AIDS Trestment News
Retroviruses Conference, Chicago 1999by John S. James
We believe that HIV-specific immunity is the most important single research area emphasized at this conference; see "Restoring HIV-Specific Immunity," below, for a summary of a few of the many presentations. We will look at clinical trials, and other treatment research, in our following issues.
Besides HIV-specific immunity, other important areas include:
Restoring HIV-Specific Immunityby John S. James
But immunity to HIV itself is different. The CD4 T-helper cell response to HIV usually appears to be eliminated very early in HIV infection, and to return very slowly or not at all, even when HIV has been well suppressed for years with antiretrovirals, and other immunities do return. And without this helper response, the HIV-specific CD8 CTLs (cytotoxic T lymphocytes), which appear to be centrally important to the control of the virus during the initial HIV infection (primary HIV disease), seem to lose their ability to respond effectively to chronic HIV infection.
No one knows for sure why HIV is different from other viruses in this way, but it is likely that because HIV specifically targets activated CD4 T-helper cells, it will selectively kill especially those cells which are able to recognize it and respond. And when HIV is not present due to being suppressed by antiretrovirals, the CD4 T-helper cells genetically able to recognize it usually do not respond -- possibly because they were wiped out earlier, or because they were damaged in some way, or simply because they will not encounter HIV antigens, and therefore not become activated and not mobilize normal immune responses.
The potential importance of the body's failure to restore HIV-specific immunity becomes clear when one realizes that long-term nonprogressors -- the small minority of persons who are infected with HIV but naturally maintain a very low viral load, with a high CD4 count and no evidence of disease progression even after many years -- usually do have a CD4 T-helper cell immune response to HIV, while those who progress and become ill invariably do not. If HIV-specific immunity could be restored, might persons who now have HIV disease become long-term nonprogressors, no longer needing any treatment, or perhaps only needing treatment occasionally if their immune system begins to lose control of the virus again? No one knows at this time, since the research is just beginning. But the results so far are promising, and a handful of patients who had been dependent on antiretrovirals have already been able to stop these drugs entirely, sometimes for more than a year, without having the viral-load rebound that almost always happens when patients stop their antiretroviral treatment (and which did happen to these individuals when they first tried discontinuing their antiretrovirals).
Strategies for Restoring HIV-Specific Immunity
Several possible approaches for restoring HIV-specific immunity are now being researched:
It is not known that producing an immune response in this way will have clinical benefit, since the results so far have been only laboratory tests, as none of these volunteers has yet chosen to stop their drugs in order to see whether or not their viral load comes back.
Here is one theory of what may be happening in this case. As a person's CD4 count increases after suppression of HIV by antiretroviral drugs, a few of the cells that make up that count are new, "naive" CD4 T-helper cells released by the thymus (naive T-cells are those which have not yet encountered the particular antigen -- such as a protein from a particular virus or bacterium -- which the cell is genetically programmed to recognize). Of these new naive cells, a small minority are, by chance, programmed to recognize HIV. Without the antiretrovirals, these cells would recognize HIV, become activated as they started to respond to it, but then be destroyed by the virus. With only the antiretrovirals, the cells would be protected from infection, but there would be so little HIV present that they would not encounter it and not create an immune response. Adding the vaccine which is made from killed virus apparently allows these cells to safely develop a normal immune response.
It is also noteworthy that the killed-virus vaccine used in this test is made from a virus from Africa which is not clade B -- the variant of HIV which is common in the U.S. and Europe. Even so, the volunteers in this small trial did develop immune responses to purified HIV p-24 antigen from two different clade B viruses, as well as to the immunogen itself -- indicating that this approach might be able to confer a broad protection against many forms of HIV, not limited only to the particular kind of virus which was used to prepare the therapeutic vaccine.
