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Limited Immune Recovery After Treatment with Antiretrovirals, IL-2; Interview with Clifford Lane,M.D.by John S. James
A person's "CD4 count" (the number of CD4+ T-cells per cubic millimeter of blood) is used as a rough indicator of immune system health. But the CD4 cells which are counted are not all the same. In a healthy individual, there are a billion or more different kinds of CD4+ T-lymphocytes -- each programmed to recognize only one specific antigen (foreign substance, such as part of a protein produced by a bacterium or virus).
In HIV infection, when the CD4 count becomes low (especially under 200), some of this "repertoire" of cells is lost; it is probably not immediately restored when the CD4 count rises in response to antiretroviral treatment (or to treatment with antiretrovirals plus IL-2 (Proleukin®), which causes growth of the CD4 cells which are still there). Eventually there may be some natural recovery of the repertoire -- or researchers might learn how to restore the repertoire by cell transplantation. Meanwhile, it may be possible for the immune system to function adequately even though some of its diversity is lost.
On May 31 AIDS Treatment News interviewed Clifford Lane, M.D., Clinical Director of the U.S. National Institute of Allergy and Infectious Disease. Dr. Lane is senior investigator of a research team which published a recent paper on immune recovery after treatment of HIV with antiretroviral therapy, or with antiretrovirals plus IL-2.(1) To introduce the interview, we wrote the following background section to explain some of the immunology involved.
Background: Different Kinds of CD4+ T-Cells
AIDS Treatment News often uses the term "CD4 cells" as a less complicated way of saying "CD4+ T-lymphocytes" -- which is technically more accurate, since there are CD4 cells which are not T-cells at all. This article is only concerned with T-cells, however.
T-lymphocytes are often named according to the molecules on their surface. CD4+ T-lymphocytes are those immune-system T- cells which have the CD4 molecule on their surface; CD8+ T- lymphocytes have the CD8 molecule. Both cells also have antigen-specific receptors on their surface. Each cell has approximately 10,000 or more copies of its antigen-specific receptor molecules on the cell surface.
The billion or more different kinds of these cells are due to a billion or more variations in the T-cell receptor. These variations occur when the cell is formed (usually near the beginning of life, in the womb or in early childhood). T- cells begin as undifferentiated stem cells -- special cells which are able to mature into any kind of blood cell. Certain stem cells are programmed by the thymus gland to become T- cells; when this happens, certain genes of the cell combine randomly, forming the immense number of different possible combinations. Many of the resulting receptors would cause the cells to attack the body itself, leading to autoimmune disease; these unwanted cells are destroyed in the thymus shortly after they are formed. A billion or more combinations remain -- probably enough to recognize some parts of all of the viruses, bacteria, or other disease-causing organisms the person will ever encounter.
Once a T-cell has been programmed, it can only recognize one antigen; its receptor cannot change further. It begins as a "naive" T-cell (one which has never encountered its antigen). If it does encounter its antigen (many cells never do), it changes into what is known as a memory cell. In a healthy adult, about half of the CD4+ T-cells are naive and half are memory cells; in people with HIV disease, the naive cells are more rapidly depleted, for reasons which are not entirely known.
Both naive and memory cells can divide and reproduce in the blood. This increases the number of cells, which can improve the immune response. But this kind of cell reproduction cannot expand the repertoire, because the new cells, whether naive or memory, are programmed the same as their parent (to recognize the same antigen). Only new CD4+ T-cells formed in a thymic environment can add to the repertoire -- and in adults, the thymus is largely inactive, so these new kinds of cells are usually formed very slowly.
Any group of cells -- usually just a few cells -- which have the identical receptor are referred to as a clonal population, since they probably all arose from a single cell (or clone). Since there can be a billion or more different clones in a healthy adult, it is not possible to count and study them all individually and know which ones are effective against which diseases. To make it possible to study this system, the clones have been divided into various families of related cells; one common system is to divide the many clones into "V-beta" families (the name is from a region of the genes which provide a major part of the variability). The recently published work of Dr. Lane and others(1) studied 22 of these families (which probably account for at least 95% of the total diversity in this cell population).
In the following interview, we occasionally added explanatory comments; these are shown [in brackets].
