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HIV/AIDS Research at the NCI:A Record of Sustained Excellence

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HIV/AIDS Research at the NCI: A Record of Sustained Excellence National Cancer Institute Institute Cancer National U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health HIV/AIDS Research at the National Cancer Institute: A Record of Sustained Excellence Letter from the Director of the CCR ............................................................................................................1 The Early NCI Retrovirus Experience ...........................................................................................................2 A New Virus Revealed ......................................................................................................................2 Risk Factors ........................................................................................................................................4 A Tale of Two Diseases ...............................................................................................................................5 Treating the Infection .........................................................................................................................5 Treating the Cancers .........................................................................................................................6 HIV and the Immune System: How They Interact........................................................................................8 Susceptibility to Infection, AIDS, and Related Diseases ..........................................................................10 Outsmarting a Formidable Foe: Viral Diversity and Drug Resistance........................................................12 HIV Variation ....................................................................................................................................12 HIV Assays .......................................................................................................................................12 The Evolution of Resistance .............................................................................................................13 Better Ways to Find Better Drugs..............................................................................................................14 Structural Biology .............................................................................................................................14 Taking Advantage of Nature’s Products ...........................................................................................15 Looking Ahead: Vaccines to Prevent Infection ..........................................................................................17 DNA Vaccines ..................................................................................................................................17 Neutralizing Antibodies ...................................................................................................................17 Novel Whole Inactivated Vaccines ..................................................................................................18 Live Vector Vaccines ........................................................................................................................19 Center of Excellence: Bringing It All Together...........................................................................................20 The many common threads between cancer and HIV/AIDS underscore the value of NCI’s involvement in HIV/AIDS research. — NCI Director John E. Niederhuber, M.D. Letter from the Director of the Center for Cancer Research In 1981, the NIH Clinical Center admit­ The NCI IRP collaborates with research­ ted its first patient with acquired immune ers and clinicians in other NIH institutes, deficiency syndrome (AIDS) into the universities, medical centers, and indus­ clinical service of the National Cancer try. To facilitate a broader, cost-effective Institute’s (NCI) Metabolism Branch. AIDS research effort, the NCI intramural Since these earliest days of the deadly program makes many resources developed epidemic, the NCI has been a leader in here available to partners in academic AIDS research. NCI intramural scientists institutions and pharmaceutical companies were able to quickly apply their expertise free of charge. These include: 1) highly in epidemiology, cancer, retroviruses, cell purified preparations of HIV and other biology, the immune system, and drug retroviruses; 2) biological reagents such as development to this public health crisis. purified proteins, antibodies, recombinant Over two decades later, their commitment DNA vectors and cell lines; 3) natural and and contributions remain strong. synthetic small molecule libraries; 4) highly sensitive methods for HIV detection; and The NCI intramural research program 5) databases, including the HIV Protease (IRP) is a unique nexus for basic, clini­ Database and the Chemical Structure cal, and translational research. Its mission Dr. Robert Wiltrout Lookup Service. Our resource sharing is a is to forge a deeper understanding and critical component of the NCI commit­ to develop more effective means for the ment to speed the development of more After more than two decades of important prevention, diagnosis, and treatment effective treatments. contributions, it seems fitting to take time of cancer and AIDS. In pursuit of this goal, to acknowledge and reflect on the cur­ Progress against HIV infection and AIDS, dedicated researchers work independently rent AIDS research effort and the many diagnoses once perceived as an automatic and in multi-disciplinary teams to make advances that have already been made death sentence, has been striking. Deaths discoveries, develop new technologies and within the CCR and NCI IRP, as these in the United States have dramatically approaches, and translate their advances achievements serve as the foundation declined since the 1990s, when effective into clinical practice. for continued scientific excellence. The combination antiretroviral therapy was research featured on the following pages The NCI IRP, which includes the Center introduced. In 2005, 17,011 people died demonstrates how NCI’s investment and for Cancer Research (CCR), has a unique of AIDS in the U.S.—about one-third sustained commitment to exploration and ability to integrate multiple scientific the 51,414 deaths in 1995. But major discovery has led to, and continues to lead disciplines and approaches in support of challenges remain. People now living to, new approaches and interventions to scientific discovery. Our Centers of Excel­ longer with HIV are facing an increased improve the lives of patients with cancer lence, Faculties, Working Groups, and Pro­ cumulative risk for AIDS-related as well as and HIV/AIDS. grams successfully cut across organizational other cancers; the pandemic of AIDS and boundaries to foster collaborative research. AIDS-associated cancers is a devastating Robert H. Wiltrout, Ph.D. The newly formed Center of Excellence presence in developing countries; and the Director, Center for Cancer Research in HIV/AIDS and Cancer Virology is one virus is notorious for outsmarting existing National Cancer Institute example of this integration. therapies. There is still much to do. National Institutes of Health HIV/AIDS Research | 1 The Early NCI Retrovirus Experience A New Virus Revealed subsequent studies showed these to be the same virus, now called HIV (or human In the years before AIDS appeared as a new disease, investigators in the Laboratory immunodeficiency virus). Drs. Gallo, of Tumor Cell Biology, led by Dr. Robert C. Gallo, were searching for cancer-inducing Mikulas Popovic and other colleagues viruses that might be responsible for human tumors. In 1980, the year before the also developed techniques for continuous first cases of AIDS were reported, Drs. Bernard Poiesz, Frank Ruscetti, Gallo, and culture of the new virus in immortalized T lymphocyte cell lines and demonstrated colleagues at NCI discovered and characterized the first human cancer-causing that patients with AIDS had antibodies to retrovirus, HTLV-1, in a patient with leukemia/lymphoma. Soon after, they identified this virus. In collaboration with Dr. Larry HTLV-2 as the second human retrovirus. Arthur at NCI-Frederick, this technology was used to develop a blood test to protect Retroviruses are unusual. Instead of the After the first cases of AIDS were reported, the blood supply. normal cellular process of transcribing Dr. Gallo’s group explored the hypothesis genetic information from DNA into RNA, that this new disease might also be caused 1984 HIV-1 demonstrated as caus - they use the enzyme reverse transcriptase by a human retrovirus, in part because ative agent of AIDS: virus cloned to convert their RNA genome into DNA HTLV-1 caused immunodeficiency and and characterized for integration into the host’s chromosomal cancer. By 1984, they showed that a new DNA to establish infection. retrovirus could frequently be isolated in After these initial discoveries, Dr. Gallo the blood of patients with AIDS. Drs. Luc and colleagues including Drs. Flossie Montagnier, Jean-Claude Chermann, and Wong-Staal, George Pavlakis, Barbara 1980 First human retrovirus (HTLV- 1): co-workers in France had just reported Felber, Genoveffa Franchini, George Shaw, T Lymphocyte cell cultures and isolating a retrovirus from the blood of growth factors Beatrice Hahn, Lee Ratner, Mark Feinberg, patients with an AIDS prodrome, and Suresh Arya, Amanda Fisher, and others defined many key points of
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