Diseases (CIRID) sponsored by the NIAID have been encouraged to emphasize treatment of AIDS patients and education of the local medical community.

As new insights in the treatment of AIDS emerged, an extensive series of outreach programs and seminars have been carried out to widely disseminate information. Over the past two years the NIH has sponsored treatment workshops on both the infectious complications of AIDS and HTLV-III. The NCI held a workshop dealing exclusively with human retroviral diseases in December, 1984. (The proceedings will be published in the September issue of Cancer Research.) NIAID has sponsored nine outreach programs in metropolitan areas across the country. It also sponsored meetings at the Rocky Mountain Laboratory in November, 1984, and, in conjunction with the NCI at the National Clinical Meetings, in May, 1985. The PHS recently held a workshop on antivirals at NIH ( copy of the report can be submitted for the record) and sponsored the International AIDS meeting held in Atlanta (April 15-17, 1985). European

investigators were also invited to attend and present their data at several of these meetings.

Under the overall guidance of the PHS Executive Task Force on AIDS, we have established a Task Force on Vaccine Development and Therapeutic Intervention under the chairmanship of Dr. James Wyngaarden, Director of NIH, to coordinate and expedite research efforts on therapeutic modalities. This is being accomplished by giving special priority to grant applications in this area, increased efforts in intramural research, expedited reviews of

IND applications by the FDA and the issuance of Requests for Applications (RFA) and/or Proposals (RFP) as appropriate. The NIAID has recently released a RFA requesting applications for comprehensive studies of AIDS, including epidemiology, basic reseach (pathogenesis, treatment, and prevention) and clinical trials.

There exists an array of distinct but complementary research efforts throughout the United States-and especially in regions where there is high incidence of AIDS-pursuing many promising leads for improving therapy of AIDS patients. The next step is to link these activities and their results to a tightly coordinated network of hospital-based research units in which patients with AIDS can gain access to the expected new therapies on a carefully controlled experimental basis-i.e., through their participation in clinical trials. It should be stressed that extensive therapeutic clinical trials cannot be undertaken unless there are well documented data to support such undertakings. Key building blocks for this network already exist--e.g. the Comprehensive Cancer Centers supported by the NCI; a consortium involving the NIAID and nine major medical centers in strategially important locations (four in California, three in New York, one in Boston, and one in Texas) and the General Clinical Research Centers supported by the NIH Division of Research Resources. The Directors of NCI and NIAID and their staffs will be holding a retreat in the near future to discuss further research collaboration. What remains to be done is to establish a coordinating mechanism based at the NIH to ensure

that this extraordinary coalition of talent and clinical facilities is energized to evaluate new AIDS therapies in human patients as promptly as is scientifically and ethically appropriate and to share the results broadly within both the medical community and the general public. The time is right for such a coordinating mechanism, and the Director, NIH, already has taken steps to establish it. I am confident that effective and efficient means for clinical testing of new AIDS therapies will be in place to exploit the new therapeutic development we expect in the years immediately ahead.

In addition to the therapeutic approaches I have outlined, the PHS is working on a vaccine to prevent AIDS. We have also developed a comprehensive plan for control and prevention of AIDS that emphasizes education and information activities and includes a framework for the research we have discussed today.

That concludes my statement, Mr. Chairman. My colleagues and I would be happy to answer any questions you might have.

A Report of the AIDS Antiviral Agent Workshop

A PHS workshop was held June 3, 1985 on the NIH campus to discuss the current status and future applications of antiviral agents to prevent or treat AIDS. In opening remarks Dr. Wyngaarden stressed the importance of this disease and the need to pursue a solution through prevention and therapeutic modalities.

The first part of the morning was devoted to discussing the difficulties encountered in developing and testing therapies for this disease. Several postulates about approaches to treatment were addressed.

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HTLV-III/LAV is an essential factor in the etiology of AIDS.
There is sufficient evidence to accept this fact.

Active replication of HTLV-III/LAV is important in the pathogenesis and progression of AIDS. Therefore, strategies to inhibit replication of virus are rational approaches in AIDS or related diseases.

Complex

Cells that are affected with HTLV-III/LAV die quickly. strategies that act quickly may be necessary. However, other reservoirs for HTLV-III/LAV may exist. If so, short courses may not be effective.

Most lymphocytes are not infected by virus at any one time. Therefore, treatment should be selective for infected lymphocytes. Immune modulators may be used to selectively stimulate the uninfected lymphocytes.

Depletion of T cells characteristic of AIDS results from spread of the virus from one cell to another either by direct cell-tocell contact or by contact with extracellular fluid containing virus. If possible, one should interact in this disease early before too many cells have become infected.

Strain variability of HTLV-III/LAV exists. When possible we should test promising agents against different strains of the virus.

We must determine the reproducibility of the assay systems for HTLV-III/LAV between labs and determine the ability of such assays to predict clinical response.

Because of the difficulty of virus isolation and quantitation, other parameters of efficacy must be sought for testing antiviral agents.

Subsequent discussions addressed the nature of HTLV-III/LAV, its likely pathogenic mechanisms, and possible targets for therapy. Ongoing studies on the molecular biology of the HTLV-III/LAV replication process are important to better understand its pathology and also to identify possible targets for antiviral agents. A possible first target is the receptor site on the cell surface. Immunoglobulin or antiviral agents could be developed which would be able to complex the virus or the cell receptor and block absorption or penetration of the virus into the target cell. HTLV-III/LAV has an envelope that is heavily glycosylated. In addition to affecting a change in this viral envelope, agents may be developed which alter the membrane of the target cell to prevent absorption or penetration. Second, reverse transcriptase (RT), a viral enzyme, catalyses the RNA to DNA transcription step in the cytoplasm of the target cell. RT is therefore a very important target. Several agents, e.g. suramin, HPA-23 and PFA, are known to inhibit RT in vitro. More effective agents may be developed which would inhibit the RT of the virus and not inhibit the cytoplasmic enzymes of the host. Agents directed at other viral proteins could also be developed. Third, viral DNA is integrated in the nucleus of the cell; some DNA may remain in the cytoplasm. Following integration, the cell will produce virus and other gene products (transacting transcriptional activation). These gene products may be specific proteins, and some may bind to portions of the virus, e.g. the LTR (long terminal reading) portion. Many unusual RNA splicings may occur. The products and splicings may hasten the maturation process of the cell and lead to cell death and lysis.

Some of the issues which emerged in the general discussion included:

What are the target cells or reservoir cells for HTLV-III/LAV? Helper cells are obviously infected, but what other cells may become infected, e.g. other lymphocytes, macrophages, neural cells?

Does one have to eliminate all infected cells to reverse the
disease process? This, unfortunately, is likely. If this is
true, patients with only a few cells infected are more likely
to respond to therapy. Therefore, treatment soon after
HTLV-III exposure may be necessary. If treatment can only
suppress and not eliminate the virus, lifetime therapy may be
needed.

Will drug combinations be needed? Probably, it appears that the virus must be removed and the immunologic system must be reinstated before health is restored.

Will drug resistance develop? If long-term treatment is necessary, this is probable. However, combinations of agents acting at different stages of viral replication may make resistance less likely.

The assay systems for HTLV-III/LAV were discussed. Virus isolation and quantitation are difficult and other means of measuring virus are desirable.