Interview with Clifford Lane, M.D.
ATN: What has been learned about the loss of diversity of CD4+ T-cells in advanced HIV disease? How much of the immunity comes back when the total CD4 count increases after treatment with antiretrovirals, or with IL-2 in addition to antiretrovirals?
Dr. Lane: The ability of the immune system to come back, following antiretroviral therapy, will depend on how much has been destroyed. The reason for this limited recovery is that the immune system is initially generated by stem cell differentiation through a thymic environment -- and this particular pathway [involving the thymus] appears to play a very small role in the mature adult human.
This has been confusing to immunologists because much of the work on this aspect of immunology has been done with mice and rats -- in which the lifespan of the animal and the lifespan of the thymus are not that different. But in humans, thymic function drops off greatly in childhood and then drops again in puberty, and the adult has very little remaining. There is some left; how much varies between people.
To understand this, it helps to look first at what happens to the adult human immune system following a major insult when HIV is not there -- for example, when the system is decreased through radiation or chemotherapy. The immune system can come back, but generally not all the way back to where it was.
With HIV, it is now clear that as immune health declines, the diversity in the repertoire of cells declines. You can block the virus and allow the total count to come up -- but what comes up, at least immediately, is mainly an expansion of the cells that were already there. The number of cells can increase to a new plateau, which may be higher or lower depending on the patient, and depending on the level of ongoing viral replication.
Even though the count does not go all the way back to normal, and some of the original diversity of cells is missing, you might still have an adequately functioning immune system. This is because the immune system has great redundancy in it. If the virus can be stopped, then with repeated antigenic challenge, what had been in effect a second-line set of clones can expand and become a first-line defense. The T-cell immune system's ability to adapt to the environment is phenomenal; this adaptability is its key characteristic.
Animal studies suggest that the number of different T-cell receptors you need [to maintain good health] is much smaller than the number you can make. You do not necessarily need a great number to be protected. In studies in rats, in which cells were transferred from a healthy animal to an ablated animal [one with its immune system destroyed], it was found that the best protection was from the memory cells compared to the naive cells -- and that it only takes a transfer of about a thousand clones to provide a good defense [in the animal; no similar experiment could ethically be done with humans]. The immune system can adapt, and low-affinity clones [those which are not especially good in recognizing a disease-causing organism] can expand to meet the needs of the environment.
ATN: And in HIV disease, the loss of diversity begins even at CD4 counts above 200, but becomes worse below 200?
Dr. Lane: It appears to be more pronounced as the count drops below 200.
ATN: Is there a similar repertoire with CD8 cells as with CD4 cells?
Dr. Lane: The CD4 repertoire is quite similar over time for a person, almost like a fingerprint; we can look at a diagram of the repertoire even after a year or more, and often tell whose blood it is. The patterns do change if a person has HIV infection, but the changes tend to be gradual over time. CD8 T-cells, on the other hand, are always coming and going in the blood, and they have a very chaotic repertoire. This difference may reflect the role of the CD4 cells as the control center of the immune system, vs. some of the more effector limbs of the system [such as the CD8 cells], that need to change more rapidly to deal with whatever the emergency is. The CD4 cells are more for surveillance, keeping an eye on things.
ATN: I heard that in cancer, after chemotherapy there could be some slow immune recovery over years.
Dr. Lane: That is true, but usually the system does not get all the way back to normal. Part of this slow recovery over time may be a trickling of cells through a thymic environment, in patients who have some remaining degree of thymic function.
ATN: What does this mean for prophylaxis of opportunistic infections -- pneumocystis, for example?
Dr. Lane: To me the first message is that if you are following a patient with a CD4 count of 50 who is on Bactrim, and start combination antiretroviral treatment and a month later the count is over 200, I would not stop prophylaxis at that point, as [immune recovery] takes time. Six months out, it would be a good question for a clinical trial. We simply do not know the answer today. Each physician needs to use his or her own judgment about the risks and benefits of prophylaxis [when it might or might not still be necessary, after partial immune recovery due to antiretroviral treatment]. The risk of an opportunistic infection is probably somewhat less [after the T-cell count rise] -- but how much less is unclear. It's not black and white; the immune system is not static but is actively changing, to try to do its best in host defense. Once the negative influence of HIV is taken away, what is left of the immune system can probably do a pretty good job.