Incidentally, the developers of Remune -- the Immune Response Corporation, later acquired by Agouron Pharmaceuticals -- prefer to call this product an "immunogen" rather than a "vaccine." It is currently being tested in a large phase III trial, separate from the small 43-person trial presented at the Retroviruses conference; data from the phase III study will be available later this year. Remune has never been tested in an HIV-negative person, as a potential preventive vaccine; some experts believe that it should be tested for this purpose.
Incidentally, this team reported the HIV-specific immune responses in CD8 CTLs (cytotoxic T lymphocytes) instead of in CD4 T-helper cells. (The CD4 cells were also measured and were concurrent with the CD8 cells, but that data was not presented at this conference). In all four patients, the strength of their CTL response was associated with how well they controlled the virus when they discontinued antiretroviral therapy.
Researchers from the Research Institute for Genetic and Human Therapy (RIGHT), of Washington D.C. and Pavia, Italy, noted that this patient (1) began treatment very early in the disease course, (2) was treated with indinavir, ddI, and hydroxyurea (any of the three might or might not have mattered), and (3) interrupted and restarted treatment twice (which might have provided occasions for CD4 T-helper cells to recognize HIV antigens while they were protected by the drugs). Later, three volunteers with undetectable viral load agreed to interrupt their therapy, under a protocol which restarted the drugs when their viral load reached 5,000. None of the three have yet been able to control the virus without the drugs; however, the time to viral rebound is getting longer with each subsequent interruption, indicating recovery of HIV-specific immunity.
HIV-Specific Immunity: Details of Presentations at Retroviruses Conference
It is important to note that the volunteers in this trial were not treated during or near primary infection, but could have been infected at any time. They were treatment naive and had a median CD4 count of 493 and a median viral load of about 8,000 copies before they began the study -- not because this approach could not be made to work for more advanced patients, but because it made sense to try the first proof-of-principle study in volunteers who had less immune damage and were easier to treat.
It is also important to remember that there is no proof yet that producing HIV-specific immunity will benefit patients -- since it is possible that long-term nonprogressors are able to resist HIV infection through some other mechanism, and that their HIV-specific immune responses are a consequence of that, not the cause of their remaining well. But the information available today does suggest that HIV-specific immunity is centrally important in the control of this virus.
Of the other two patients in this study, both stopped treatment more abruptly. One kept the virus at a low level without drugs for several months, but then "CTL responses faded and plasma virus rebounded." The other "had a rapid viral rebound and a low frequency of HIV-specific CTL."
There is concern that this early work may be misinterpreted to justify casual experiments in drug discontinuation; it is widely agreed that experiments with drug discontinuation to boost HIV-specific immunity should only be done in a research setting. These patients, unlike most, started treatment within 90 days of infection. The researchers had access to tests of HIV-specific immune function, which are not available commercially. And only two of the four who stopped therapy were able to control the virus for over a year without treatment.
All three volunteers started with stable viral loads (719,000, 22,665, and 33,707 copies). They began treatment early, but after primary infection. They were treated for three weeks with indinavir, d4T, ddI, and hydroxyurea; viral load went below 400 copies for all three of them, during this first course of treatment. Then the drugs were stopped for one week, followed by two cycles of treatment for three months, followed by interruption and then resumption of treatment when the viral load reached 5,000.
The first time therapy was stopped for 7 days. On the next interruption, it took an average of 14 days for the viral load to reach 5,000. On the third interruption, it took an average of 37 days for the viral load to reach that level. The trial is ongoing.
The researchers believe that the treatment interruptions may have prolonged the time to viral rebound. Also, Dr. Lori, who presented the results at the conference, believes that hydroxyurea may have some immune benefit, as well as enhancing the antiretroviral activity of ddI and some other drugs. The mechanism of any possible immune benefit is not known.
A followup on the Berlin patient was also presented at the Retroviruses conference.4
Measuring HIV-Specific CD4 and CTL Activity
Dr. Valentine, who presented the HAART plus Remune experiment, measured the ability of patients' CD4 T-helper cells to respond to HIV; the Aaron Diamond study measured the response to HIV of CD8 CTLs (cytotoxic T lymphocytes), instead of CD4 T-helper cells. What is the contribution of these two kinds of immune cells?
