Our Science – Franchini Website
Genoveffa Franchini, M.D.
Her accomplishments in HIV vaccine development have secured patent rights to the US Government on the use of poxvirus vectors alone or in combination with DNA. One of the vaccines developed and tested in Dr. Franchini's laboratory is in clinical trials in 16,000 volunteers in Thailand. Dr. Franchini's laboratory genetically characterized SIV (Nature 1987) and defined the regulatory function of HIV-1/2 and SIV genes (Science 1986, 1990). She first demonstrated the importance of Vpr in HIV-1 infectivity in macrophages (PNAS, 1990) and the SIV fusion peptide (Science, 1989). Her work in immunological mechanisms furthered the understanding of vaccine efficacy and protection (Nature Medicine, 2005). In the therapeutic arena, Dr. Franchini provided the first proof of principle that vaccination provides transient benefit to SIV-infected macaques (Nature Medicine, 2001), and she pioneered strategies to down-modulate regulators of immune response in HIV-1-infected individuals.
Dr. Franchini serves the scientific field through editorial boards of peer-review journals, including AIDS Research and Human Retroviruses, AIDS Reviews, and Journal of Virology. She is an associate editor for Blood. She is in frequent demand to review manuscripts for prestigious journals including Journal of Clinical Investigation, Journal of Experimental Medicine, Journal of Immunology, Journal of Infectious Diseases, Journal of Virology, Nature Medicine, Nature Reviews Immunology, and Oncogene. Dr. Franchini serves on search and thesis committees, study sections, scientific committees, faculties, and advisory and review boards in intramural and extramural capacities. She has a strong mentorship record: former fellows now serve in important scientific positions at Harvard University, Institut Pasteur, in private industry, and at respected education and research institutions throughout the United States, Europe, and South America.
PROJECT 1: T Cell Transformation by Oncoviruses
One line of research in my laboratory is related to understanding human T cell leukemia/lymphoma virus type 1 (HTLV-1) pathogenesis. HTLV-1 is the only known retrovirus that causes human cancer. Epidemiological, molecular, and biochemical evidence suggests that HTLV-1 persistence in the host is associated with T cell clonal expansion and consequent accumulation of genetic lesions, resulting in leukemia. Thus, the understanding of mechanisms of viral persistence is essential to prevent the occurrence of leukemia. We continued to study the function of the p12I and p30II proteins encoded by the 3' end of the viral genome. We hypothesized that they may play an essential role in viral persistence and pathogenesis. We found that p12I affects proximal T cell receptor (TCR) signaling, and phosphorylation of PLC-gamma1, Vav, and linker for activation of T cells (LAT). Consequently, calcium release and nuclear factor of activated T cells (NFAT) transcription are decreased. p12I, like LAT, is located in the lipid rafts and is recruited to the immunological synapse within minutes from TCR ligation. p12I also decreased MHC class I-restricted recognition of targeted cells by cytotoxic T cells. These findings may relate to the immunosuppression and immune evasion observed in HTLV-1 infection. Another exciting new development has been the finding that the p30II protein encoded by the ORF II at the 3' end of the viral genome decreases proviral expression by a novel post-transcriptional mechanism. We found that p30II binds to the doubly spliced Tax/Rex mRNA and retains it in the nucleus. As expected, expression of p30II in HTLV-1-infected T cell lines also decreases viral replication by decreasing the level of Tax. A protein (p28II) with similar function is also found in HTLV-2, a virus genetically related to HTLV-1.
PROJECT 2: Preventive and therapeutic T cell vaccines to mitigate HIV-1 replication; Prevention and treatment of complications of smallpox vaccination in a macaque model of acquired immunodeficiency
Direct evidence indicates that both Abs and CD8+ T cells contribute to restriction of simian immunodeficiency virus (SIV) replication. In the case of CD4+ T cells, however, it has been difficult to ascertain their contribution as they are also the target for viral infection. SIVmac251 infection of macaques is an excellent model whereby to assess these questions. Our lab and others demonstrated that preventive vaccination delays SIV disease in macaques. Cross-sectional studies performed in our infected macaques defined cell-mediated immune response in effector or privileged sites, and prospective studies with optimized T cell vaccines addressed immune correlates of protection from disease. We showed that a combination of DNA and a highly recombinant poxvirus-based SIV vaccine (NYVAC) is superior to NYVAC-SIV alone and that CD8+ central memory T cells (TCM) but not cytotoxic T lymphocytes (CTLs) inversely correlate with protection from disease. Importantly, we provided the first evidence that virus-specific CD4+ T cells also inversely correlate with low levels of primary and chronic viremia. Our next studies demonstrated that the breadth of immune response is important and that antigens encoded by nonstructural viral proteins contribute to protection.
As preventive vaccination with T cell vaccines ameliorated the virological outcome following viral challenge, we explored strategies to augment virus-specific immune responses in already infected macaques treated with antiretroviral therapy (ART). We demonstrated in two independent studies that vaccination of SIV-infected ART-treated macaques with either ALVAC-SIV-based or NYVAC-SIV-based vaccines resulted in better control of viral replication after ART interruption. These studies provide the proof of concept to explore therapeutic vaccination approaches in HIV-1-infected individuals.
Over the years, our preclinical data provided proof of principle for the initiation and continuation of human trials. ALVAC-HIV-based vaccine candidates are now in a phase III trial in adults in Thailand and a phase I trial in neonates in Uganda is being prepared. The combination of DNA plus NYVAC-HIV will be tested by EuroVac in healthy volunteers. Lastly, therapeutic phase I and II trials with ALVAC-HIV are ongoing at several sites and I plan to perform a phase I therapeutic trial with NYVAC-HIV in the U.S.
The induction of poxvirus-specific immunity limits repeated exposure to these viral vectors. How the quality and extent of the vector-induced cellular immune response integrate with the immune response to the transgene has not been fully elucidated. Therefore, we initiated studies in macaques to define the immune responses that limit vaccinia and related poxvirus replication. A surprising byproduct of these studies, highly relevant to the national bioterrorism prevention effort, was the finding that SIV-infected immune-compromised macaques could be vaccinated safely with the smallpox vaccine Dryvax when a highly attenuated poxvirus was used as a prime but nonetheless were not protected against a monkeypox challenge exposure. We demonstrated that Abs alone but not cell-mediated responses conferred protection, and IgM to IgG switching was impaired in conditions of severe CD4+ T cell depletion. These data shed light on the mechanisms of protection of a vaccine that has eradicated a human viral pathogen, and they suggest that, even if HIV-1 immunogens able to induce neutralizing Abs to HIV primary isolates were available, their therapeutic effect in immune-compromised individuals would be limited.
This page was last updated on 8/15/2013.