IL-2 and CD4 Cell Increase
[Note: Dr. Lane suggested that AIDS Treatment News disclose that, as part of his government duties, he received a patent for his work with IL-2.]
ATN: In the recent paper(1), your team studied not only antiretroviral therapies to increase T-cell counts, but also IL-2 [which stimulates the growth of T-cells]. Is it the same picture with IL-2, of increasing only the cells that are already there?
Dr. Lane: Yes, with IL-2, the cell increases you get are an expansion of the cells already present. But there is one slight difference. The paper(1) looks at the increase in two different ways. Besides the V-beta families, our study also measured naive vs. memory cells, and found that in the setting of antiretroviral therapy alone they increased in parallel. (Naive cells are depleted most rapidly in HIV, and some patients with CD4 counts under 50 may have almost no naive cells.)
With IL-2 there is some preferential increase in naive cells. But though this makes the ratio of naive to memory cells more normal, it is probably not a benefit -- it may make the increase with IL-2 a little less desirable than the increase with antiretrovirals. Because with antiretrovirals, the cells that increase will tend to be in proportion to what antigens, what pathogens, are there. So, with antivirals alone, you may get a cell expansion which is directed more appropriately to each individual patient -- while with IL-2 you may get more of an expansion of whatever clones are there.
I do believe that the new cells [produced by IL-2 treatment] are totally functional CD4 T-cells.
ATN: But the only way to prove that is a large clinical trial -- since we do not have an accepted marker, like viral load, for immune treatments?
Dr. Lane: I feel very strongly that a phase III trial is needed. Before using IL-2 on a large scale for HIV treatment, we need to be sure that its benefits outweigh its disadvantages. There is often a burst of virus when IL-2 stimulates T-cell growth. And there are side effects of this drug. The T-cell increases are substantial and impressive. But unless they provide clinical benefit, they would not be very meaningful.
The problem is that to deliver IL-2 easily, you want to work with an earlier patient population -- because then you can use lower doses and give the drug less often. But to obtain clinical endpoints in an early cohort requires many patients to be followed for a long time.
This is a central challenge now in HIV medicine -- how do we determine the best way to manage patients? While short studies looking at changes in viral load will be helpful in determining the most potent antiviral drugs, I am not sure they will give us a clear picture on how best to manage patients over years.
ATN: What patient population should be studied with IL-2?
Dr. Lane: We are talking about those with a CD4 count of 350 and above -- and letting the antiretroviral strategy be at the discretion of the physician-investigator.
ATN: In that case, if the antiretrovirals work well enough, the trial will not get clinical endpoints, and it will not prove anything. But in case the antivirals do not work well enough over the long period, then you will see if there is any additional benefit from the IL-2. Is that the rationale of this trial?
Dr. Lane: Exactly. You are trying to increase your margin, increase the safety net. If drug resistance eventually develops, the patient will probably be better off with a CD4 count of perhaps 1,000 than with a CD4 count of 200. But if we can totally block the virus and maintain a healthy immune system with antiretrovirals alone, there will be no role for IL-2.
We now know how to use IL-2 with less toxicity than before and how to generate similar results with self-administered subcutaneous dosing(2), especially in early patients (in advanced patients you need higher doses). In early patients, my guess is that after three 5-day cycles of IL-2 over a six month period of time, we will be able to almost double the CD4 count. Then we can spread out the cycles of IL-2 -- maybe once a year, or once every two years.
ATN: Measure the CD4 count and give IL-2 only when they need it?
Dr. Lane: Yes. This is like the induction vs. maintenance used with many different kinds of therapies.
ATN: But with advanced patients you would have to treat more often?
Dr. Lane: Probably. It would become a more difficult clinical trial to carry out. And the answer for one group of patients should apply to the other as well -- since the key question is whether increasing the CD4 count as a result of IL-2 therapy is of clinical benefit. I think that the strategy of running a trial with more patients for a longer period of time, but with a regimen which is easier to administer, is probably more effective [than a smaller trial which uses a higher dose of IL-2 with more side effects].
