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Recent Meeting with NCI Director Dr. John Niederhuber Highlights the History, Strategy, and Successes of HIV/AIDS Research at the CCR
n November 6, 2006, NCI Director John Niederhuber, MD, met with several of CCR’s leading scientists conducting research in HIV/AIDS and AIDS-associated malignancies to discuss the advances they have been making in the laboratory and the clinic. NCI’s Intramural Research Program (IRP) has played a leading role in HIV/AIDS research for almost 25 years. In this article, which is based on discussions from the meeting with Dr. Niederhuber, I briefly review the history of HIV/AIDS research in the IRP, describe the important role that IRP scientists play in this area of research today, elucidate CCR’s strategy for HIV/AIDS research, and summarize current research efforts and the tremendous gains our scientists are making in these investigations. History Robert Yarchoan, MD, Chief of the HIV and AIDS Malignancy Branch, opened the meeting by providing background information on HIV/AIDS research in the IRP. As Dr. Yarchoan noted, one of the first signs of the AIDS epidemic was an outbreak of Kaposi’s sarcoma in young men; indeed, AIDS would go on to fuel an epidemic of certain cancers. In response to this, several NCI researchers immediately turned their attention to this new disease. At the onset of the AIDS epidemic, IRP investigators possessed critical expertise in several key areas that allowed them to address this public health crisis:
In part, as a result of this expertise, IRP scientists were able to make quick, substantive advances in the emerging HIV/AIDS crisis in the early 1980s. Without their contributions, progress in HIV/AIDS research would not be as advanced as it is today. In 1984, just three years after the first AIDS patient was admitted to the Clinical Center (Metabolism Branch), the group led by Robert Gallo, MD, then at the NCI’s Laboratory of Tumor Cell Biology, and a team at the Pasteur Institute in France were able to identify the retrovirus HIV as the causative agent of AIDS. That same year, the first diagnostic blood test for HIV infection was developed at the NCI. Soon thereafter, Samuel Broder, MD, Robert Yarchoan, MD, and Hiroaki Mitsuya, MD, PhD, began to seek effective therapy for AIDS, and discovered or co-developed the first effective drugs—AZT (zidovudine), ddC (zalcitabine), and ddI (didanosine). In particular, this group identified the anti-HIV activity of these drugs and, with support from other NCI components, conducted the initial clinical trials. These drugs would become the first U.S. Food and Drug Administration (FDA)–approved anti-HIV drugs. Today, they are combined with other agents to form a treatment called highly active antiretroviral therapy (HAART). Since they were first introduced, AIDS therapies are estimated to have saved at least 3 million life-years in the United States (Walensky RP et al. J Infect Dis 194: 11–19, 2006) and have reduced the burden of HIV-associated cancers such as Kaposi’s sarcoma and certain lymphomas. This kind of research productivity continues to this day. The CCR currently has one of the largest and most productive HIV/AIDS research programs in the world.