The ultimate answer is unknown, but there is strong evidence that CD8 CTLs are critically important for controlling HIV. It also appears that during primary HIV infection, when the level of virus is very high, CTLs may be able to control the virus with little or no help from the CD4 T-helper cells -- but that this help is essential for mobilizing the CTLs to keep the long-lasting chronic infection under control.
The HIV-specific CD4 T-helper cells (a small minority of the total T-cell count) may be especially important to measure -- and to restore -- because they are highly vulnerable to HIV infection -- which may explain why the HIV-specific T-helper response usually does not come back on its own.
1. Valentine F, DeGruttola V, and the Remune 816 Study Team. Immunological and virological evaluations of the effects of HAART compared to HAART plus an inactivated HIV immunogen after 32 weeks. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 [abstract #346].
2. Ortiz GM, Jin X, Demoitie MA and others. Containment of breakthrough HIV plasma viremia in the absence of antiretroviral drug therapy is associated with a broad and vigorous HIV specific cytotoxic T lymphocyte (CTL) response. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 [abstract #256].
3. Lori F, Zinn D, and Varga G. Intermittent drug therapy increases the time to HIV rebound in humans and induces the control of SIV after treatment interruption in monkeys. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 [abstract #LB5].
4. Lisziewicz J, Rosenberg E, Lieberman H and others. Immune control of HIV after suspension of therapy. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 [abstract #351].
Note: For instructions on how to obtain these abstracts, see "HIV-Specific Immunity: Major Conference Sessions," below.
HIV-Specific Immunity: Major Conference Sessions
You can read these abstracts on the Web. Go to http://www.retroconference.org/99/abstract.htm, and select 'Conference Abstracts.' Search for 'abstract nnn', where nnn is the abstract number given in the list below: e.g. 'abstract 256', or 'abstract 21' (without the single quotes). You will see the title and authors; click the underlined abstract number to see the full abstract.
You can also search the abstracts for a word or phrase. However, searching on authors' names is not reliable at this time (since any superscript which appears must be typed as part of the name).
Other Sessions Available by Computer
There is also a half-hour lecture with slides, "T-Cell Immunity During Acute and Chronic Viral Infection," which can be heard and seen in full on the Web, although no abstract was published. At the http://www.retroconference.org Web site, select 'Hear the Lectures', then select this one from the list.
A symposium, Immune Reconstitution and Clinical Implications, consisting of five lectures and slide presentations, can also be heard and viewed at the site. Select 'Hear the Symposia', then select this one, under Thursday, Feb. 4.
Houston, April 30: Eleventh Annual Houston Conference on AIDS in America
This event is free and open to the public. Continuing medical education credit is available (there is a $25 fee for the credit). The meeting will be held at the George R. Brown Convention Center, Friday April 30, with registration and continental breakfast starting at 7:00 a.m. and the first talk at 8:00 a.m. Advance registration is recommended; call International Meeting Managers Inc. at 713-965-0566.
3rd International Conference on Nutrition and HIV Infection (Focusing on Metabolic Complications)
Cannes, France, April 22-25
The official languages of the conference will be French and English, with simultaneous translation during the plenary sessions, slide sessions, and workshops. Slides and posters will be in English.
Advance registration is recommended, but there will also be on-site registration. For registration, fee, and hotel information, contact:
Or to obtain a copy of the Second Announcement of the meeting, send an email request to: email@example.com
International Health: Preparing for the 21st Century
San Francisco, February 27
Registration is $35 general, $15 student, and $50 exhibitor. For more information, contact Claire Norris, Conference Coordinator, International Health Office, 313 Warren Hall, School of Public Health, University of California, Berkeley, CA 94720-7360; telephone 510-642-6915, fax 510-643-8236, email firstname.lastname@example.org.
Note: Registration deadline is February 19; use the email address to request a copy of the registration form.
Copyright 1998 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.