ATN: The ethics and acceptability of this trial look quite good. It would not interfere with peoples' antiretroviral treatment at all; they would use whatever they want, and the IL-2 treatment would not be onerous.
Dr. Lane: This trial would find out if the benefit of T-cell expansion with IL-2 is enough to warrant the cost and trouble, and the side effects.
ATN: Is such a trial likely?
Dr. Lane: I believe we are going to do it -- but am not yet entirely sure of all the researchers and organizations who will be there when we start. A group of European and U.S. investigators who have expressed strong interest in such a trial will be at a meeting in mid June to make some final decisions on a draft protocol for review by the entire group. Hopefully at a meeting of the CPCRA (NIAID's Community Program for Clinical Research on AIDS) in July, we will come to final decisions on the protocol. In addition to the CPCRA and intramural NIAID, a consortium of European and Australian investigators, and the Canadian trials network, are currently part of this effort. My hope is that we will build the support close to a critical mass, and then get the additional help that we need so that this trial can happen.
The data are quite solid. The clinical data we have fit with the immunologic data. The viral levels certainly have not been going up in the randomized study. Our knowledge of many of the immunological and virological subtleties is in place as well.
[Note: An earlier clinical trial in 60 patients(3) found that when IL-2 was added to an antiretroviral regimen for 12 months, the average CD4 count increased from 428 to 916. In the control group with the same treatment except for the IL- 2, the average CD4 count fell from 406 to 349. But this trial was too small to show whether or not increasing the CD4 count in this way was beneficial to patients. In the long-term followup of this cohort there have been seven patients with AIDS-defining events among the patients originally randomized to the control arm, compared to two AIDS-defining events among the patients originally randomized to IL-2.]
1. Connors M, Kovacs JA, Krevat S, Gea-Banacloche JC, Sneller MC, Flanigan M, Metcalf JA, Walker RE, Falloon J, Baseler M, Stevens R, Feuerstein I, Masur H, and Lane HC. HIV Infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. NATURE MEDICINE May 1997; volume 3, number 5, pages 533-540.
2. Davey, Jr., RT, Chaitt DG, Piscitelli SC and others. Subcutaneous administration of interleukin-2 in HIV-1 infected individuals. JOURNAL OF INFECTIOUS DISEASES 1997; volume 175, number 4, pages 781-789.
3. Kovacs JA, Vogel S, Albert JM, and others. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. NEW ENGLAND JOURNAL OF MEDICINE October 31 1996; volume 335, number 18, pages 1350- 1356.
Viral Load in Clinical Trials: FDA Advisory Committee Meeting July 14-15, 1997
An important public meeting on using sustained changes in viral load as a substitute for clinical endpoints in certain trials of antiretroviral drugs will be held July 14 and 15 near Washington, D.C. The FDA's Antiviral Drugs Advisory Committee will meet from 8:30 a.m. to 5:00 p.m. each day in Room 204 of the Armory Place, 925 Wayne Avenue, Silver Spring, Maryland. (On July 16 the Advisory Committee will also meet at the same time and place, but on a separate topic -- approval of AmBisome® liposomal amphotericin B as empirical therapy for presumed fungal infection in febrile, neutropenic patients.) All three days of meetings are open to the public.
Persons who want "to participate in the open public hearing or to submit data, information or views to the committee" may do so during a public hearing scheduled for July 14 from 11 a.m. to noon. Those who want to speak should notify Rhonda Stover or John Schupp, at the Center for Drug Evaluation and Research (HFD-21), Food and Drug Administration, 301/443- 5455, or by fax at 301/443-0699, by July 7.
The Armory Place is near the Silver Spring Metro stop. Long- term metered parking is available at Fenton Street and Pershing Drive (payable with quarters only), and there is other parking in the area.
If there are any changes to the meeting schedule, they will be announced on the FDA Advisory Committee Hotline, 800/741- 8138 or 301/443-0572. The 5-digit code number for information about the Antiviral Drugs Advisory Committee is 12531.
Meetings Calendar, June 1997 - 1998
The following list includes research conferences (where new scientific information will be presented), plus selected other meetings that may interest our readers. We have not included invitation-only conferences.
If you know of other meetings that should be on this list, please let us know.
