|AIDScience Vol. 2, No. 20, 11 October 2002|
|Anti-R7V antibodies may protect some HIV-infected patients from developing AIDS:|
|A conversation with Jean-Claude Chermann|
Presenters at the 2002 International Meeting of the Institute of Human Virology gave us some new insights on antibodies that broadly neutralize different HIV clades (see AIDScience article) and drug escape mutants. Jean-Claude Chermann (see insert) et al. presented data on antibodies against the b2 microglobulin-derived epitope R7V (sequence: RTPKIQV), which occur in HIV-infected patients who have been asymptomatic for several years (clinical nonprogressors) [PubMed]. b2 microglobulin is a normal cell surface protein that HIV particles acquire during the budding process. They have found that antibodies against R7V neutralize all clades of HIV, as well as drug escape mutants.
In a retrospective study of 83 HIV infected patients followed for more than ten years Chermann found only 16 patients who were anti-R7V antibody negative, and all these patients developed AIDS or died of the disease. The rest of the patients were positive for anti-R7V antibodies and asymptomaticsome were under drug treatment and others had never received any treatment. Some of the patients under drug treatment lost the antibodies with time.
This correlation between the presence of anti-R7V antibodies and clinical nonprogression suggests a protection that could be potentially exploited for the development of a new treatment or a therapeutic/prophylactic vaccine. Chermann spoke with Roberto Fernandez-Larsson, AIDScience's senior editor, and answered a few questions about his project.
[AIDScience] Are anti-R7V antibodies present in normal noninfected people?
[Jean-Claude Chermann] We find anti-R7V antibodies in only about 2% of the noninfected population.
I heard you talk about how the R7V epitope might present itself to the immune system. Obviously, b2 microglobulin is a normal cell surface protein. Therefore, something must happen during the virus budding process to expose epitopes in b2 microglobulin that are not normally exposed.
Absolutely. What is very important is that the R7V epitope is exposed not only in the HIV-1 but also in the HIV-2 budding process.
Why are there no anti-R7V antibodies in clinical progressorsindividuals with chronic progressive HIV-1 infection?
The hypothesis is that they are clinical progressors because they do not have antibodies to the R7V epitope. In support of this idea, we have isolated total immunoglobulin G (IgG) and then purifying the antibodies using affinity columns, followed by neutralization tests.
Also, clinical nonprogressors can become antibody negative. In reality that is not really the casethe antibody is associated, forming complexes with the virus and can be dissociated. This cannot be done with patients that do not have the antibodies.
Since that putative conformational change in b2 microglobulin would occur in every HIV-infected individual when the virus buds out of cells, it is still puzzling to me why some patients, the clinical nonprogressors are making the anti-R7V antibodies while others are not.
This is something we do not understand and will try to learn in the future. We are going to look into a panel of patients that seroconverted recently to determine when the anti-R7V antibodies appear. A panel of infected and noninfected hemophiliacs from the U.S. NIH is available for this study. Clinical samples are available from these patients from before and after they became infected with HIV. This retrospective study will answer other questions as well. For example, we want to know if noninfected patients that were exposed to the virus have anti-R7V antibodies that caused them to have an abortive infection.
It would be interesting to see if highly exposed persistently seronegative (HEPS) individuals, from the Nairobi sex workers study for example [PubMed], have titers of anti-R7V antibodies.
We have not looked at those kinds of people yet. So far, we have been trying to establish the correlation between anti-R7V titers and clinical progression to AIDS status.
Do you know if clinical progressors, who do not have anti-R7V titers, have the R7V epitope exposed on the surface of the HIV particles?
Yes, of course. For example, we know that after highly active antiretroviral therapy (HAART) in clinical progressors drug-resistant viruses appear that can be neutralized by anti-R7V antibodies. So these viruses have the epitope on their surface but these patients are not making the antibodies. We do not know the reason for this.
Have you done any passive transfer studies with anti-R7V antibodies in monkeys or other animals?
No, we have not yet. I would like to be ready to do a compassionate trial of passive transfer of antibodies [obtained from clinical nonprogressors] to clinical progressors, because the minute we find out that something like this works we will be inundated with requests for treatment. We will need, in my opinion, 3 or 4 months to get to that point. The amount of antibody necessary for a passive transfer needs to be determined.
You mentioned that you might develop this idea as a therapeutic agent or as a preventive vaccine...
We are exploring several possibilities. You cannot successfully vaccine highly immunocompromised patients because they will not respond, so for them we will have to develop therapeutic possibilities with antibodies. For a vaccine, we will use a vector, which will make it more available to the masses.
Editor's note: Since our discussion with Dr. Chermann, the U.S. Food and Drug Administration has evaluated the Anti-R7V diagnostic kit dossier and granted URRMA Biopharma's IDE (investigational device exemption). This is equivalent to a Phase II completion in the more commonly used terminology pertaining to FDA pharmaceutical drug regulations, and will allow URRMA to proceed with Pre-Market Approval (PMA) clinical studies (Phase III equivalent). URRMA's diagnostic kit will help distinguish patients between progressors and nonprogressors and hopefully be of help to physicians in deciding whether or not to initiate antiretroviral therapy. You can access URRMA's press release here.
|Copyright © 2001 by The American Association for the Advancement of Science|