During the meeting, Dr. Niederhuber noted that cancer research is a model for research in many other areas and that there are common threads between cancer and AIDS. During his presentation, Dr. Yarchoan expanded on this theme by explaining the interrelationships between research on AIDS-associated malignancies and research on HIV itself. He explained that there is a unity to research on all retroviruses, including those that cause cancer and AIDS. At the translational level, anti-HIV therapy is much like cancer therapy. Both involve multidrug therapies, long-term treatment, and problems of toxicity and drug resistance; these particular similarities stem from the fact that HIV infection and cancer are both chronic diseases that evade and/or suppress the immune system. Jay Berzofsky, MD, PhD, of the Vaccine Branch, noted that “Because of these parallels, there is much opportunity for cross-fertilization between the two fields of study.” For more than two decades, the intramural program has made many contributions to HIV/AIDS research, providing new ideas, fresh approaches, and a long history of successes, ranging from the establishment of diagnostic tools to drug development and clinical treatments. HIV/AIDS research evolved naturally in the IRP because of the retroviral work already being performed in the program prior to the onset of the AIDS epidemic. Today, the CCR has one of the greatest concentrations of scientists combating HIV/AIDS. Our investigators have broad, complementary, and synergistic expertise that they direct toward a better understanding of this disease, and continually provide abundant returns on the investments made in CCR's HIV/AIDS research programs. Interactions with the Extramural Community IRP investigators are encouraged to pursue high-risk research that can have a major impact, but which may be too difficult or risky for academia or industry. However, they have forged fruitful partnerships with extramural scientists as well as investigators in other institutes of the NIH. A large part of the success of these partnerships stems from the resources our investigators have shared with the other researchers. Stuart Le Grice, PhD, of the HIV Drug Resistance Program (DRP) Resistance Mechanisms Laboratory, noted that the large-scale virus culture facilities of the NCI-Frederick AIDS Vaccine Program, which were critical to the initial development of diagnostic kits to screen the blood supply for HIV-1 two decades ago, have since provided an invaluable source of highly purified virus for both basic and applied research. Intramural investigators have long been prolific and generous providers of reagents for HIV research. These materials have been shipped worldwide to academic institutions, industry, and governmental agencies. Although some reagents have been licensed to commercial enterprises, most are provided at no charge to qualified scientists trying to develop more effective ways to treat HIV/AIDS. Additionally, intramural scientists have developed and shared highly sensitive methods of HIV detection for analyses of patient samples from a variety of clinical studies. They have also given others free access to the databases they have developed and maintained over the years, which continue to serve as important sources of information for many scientists, educators, and students. Strategy, Investigations, and Recent Successes The CCR has developed an infrastructure that allows flexibility and fosters innovation. Although basic research is a substantial part of the CCR’s work, the Center has as strong a commitment to translational and clinical research. Basic, translational, and clinical scientists form multidisciplinary teams that are pursuing new approaches for the prevention and treatment of HIV/AIDS. CCR investigators have been integrating discoveries made in basic research laboratories and in animal and tissue models with clinical research and are working to produce new drugs and technologies that will improve the lives of patients with HIV/AIDS. The principal areas of focus of HIV/AIDS research at the CCR are drug resistance and drug development, vaccines and immunotherapy, AIDS-associated malignancies, and translational and clinical research in these areas. Specific examples of the high-impact research being performed by CCR investigators were presented to Dr. Niederhuber and are briefly described below. Drug Resistance and Drug Development Stephen Hughes, PhD, of the HIV DRP Retroviral Replication Laboratory, discussed efforts to develop new drugs and drug strategies that will be effective against both wild-type HIV-1 and the known drug-resistant mutants. He described ongoing efforts within the CCR to better understand the structures of two key drug targets—integrase (IN) and reverse transcriptase (RT)—and to better understand the mechanisms by which RT develops resistance to the available drugs. Data from these studies have been made available to intramural and extramural researchers and are being used to develop new and more effective inhibitors of HIV-1. Dr. Hughes also described complementary efforts within the CCR to screen and develop drugs that work against new targets, such as RT-associated RNaseH activity and the viral structural protein Gag. Panacos Pharmaceuticals, working with CCR scientists, has developed a novel inhibitor that blocks a specific step in the maturation of Gag. The inhibitor is currently in late-stage clinical trials. Vineet KewalRamani, PhD, also of the HIV DRP Retroviral Replication Laboratory, discussed his work in developing a new macaque model that can be used to test anti-HIV therapies and to investigate the cellular origins of HIV reservoirs in humans. The new model uses RT-SHIV, a chimeric virus that is based on a simian immunodeficiency virus (SIV) and encodes a key drug target, RT, from HIV-1. Unlike SIV, RT-SHIV is susceptible to a commonly employed HAART. Dr. KewalRamani is using the model to screen for the virus-infected cells that persist during HAART. He also noted that the model has the potential to help answer critical questions about the development of antiviral drug resistance and will be a valuable tool for the development and evaluation of new drugs.