** New Perspectives in Treatment: Eradication, Suppression, & Lifelong Adherence: Where Are We? June 14, Cambridge, Massachusetts. Contact: New England AIDS Education and Training Center, 617/566-2283.
** HIV Treatment in the New Millennium: Is HIV Eradication Possible, June 18, New York. Contact: Saint Vincents Education & Training Department, Max Vaval or Andrew Boreland, phone 212/228-8000 x243 or x231.
** Fourth International Symposium on Clinical Immunology, June 19-22, Amsterdam, The Netherlands. Contact: Conference Secretariat, Fourth International Symposium on Clinical Immunology, Amsterdam RAI-OBA, P.O. Box 77777, 1070 MS Amsterdam, The Netherlands. Web site: http://www.rai.nl/congress/cic/en/welcome.html.
** FDA Antiviral Drugs Advisory Committee, July 14-15, also July 16, Silver Spring, Maryland. Contact: FDA, 301/443-5455. (See separate announcement in this issue.)
** AIDS Clinical Trial Group (ACTG), July 19-22, Washington, D.C. Contact: NIAID, 301/496-8215.
** HIV/AIDS in Cuba: Building Bridges, Crossing Borders, August 6-13, Havana, Cuba. Contact: U.S.- Cuba Medical Project, One Union Square West, Suite 211, New York, NY 10003. 212/727-3247, fax 212/727-3265, email firstname.lastname@example.org .
** National Black Nurses Association, 25th Institute and Annual Conference, August 7-10, New York, NY. Contact: NBNA, 1511 K Street NW, Suite 415, Washington, D.C. 20005; 202/393- 6870, fax 202/347-3808.
** The 15th Annual Symposium of the Gay & Lesbian Medical Association, August 21-23, San Francisco, California. Contact: GLMA Symposium, 459 Fulton St., Suite 107, San Francisco, CA 94102; 415/255-4547, fax 415/255-4784, email email@example.com, web site http://www.glma.org.
** Clinical Care of the AIDS Patient: Summer Symposium, August 21-26, Sun Valley, Idaho. Contact: Department of Medicine at the University of California San Francisco, School of Medicine, 415/476-5208, web site http://cme.ucsf.edu/.
** A Conference on Global Strategies for the Prevention of HIV Transmission From Mothers to Infants, September 3-6, Washington, D.C.
Logistics and abstract submission: Contact Ms. Andrea Hall, Social & Scientific Systems, Inc., 7101 Wisconsin Ave., Suite 1300, Bethesda, MD 20814-4805; 800/749-9620 (U.S. calls only), 301/986-1216 (dedicated meeting phone number), 301/986-4870 (accepts collect calls from outside the United States for "Global Strategies Conference" between 9:00 a.m. and 5:00 p.m. Eastern time), fax 301/913-0351, email firstname.lastname@example.org. (Dates: Early registration by July 3 receives discount. Abstracts due by June 27, late-breaking research by August 15.)
Scientific Program: Contact Arthur Ammann, M.D., 415/451- 1814, fax 415/456-2622, email Ammanndoc@aol.com.
** Community Programs for Clinical Research on AIDS (CPCRA), September 4-5, Washington, D.C. Contact: Elaine Allison, CPCRA Operations Office, 301/230-9670, fax 301/230-7190, email email@example.com.
** AIDS, Medicine and Miracles: 10th Annual HIV Conference Retreat, September 4-7, Phoenicia, New York. Contact: AIDS, Medicine and Miracles, 800/875-8770, email firstname.lastname@example.org.
** HIV-1 Infection, Mucosal Immunity & Pathogenesis, September 11-13, Natcher Conference Center, National Institutes of Health, Washington, D.C. Contact: Mr. Fred Hill, Conference Manager, HIV-1 Infection, Mucosal Immunity & Pathogenesis, c/o ComputerCraft Corporation, 6707 Democracy Blvd., Suite 101, Bethesda, MD 20817; 301/493-9674, fax 301/530-0634. (Registration Deadline: August 1, 1997; due to space limitations, early registration is encouraged.)
** International Congress on Biomedical Peer Review and Global Communications, September 17-21, Prague, Czech Republic. Contact: Annette Flanagin, American Medical Association, 515 N. State St., Chicago, IL 60610; 312/464- 2432, fax 312/464-5824.
