A recent report on two specialized scientific conferences looks at some of the most important current ideas on developing new kinds of HIV treatments. The conferences took place in April 2004, and the report,1 by immunologist Gareth Hardy, Ph.D., was published in July. I was not at the meetings but noted the following ideas from the writeup, and added my own explanations and comments. Dr. Hardy's article is at www.i-base.info/pub/htb/v5/htb5-6/Keystone.html.
APOBEC and Vif: APOBEC is a family of proteins produced by the body that help to protect it against certain viruses. Much of the interest today is in one of these proteins, APOBEC3G (also called CEM15). HIV is able to infect humans only because it has a gene, Vif (viral infectivity factor) that blocks APOBEC3G. Researchers from London reported at the meeting that Vif does this in at least three different ways -- keeping APOBEC3G from getting where it is needed, speeding up its destruction, and making it work less efficiently. As more is understood about these mechanisms, one or more of them might be a target for an entirely new kind of anti-HIV drug.
Finding agents that stop the action of Vif could lead to new ways to interfere with HIV infection. And since Vif is not naturally in the body, blocking it is less likely to interfere with normal human biochemistry.
SIV (simian immunodeficiency virus) infects certain monkeys and other primates. But it does not cause AIDS-like disease in those animals that it naturally infects. When it is transmitted to other animals, however, it does cause disease. (In humans, SIV is believed to be the source of HIV-2, a virus less damaging to people than HIV, although it causes an AIDS-like disease that can be fatal. HIV-2 is found mostly in a few areas in Africa.)
In at least one animal that SIV naturally infects, the sooty mangabey, it causes a very high viral load with little immune response, but does not hurt the animal. The fact that this is possible suggests that it might be the body's response to HIV that is causing the damage, rather than the virus itself, Apparently the animal species that have been infected for some time have evolved to manage this kind of virus by learning to live with it rather than by eradicating it. Researchers are now studying the immunological differences in the responses of animals that do or do not get sick as a result of SIV infection. Understanding these differences might show how to develop an immune-based treatment that helped the human body manage HIV infection in the same way. (Such a treatment might be hard to identify, since it would increase viral load.)
Taking a completely different approach, researchers in Switzerland treated a few patients with a combination of monoclonal antibodies, after they discontinued antiretroviral treatment. The antibodies seemed to work at least as well as HAART in suppressing HIV -- except in one patient, whose virus rapidly returned, probably due to viral resistance to those particular antibodies.
Another study suggested that antibodies could work better with the help of complement (another part of the immune system) -- suggesting that some antibodies to HIV that have failed to stop the virus in certain lab tests might be more effective when tested in the presence of complement, which is more akin to what happens in the body.
Other researchers showed that HIV grew much better and evolved much faster in HIV-specific CD4 T cells than in other CD4 cells. This is not surprising, because the cells that recognize the virus become activated as a result, and HIV grows much faster in activated cells. This does not happen with most viruses, because they do not infect the CD4 cell.
The fact that HIV grows best in the cells naturally programmed to recognize it may explain why therapeutic vaccines have been unable to induce a lasting HIV-specific CD4 response -- since the cells are activated and do not live long, and fail to produce memory cells (which are not activated and normally can live for years, ready to protect against a particular virus or other disease-causing organism if it is seen again). A better understanding of this problem may allow scientists to find a way to enable HIV-specific CD4 cells to do their job in controlling this virus, as CD4 cells do with other viruses. (One possible approach would be to genetically engineer a CD4 cell that cannot be infected by HIV.)
Structured treatment interruption was discussed, but it did not seem to enable even carefully selected patients to develop immune responses so that they could control HIV permanently without drugs, as some had hoped.
New information from several studies casts doubt on the Elispot test, which has become popular in the last few years as a way to get an early idea of whether an experimental vaccine or immune-based treatment seems to be working. Elispot measures interferon-gamma, which has been used to indicate a CD8 T cell response. But new results suggest that interferon gamma production does not seem to correlate with reduced viral load or any other benefit to patients. Other measures of CD8 response do seem to indicate protection. For these reasons some experts are coming to believe that interferon gamma is not a good marker of immune function to be measuring in vaccine or immune-based therapy trials. If this is true, and other markers are validated, future treatment and vaccine research projects will have a higher chance of detecting protective immune responses.
- The two conferences were Molecular Mechanisms of HIV Pathogenesis, and HIV Vaccine Development, both organized by Keystone Symposia; they took place April 12-18, 2004 in Whistler, British Columbia, Canada. The 5600-word summary by Gareth A. Hardy, Ph.D., of the HIV Immunology Unit, Department of Immunology and Molecular Pathology, Royal Free and University College Medical School, London, was published in HIV Treatment Bulletin, Volume 5 Number 6, July 2004, and is available at www.i-base.info/pub/htb/v5/htb5-6/Keystone.html.
ISSN # 1052-4207
Copyright 2004 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.