Dr. Berzofsky gave an overview of the challenges in vaccine development, such as HIV strain diversity and rapid mutation rate, latent reservoirs of virus, lack of CD4 T-cell help, and the difficulty with HIV envelope structure for inducing broadly neutralizing antibodies. He also summarized results indicating the need for high-avidity T cells to clear virus infection and for mucosal immunity, both to prevent mucosal transmission and to clear the major reservoir of virus in the gut mucosa, based on data from his lab and the Vaccine Branch. He noted that CCR scientists are well positioned to address these challenges because of expertise in cancer vaccines, T-cell immunology, mucosal immunology, and retrovirology. Marjorie Robert-Guroff, PhD, also of the Vaccine Branch, described her work in developing a replication-competent adenovirus-HIV recombinant vaccine that has mucosal tropism for induction of mucosal immunity, critically important for preventing HIV infection. This live, replicating vaccine elicits enhanced immune responses compared to current non-replicating vaccine candidates and has demonstrated potent protective efficacy in preclinical studies. Dr. Robert-Guroff is establishing a phase I trial of oral, replication-competent adenovirus-4-HIV env in HIV-negative volunteers, to be conducted at the Clinical Center in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID). Jeff Lifson, MD, of the AIDS Vaccine Program, summarized research on a novel vaccine approach based on chemically inactivated virions that retain structurally and functionally intact envelope glycoproteins on their surfaces. These virions, developed as an outgrowth of basic research findings by AIDS Vaccine Program investigators, are being extensively used as reagents by hundreds of investigators for a variety of research applications. Dr. Lifson and his colleagues are studying their potential as vaccine immunogens in non-human primate models and are working with leading clinical investigators in the United States and Europe to establish an early phase clinical trial. Clinical Applications/AIDS-associated Malignancies John Coffin, PhD, of the HIV DRP, discussed recent advances in the area of clinical research. He discussed the development, in the HIV and AIDS Malignancy Branch, of combinations of drugs containing interleukin-12 as novel therapies for Kaposi’s sarcoma. He then noted that DRP investigators have devised highly sensitive assays that can be used to measure HIV levels in plasma less than 1 virion per mL and to determine the frequency of drug-resistant mutants in infected patients. These investigators have been working closely with collaborators in the NIAID HIV clinical program and at academic institutions and pharmaceutical companies worldwide to apply these assays to patient samples from a variety of clinical studies. DRP investigators have also shown that treating South African women with a single dose of the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (to prevent mother-to-child transmission) induced persistent NNRTI-resistance mutations in approximately 70% of the study subjects. Dr. Coffin stated that the potential of these mutations to compromise further treatment options for women treated with this agent is a serious but, as yet, poorly understood issue. Mary Carrington, PhD, of the Laboratory of Genomic Diversity, summarized her
research with the chemokine receptor gene CCR5, which encodes a protein that serves
as the major cellular co-receptor for HIV-1. CCR investigators were among the first to identify a 32–base pair deletion in the coding region of this gene that protects against HIV-1 infection in people who are homozygous for the mutation and slows AIDS progression in heterozygous individuals. This was the first major success in the identification of a genetic variant that affects the outcome of HIV-1 exposures and infections. Dr. Carrington noted that in some cases, genetic studies have guided functional work, and that the design of drug therapies and vaccines against HIV has been based partly on genetic studies. Dr. Niederhuber’s goal for the meeting was principally to have a dialogue with key researchers about the basic, translational, and clinical research over the last two decades to combat HIV/AIDS. He also wanted to express his appreciation for CCR’s HIV/AIDS and AIDS malignancy research programs and to stress their importance to the Institute. The CCR has a rich and proud history of HIV/AIDS and AIDS-associated malignancies research. We have continuously proven ourselves to be a powerful force in the worldwide effort to resolve this growing health crisis, and we look forward to future successes. We are very grateful to Dr. Niederhuber for taking time from his busy schedule to have a scientific discussion with us, and we are particularly grateful for his continued support of our HIV/AIDS and AIDS malignancy research programs.
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NCI’s HIV/AIDS Research—An Excellent Investment
Vaccines and Immunotherapy