extra copy by email. Individuals: $120/year, or $70 for six months. Special discount for persons with financial difficulties: $54/year, or $30 for six months. If you cannot afford a subscription, please write or call. Outside North, Central, or South America, add air mail postage: $20/year, $10 for six months. Back issues available. Fax subscriptions, bulk rates, and multiple subscriptions are available; contact our office for details. Please send U.S. funds: personal check or bank draft, international postal money order, or travelers checks. ISSN # 1052-4207 Copyright 1999 by John S. James. |
Dr. Robert Gallo 
For a preventive vaccine, you would not combine the anti-tat
vaccine with vaccination against alpha interferon. Instead,
you would combine the Tat toxoid with viral antigens.
Anthony Fauci 
© 1997-98 BEI