FRANCIS W. RUSCETTI, Ph. D.

Laboratory of Leukocyte Biology, Division of Basic Sciences, National Cancer Institute, Frederick Cancer Research and Development Center, National Institutes of Health

Dr. Ruscetti is Chief of the Laboratory of Leukocyte Biology, NCI-FCRDC. He obtained his Ph.D. from the University of Pittsburgh working on prokaryotic RNA metabolism under Lew Jacobsen; did post-doctoral work on hematopoiesis under Dane Boggs. From 1975-1983, he studied human retroviruses and T-cell biology in Laboratory of Tumor Cell Biology, NCI.

Cell cycle control of cell growth and differentiation is tightly regulated by a series of complex interactions. It is the main tenet of our studies that unrestricted growth control and inappropriate transcriptional activation, due to defects in negative regulatory control, plays a major role in oncogenesis and retroviral pathogenesis.

Negative regulation of viral and cellular genes during Retroviral Infection. We previously demonstrated HIV-1 latency in monocytes in vivo. The presence of latently infected monocytes constitutes a possible source for reactivation of virus production during the normal immune response. We have identified immune activation of latently infected monocytes to be a mechanism by which latent HIV-1 can be reactivated to produce infectious virus. Ongoing studies involve identification of these genes as well as signal transduction pathways involved in immune activation of latent HIV-1.

The development of the appropriate immune response mediates microbial resistance. However, several studies suggest that in some cases an infectious agent can stimulate inappropriate cytokine responses, thus increasing the pathology caused by that agent. Since CD4+ T-cells are the preferential targets of HIV, much interest has developed over the TH1-TH2 cytokine responses during HIV infection and pathogenesis. It has been proposed that a preferential replication of HIV in TH2 and TH0 over TH1 cells occurs in the development of AIDS. However, studies in our lab showed similar levels of viral replication in TH1, TH2 and TH0 cells. In TH2 cells, HIV mediated apoptosis was delayed and less in magnitude than in some TH1 clones over a 7-14 day culture period. Current studies address the mechanism(s) of the differential apoptosis in TH1 and TH2 cells.

Although largely unknown, the cellular events triggered by HTLV-1 infection in the lymphoproliferative process are of major importance to the establishment of leukemia. We have recently characterized an infectious clone of HTLV-1 as well as a susceptible expressing cell line to study the molecular interactions of this infectious clone. We have shown this infectious clone to be highly transforming for T-cells. Future studies include delineating viral elements necessary for cytokine dependent and independent transformation as well as the signalling pathways, initiated by HTLV-1, resulting in T cell immortalization.

Recent Publications:

• Wong P et al. Immortalized hemopoietic cells with stem cell properties. Immunity 1994;1:571-583
• Mikovits J et al.  IL-4 and IL-13 have overlapping but distinct effects on HIV production in monocytes.  J. Leukocyte Biol 1994;56:340-346
• Mayers D et al. Anti-human im munodeficiency virus 1 (HIV-1) activities of 3-deazaadenosine analogs: increased potency against 3'-azido-3'-deoxythymidine-resistant HIV-1 strains.  Proc Natl Acad Sci USA 1995;92:215-219
• Derse D et al. Virions relea sed from cells transfected with a molecular clone of human T-cell leukemia virus type I give rise to primary and secondary infections of T cells.

J Virol 1995;69:1907-1912
• Sitnicka. E. et al. Transforming growth factor beta 1 directly and reversibly inhibits the initial cell divisions of long-term repopulating hematopoietic stem cells.  Blood 1996;88:82-88

Last revised on June 23, 1998 by Debra L. Dixon. 

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