** United States Conference on AIDS, September 18-21, Miami Beach, FL., sponsored by the National Minority AIDS Council (NMAC) Contact: Conference Registrar, The United States Conference on AIDS, 1931 13th St. NW, Washington, D.C. 20009- 4432; 202/483-6622 x313, fax 202/483-1127.
** 37th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 28- October 1, Toronto, Ontario, Canada. Contact: American Society for Microbiology (ASM), Meetings Department, 1325 Massachusetts Ave. NW, Washington, D.C. 20005-4171; 202/942- 9356, fax 202/942-9340. [Comment: ICAAC is likely to be important this year, because in odd-numbered years there is no International Conference on AIDS (now named World AIDS Conference) to draw research presentations away. Note: Future ICAAC meetings have been scheduled for September 1998 in San Diego, and September 1999 in San Francisco.]
** 6th European Conference on Clinical Aspects and Treatment of HIV Infection, October 11-15, Hamburg, Germany. Contact: K.I.T. GmbH, Kingress und Incentive-Organisation, Karl- Liebknecht Strasse 5, D-10178 Berlin, Germany; +49 30 2382 6900, fax +49 30 2382 6940, email email@example.com , web site: http://www.kit.de.
** Sixth Regional Symposium on the Design & Methods of Clinical Trials, October 17-18, San Francisco. Contact: Office of Continuing Medical Education, University of California, San Francisco, 415/476-5808 to register, 415/476- 4251 to receive a brochure when it is available.
** International Congress of Sexually Transmitted Diseases, October 19-22, Seville, Spain. Contact: International Congress of STD, Apartado 6077, 41080 Seville Spain; +34 5 4903409, fax +34 5 4377413. Or, HCC/ICSTD, One Bridge Plaza, Suite 350, Fort Lee, NJ, 07024, 201/947-5545, fax 201/947- 8406.
** 3rd Annual Conference: A Time for Healing--Women and HIV, October 22-24, Las Vegas, NV. Contact: Pat Stachewicz or Marlo Tonge, 702/383-1397.
** 4th International Congress on AIDS in Asia and the Pacific, October 25-29, Manila, Philippines. Contact: Secretariat, 2nd Floor, Physicians' Tower, 533 United Nations Ave., Ermita, Manila 1000, Philippines; +63 2 526-8103, or +63 2 526-8105, fax +63 2 522-1090 or +63 2 522-8130, email firstname.lastname@example.org, web site http://www.hain.org/ aidsphil.html.
** GNP 8th International Conference for People Living with
HIV/AIDS, November 5-12, Chiang Mai, Thailand. Contact:
GNP/ICW Conference Secretariat, 12/14 Rajchiangsaen Road,
Soi 2 Kot, Haiye, Chiang Mai 50100, Thailand, phone 53 206 760,
fax 53 206 761, email email@example.com;
Or, Conference Secretariat, Bangkok, +66 2 526 8311, fax +66 2
968 8021, email firstname.lastname@example.org. Or, GNP+ central
Secretariat, Amsterdam, +31 20 689 8218, fax +31 20 689 8059,
email email@example.com. Or, ICW Secretariat, London, +44 171
222 1333, fax +44 171 222 1242, email firstname.lastname@example.org.
** Tenth Annual Association of Nurses in AIDS Care Conference, November 6-9, Miami Beach, FL. Contact: ANAC Tenth Annual Conference, 11250 Roger Bacon Dr., Suite 8, Reston, VA 20190-5202; 800/260-6780.
** National AIDS Treatment Advocates Forum, November 9-12, San Diego, CA. Contact: David Barre, NATAF Registration, c/o National Minority AIDS Council, 1931 13th Street NW, Washington, D.C. 20009; 202/483-6622 x327, fax 202/483-1135, email NMACtx@aol.com
** Healthcare Resource Allocation for HIV/AIDS and Other Life-Threatening Illnesses, November 10-11, Washington, D.C. Contact: Paul Rathe, International Association of Physicians in AIDS Care, 312/419-7074, fax 312/419-7079, email email@example.com .
