Marjorie Robert-Guroff, Ph.D.
Dr. Robert-Guroff established an etiologic link between the human T cell leukemia/lymphoma virus (HTLV) and adult T cell leukemia early in her career, and with the onset of the AIDS epidemic, turned to HIV vaccine development. She pioneered use of a replication-competent adenovirus-based vaccine approach, which has now reached human clinical trials. Her current research interests include identifying immune responses correlated with protective efficacy using the SIV macaque system as a model, with a special focus on functional systemic and mucosal antibodies.
1) HTLV seroepidemiology, 2) HIV vaccine development, 3) neutralizing and non-neutralizing antibodies, 4) mucosal immunity, 5) non-human primate models, 6) retrovirology
Historically, live viral vaccines have been most effective, eliciting essentially life-long immunity. Based on this rationale, my lab is developing a human immunodeficiency virus (HIV) vaccine based on replication-competent adenovirus (Ad) vectors with a focus on Env-specific humoral immunity. We have employed a prime/boost strategy, immunizing first mucosally with Ad-recombinants, and then boosting intramuscularly with Env protein. We have conducted extensive studies using an Ad5 host range mutant vector able to replicate in rhesus macaques as a prototype vaccine. Based on these pre-clinical findings showing strong immunogenicity and potent protective efficacy, we have achieved a major goal of translating this approach to the clinic for evaluation in humans alongside non-replicating Ad-HIV vaccines and other approaches.
As the replicating Ad4-HIV platform has now reached clinical trials, we are focused on improving the vaccine regimen and elucidating immune correlates of protection and their mechanisms of action, taking advantage of the rhesus macaque model as an effective way to efficiently test new vaccine concepts and strategies. We have shown that anti-Env antibodies possess multiple activities and characteristics associated with protective efficacy. In addition to neutralization, these include non-neutralizing activities such as ADCC and ADCVI, antibody avidity and viral-specific B cell memory. We have also shown that vaccine-elicited anti-Env-specific antibodies in rectal secretions mediate transcytosis inhibition and are significantly correlated with delayed SIV acquisition following a challenge exposure.
While we believe all components of the immune system will be needed to develop an effective HIV vaccine, we are currently focused on improving mucosal immunity, as HIV is primarily transmitted across mucosal epithelium. Our recent study of the biodistribution of replicating Ad in the macaque showed that regardless of administration route, it is broadly distributed and elicits comparable levels of mucosal IgA in rectal, vaginal, and nasal secretions. The vector also targets professional antigen presenting cells, and persists for at least 25 weeks after administration in rectal macrophages. We have a major interest in B cell development and maturation, as we believe antibody responses are crucial for a protective HIV vaccine. In view of the broad array of antibody activities that can mediate protection, we are also investigating effector cells that mediate antibody activities. Finally, we are initiating studies of combined vaccine approaches, taking advantage of mucosal immunity elicited by the replicating Ad vector.
Selected Key Publications
Natural antibodies to the human retrovirus HTLV in a cluster of Japanese patients with adult T cell leukemia.Science. 215: 975-8, 1982. [ Journal Article ]
- Nature. 316: 72-4, 1985. [ Journal Article ]
Generation of a neutralization-resistant variant of HIV-1 is due to selection for a point mutation in the envelope gene.Cell. 54: 57-63, 1988. [ Journal Article ]
- Nature Med. 3: 651-8, 1997. [ Journal Article ]
Multiple vaccine-elicited non-neutralizing antienvelope antibody activities contribute to protective efficacy by reducing both acute and chronic viremia following simian/human immunodeficiency virus SHIV89.6P challenge in rhesus macaques.J Virol. 84: 7161-73, 2010. [ Journal Article ]
Dr. Robert-Guroff, Chief, Immune Biology of Retroviral Infection Section, received her Ph.D. degree from Georgetown University, and was a post-doctoral fellow of the Leukemia Society of America at the NCI, and of the Friedrich Miescher-Instuitut, Basel, Switzerland. She has conducted research continually at the NCI since 1971, and was instrumental in establishing the etiologic link between the human T-cell leukemia virus, HTLV, and adult T-cell leukemia. With the onset of the AIDS epidemic in 1981, her research shifted to the study of HIV and focused on development of a vaccine for HIV/AIDS. In 2011 she was elected a AAAS Fellow, Medical Sciences Section, and cited for HIV/AIDS vaccine development, replicating and non-replicating Adenovirus vectors, mucosal and systemic vaccination strategies, and neutralizing and non-neutralizing mechanisms of antibody protection.