Basic science priorities for therapeutics research.

Abstract

For more than 10 years, drug discovery efforts have concentrated on relatively few viral targets: reverse transcriptase (RT) and protease (PR). While viral load can be reduced by combining RT and PR inhibitors in regimens referred to as highly active antiretroviral therapy (HAART), recent studies suggest that many treatment failures occur because of the development of drug resistance and lack of adherence to complicated and often toxic regimens. Recently, new classes of agents directed at the virus binding and entry process have entered the development pipeline, with one such agent now approved for use in patients with HIV. Early data suggests, however, that the development of resistance will continue to be a problem as new agents are introduced into HAART regimens. With regard to the immune system, it has become clear that the damage caused by HIV infection is only partially reversed by HAART. Vaccination represents a major new immunologic approach to complement drug treatment. Thus, while advances continue to be made, there remains an urgent need for the identification of new host and viral targets, novel drugs and delivery systems, and immunologic approaches to address the dual problems of drug resistance and toxicity. To address this need, the Division of AIDS has established basic science priorities in the following areas of therapeutics research: host and viral targets, inhibitors, vaccines, innate immunity, viral reservoirs, and gene therapy.

Presentation Summary

Sandra Bridges, PhD, is the Chief of the Targeted Interventions Branch in the Basic Sciences Program at the Division of AIDS (DAIDS) at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services (DHHS). Part of her job as a program officer at DAIDS is to formulate the basic science priorities for HIV/AIDS therapeutics research and then to facilitate research in those areas. In her keynote address, Bridges outlined the most important questions of basic science research as identified in an earlier basic sciences program retreat in which she participated.

Are there important viral or host targets yet to be exploited? The most commonly used therapies target 2 viral enzymes, reverse transcriptase (RT) and protease (PR), and a great deal of research is being done on improving dosing, overcoming problems of viral resistance, reducing toxicities, etc. However, not enough emphasis is being placed on identifying new targets that, for instance, would not be affected by viral RT or PR resistance. Some of the targets that might be important include structural elements (such as the highly conserved zinc finger motif of the HIV nucleocapsid or the viral enzymes integrase and RNase H), regulatory and accessory proteins, processes (such as transcription, nuclear import and export of viral nucleic acid, and macromolecular interactions), and host targets (adhesion molecules, transcription factors, apoptosis, and signaling pathways). One important aspect of working on a new target for an anti-HIV drug is to validate the target in vivo using an animal model.

What are the best candidates for development as topical microbicides? Bridges noted that research in this area is still in its infancy. Such agents might be HIV-specific or nonspecific, and one challenge has been to identify chemical classes of potential microbicides. Nonhuman primates are being used to study topical microbicides for the prevention of sexual transmission, but such a model has not yet been validated (ie, there is no "gold standard" to match any success against) and the development of other animal models may prove useful. Also, some experimental drugs that are not suitable for systemic use because of toxicity or unfavorable physical characteristics (eg, solubility) may be applicable as topical microbicides.

Can innate immunity be manipulated to benefit HIV-infected individuals? The identification of molecules that affect innate immunity remains a challenge. Bridges pointed out that it might be better to find agents that stimulate innate immune cell expansion and function in vivo rather than simply to administer already identified molecules, such as cytokines, which may be insufficient to mimic the complex interactions that lead to responses in vivo.

Fully characterizing innate immune responses in infected humans or animals remains to be accomplished, as does the development of nonhuman primate models to study potential interventions.

Can vaccines be useful in the treatment of HIV-infected individuals in the era of HAART? With therapeutic vaccine candidates, the route and schedule of administration, as well as the type of patient populations (for instance, acutely versus chronically infected patients) that can most benefit from such vaccines, have yet to be determined. In addition, there are safety issues to consider. Early attempts to study therapeutic vaccines did not yield promising results because viremia could not be controlled. However, according to Bridges, HAART offers a second chance for such vaccines to be studied, and this area of research is a high priority for the basic science program at DAIDS. The goal of this approach would not be to cure HIV, but to allow infected individuals to better control viremia, to build better immune responses, and to spend less time on HAART.

Can viral reservoirs be targeted therapeutically? Viral reservoirs continue to be an area of interest in HIV research. One challenge in this area is that new reservoirs in the human body continue to be discovered. Some reservoirs comprise cells that are transcriptionally silent, while others contain cells that allow restricted HIV replication. Ongoing work aims to identify molecules or agents that can "purge" reservoirs. Recently, Robert Siliciano's group has developed a complete set of reagents for quantitating reservoirs in nonhuman primates. This development will be helpful in assessing the actual effects of new therapeutic vaccines or pharmacologic agents on the reservoirs (eg, determining whether the reservoir has been reduced and by how much). Several preclinical and clinical studies on viral reservoirs have been carried out or are in progress using agents such as interleukin-2, OKT3, interferon-[gamma], and prostratin.

What are the current obstacles to the clinical assessment of gene therapy strategies for HIV/AIDS? Now that several therapeutic targets have been identified for HIV, gene therapy in HIV research faces the same challenges that confront gene therapy for any disease. One such problem is low transduction frequency. Other challenges include establishing long-term and stable expression of transgenes, ensuring survival and expansion of transduced ceils in vivo, and improving delivery of gene therapy.

In conclusion, Bridges reviewed the resources available to researchers through the Division of AIDS. In terms of funding, besides the unsolicited R01 grants, innovation grant programs in therapies (R21 grants) are now available. Another funding program is "Targeting Research Gaps." A third program deals with translational research, which brings mature therapeutic concepts from basic science into clinical study in small numbers of patients, usually with a commercial partner. Several vaccines and other therapeutic approaches are being tested through this program (see Figure). Other resources include the NIH AIDS Research and Reference Reagent Program, as well as the Inter-Institute Program between the National Cancer Institute (NCI) and NIAID. The Inter-Institute Program facilitates access to specialized contract resources such as pharmacology and toxicology, drug resynthesis, immunology, confirmatory in vitro testing, and testing in animal models including SCID-hu mice, nonhuman primates, etc.

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For more information and related resources, visit www.niaid.nih.gov/daicls/on the Web.

Sandra Bridges, PhD

Division of AIDS, National Institute of Allergy and Infectious Diseases