** International Conference on AIDS Wasting, (title may change), November 16-19, Ft. Lauderdale, Florida. Contact: IFARA (International Foundation for Alternative Research on AIDS), 954/630-8002.
** Clinical Care of the AIDS Patient, December 4-6, Palace Hotel, San Francisco. Contact: University of California San Francisco, Department of Medicine, Postgraduate Programs, Box 0656, San Francisco, CA 94143-0656; phone 415/476-5208, web site http://cme.ucsf.edu/ .
** AIDS Clinical Trial Group (ACTG), December 5-10, Washington, D.C. Contact: NIAID, 301/496-8215.
** Xth International Conference on AIDS & STD in Africa, December 7-11, Abidjan, Cote d'Ivoire. Contact: Programme National de Lutte contre le SIDA les MST et al Tuberculose, 04 BP 2113, Abidjan 04, Cote d'Ivoire; +225 243013, or +225 243014, or +225 244306, fax +225 243119, web http://www.us.unaids.org/lowband/events/abidjan/introduction. html
** T Lymphocyte Activation, Differentiation and Death, January 26-February 1, Keystone, Colorado. Contact: Keystone Symposia, Drawer 1630, Silverthorne, CO 80498; 800/253-0685 or 970/262-1230, fax 970/262-1525, email firstname.lastname@example.org, web site http://www.colorado.net/symposia .
** 5th Conference on Retroviruses and Opportunistic Infections, late January or early February, 1998. In previous years this conference has been held in Washington D.C., but other cities are now being considered.
** Molecular Aspects of Viral Immunity, February 16-22, Tamarron, Colorado. Contact: Keystone Symposia, Drawer 1630, Silverthorne, CO 80498; 800/253-0685 or 970/262-1230, fax 970/262-1525, email email@example.com, web site http://www.colorado.net/ symposia.
** Cell and Molecular Biology of Dendritic Cells, March 7-13, Santa Fe, New Mexico. Contact: Keystone Symposia, Drawer 1630, Silverthorne, CO 80498; 800/253-0685 or 970/262-1230, fax 970/262-1525, email firstname.lastname@example.org, web site http://www.colorado.net/ symposia.
** HIV Pathogenesis and Treatment, March 13-19, Park City, Utah. Contact: Keystone Symposia, Drawer 1630, Silverthorne, CO 80498; 800/253-0685 or 970/262-1230, fax 970/262-1525, email email@example.com, web site http://www.colorado.net/ symposia.
** Angiogenesis and Vascular Remodelling, March 28-April 3, Steamboat Springs, Colorado. Contact: Keystone Symposia, Drawer 1630, Silverthorne, CO 80498; 800/253-0685 or 970/262- 1230, fax 970/262-1525, email firstname.lastname@example.org, web site http://www.colorado.net/ symposia.
** TB: Molecular Mechanisms and Immunologic Aspects, April 2- 8, Keystone, Colorado. Contact: Keystone Symposia, Drawer 1630, Silverthorne, CO 80498; 800/253-0685 or 970/262-1230, fax 970/262-1525, email email@example.com, web site http://www.colorado.net/ symposia. (Note: registration for this conference also allows for attendance at the meeting below.)
** Opportunistic Infections in AIDS, April 2-8, Keystone, Colorado. Contact: Keystone Symposia, Drawer 1630, Silverthorne, CO 80498; 800/253-0685 or 970/262-1230, fax 970/262-1525, email firstname.lastname@example.org, web site http://www.colorado.net/ symposia. (Note: registration for this conference also allows for attendance at the meeting above.)
** 12th World AIDS Conference, June 28 - July 3, 1998, Geneva. Deadline for regular abstract submission, and for scholarship applications, is February 2, 1988. Contact: Secretariat, 94 rue des Eaux-Vives, CH-1207 Geneva, Switzerland; phone +41 22 737 33 44, fax +41 22 700 33 11, email email@example.com, web site http://www.aids98.ch.
** 4th International Congress on Drug Therapy in HIV Infection, November 8-12, 1998, Glasgow, Scotland. Contact: Gardiner- Caldwell Communications Ltd., +44-1625-664000, fax +44-1625-610260.
Copyright 1997 by John S. James.
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