Our understanding of viruses and their roles in human cancer is undergoing evolutionary and revolutionary change. Long-held views on the roles for viruses in cancer are being replaced with systematic scientific investigation into the complex host:virus interactions that eventually control disease onset and severity.
Viral oncology is a long-standing interest within the Institute of Human Virology, stemming from Dr. Gallo’s pioneering studies of the first oncogenic human retrovirus (HTLV-1) and the continuing studies of HIV disease where cancer is now the leading cause of death for persons with AIDS in the United States. A multidisciplinary effort within the Institute of Human Virology will define changes in host immunity that result from exposure to environmental carcinogens including immunodeficiency viruses such as HIV, show how these changes impact persistent viral infections, understand why virus persistence increases the chances for malignant transformation of cells and characterize the roles for other infectious agents that promote the onset of cancer in persons with HIV.
High rates for multiple cancers have been observed among HIV patients in Baltimore; our research programs are targeting lung, breast, lymphatic, skin and oral cancers for research on the causes, special characteristics when these cancers are present in the context of HIV infection, and novel therapeutic approaches that accommodate the patient’s need for continuing antiretroviral treatment even during cancer therapy.
The Viral Oncology (VO) Program seeks to understand the etiology, genesis and clinical manifestations of virally-induced cancers. A major focus is the pathobiology of HIV/AIDS, its relation to increased risk for malignant disease, mechanisms explaining this relationship and approaches to prevention. Clinical manifestations of human papillomavirus infection, with or without HIV, is another area of interest where we focus on oral HPV infection and racial disparities in oral cancer. Human herpesvirus 8 (HHV-8) is another area of interest. In addition to cancers with known tumorigenic viruses, we are studying cancers with potential viral etiology including lung cancer in “never smokers.” Thus, the VO program is helping to define familiar viruses associated with new diseases and to search for emerging viruses that might be associated with malignant disease. The search for new infectious causes of cancer exploits an emerging cancer surveillance network in West Africa that is growing from our PEPFAR programs for HIV diagnosis, treatment and prevention. A substantial presence in Nigeria (more than 200 clinical sites and a growing research infrastructure) anchors the surveillance for new viruses that have already helped uncover new human retroviruses. With clinical and basic research on virus-associated cancers, allied closely with epidemiology and public health expertise, VO is poised to move aggressively in building an internationally recognized program in virus-associated cancer.
Drs. DeVico, Lewis and Gallo pioneered a new potential preventive vaccine against HIV, based on building a structurally constrained viral envelope glycoprotein that elicits protective antibody responses. Termed full-length single chain (FLSC), this molecule represents a transitional intermediate for the process of virus attaching to cell receptors and initiating the entry process. Within the FLSC, crucial epitopes are exposed to elicit antibody responses that are broadly protective against multiple HIV isolates. This novel vaccine has been successful in pre-clinical nonhuman primate studies and is moving forward in human clinical studies in the near future. These investigators have also uncovered surprising new antibodies against HIV using molecular cloning techniques to capture recombinant antibodies from HIV elite controllers (individuals without detectable viremia despite never using antiretroviral drugs). When B cells from elite controllers were used as RNA sources and recombinant antibodies were cloned and expressed, the investigators uncovered virus blocking specificities that are creating new insights into virus control by the human immune system.
Drs. Pauza, Sajadi, Riedel and Redfield study the elite controller cohort to understand cellular mechanisms for virus control. During progressing HIV disease there is a substantial and long-lasting depletion of gd T cells that are involved in virus control. Elite controllers have gd T cells at twice the levels found for uninfected controls matched for age, gender and race. Importantly, gd T cells are part of the natural tumor surveillance mechanism, capable of both direct and antibody-dependent tumor cell cytotoxicity. The characterization of elite controllers with high gd T cells is guiding us to new clinical trials in HIV/AIDS, where bisphosphonate drugs will be used to activate and expand gd T cells in HIV+ individuals to mimic the condition in elite controllers.
Dr. Wuyuan Lu and colleagues devised novel inhibitors of MDM2, though structural studies and rational design. MDM2 is elevated in many tumors where it binds and blocks the activity of p53 onco-suppressor protein. In Kaposi’s sarcoma, the LANA protein of HHV-8 “cross-links” MDM2 and p53 to inactivate onco-suppressor activity. By complexing MDM2 with an inhibitor made from D-amino acids, thus resistant to L-peptide-specific proteases, the suppressor activity of p53 was restored. The Lu laboratory continues with the development of peptidic inhibitors of MDM2/MDMx as part of a long-term strategy for increasing p53 function and tumor suppression.
An inter-programmatic collaboration involving Drs. Pauza, Chapoval and Strome has uncovered a key role for CD56+ gd T cells in the cytotoxic response to tumor cells. These gd T cells regulate NK cell cytotoxicity though the 4-1BB costimulatory receptor (Maniar). These same CD56+ gd T cells are depleted in HIV disease, leading to the conclusion that early effects of HIV on specific cell subsets (including gd T cells) cripple tumor surveillance capacity and contribute to risk for AIDS-associated malignancies. In a related study, the same gd T cell subset depleted by HIV was found at 5x lower baseline levels in healthy African Americas compared to European Americans. While it is too early to conclude that racial differences in this cell population contribute to any of the recognized disparities in cancer outcome, we are evolving a program to undertake these studies and define their role for gd T cells in tumor surveillance.
Dr. Suzanne Gartner reported the discovery of nurse macrophages and their functional capacity to support T cell replenishment. Surviving through a unique mechanism called endoreplication, these nurse macrophages may have important roles in the pathogenesis of HIV. Ongoing studies seek to link these cells with the mechanisms for initiation of Hodgkin’s disease.