By Anne Arthur, Guest Writer
The Second Annual David Derse Memorial Lecture and Award presentation was held on November 12, 2013, at the NCI at Frederick Conference Center to honor David Derse’s outstanding research accomplishments and to stimulate the exchange of innovative ideas that Derse was well known for promoting throughout his scientific career.
The Annual David Derse Memorial Lecture and Award is sponsored by the HIV Drug Resistance Program, with support from Hye Kyung Chung-Derse, Ph.D., the National Cancer Institute (NCI), the Foundation for the National Institutes of Health (NIH), and colleagues and friends of Derse who contributed to the memorial fund in his honor. During his 25 years at NCI, Derse investigated the molecular mechanisms of retrovirus infection and replication, concentrating most recently on human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type 1 (HTLV-1).
Chou-Zen Giam, Ph.D., delivered the second lecture in this annual series. The title of his presentation was “Outcomes of HTLV-1 Infection: Senescence, Latency, Reactivation, and Pathogenesis.”
Giam is professor and vice chair of the Department of Microbiology and Immunology at the Uniformed Services University of the Health Sciences, in Bethesda, Md. He has served on the editorial boards of the American Society for Microbiology, Journal of Virology, and Retrovirology, and has been appointed as a member of numerous NIH study sections and scientific panels, including the Scientific Advisory Committee of the American Foundation for AIDS Research and Pediatric AIDS Foundation. He has more than 27 years of experience investigating the molecular biology and pathogenesis of human viruses, with a long-standing interest in HTLV-1 and HIV, and more recently, Kaposi sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV-8).
Giam’s research program is focused on the mechanisms of action of viral regulatory proteins and how they impact cellular mRNA transcription, cell cycle control, and signal transduction pathways to affect viral replication and pathogenesis, especially oncogenesis.
Transcription factors of the NF-kappaB/Rel family, which are critical for the proliferation of lymphocytes and the expression of genes that mediate inflammatory and immune responses, are often aberrantly activated in human cancers, especially leukemia, where they confer survival and proliferation advantages. Through the study of the HTLV-1 trans-activator/oncoprotein, Tax, Giam’s laboratory found that persistent and potentially oncogenic activation of I-kappaB kinases (IKKs)/NF-kappaB by Tax triggers a cellular senescence checkpoint response that is induced by hyperactivated p65/RelA and mediated by two cyclin-dependent kinase inhibitors, p21 and p27, in a p53- and pRb-independent manner. This checkpoint response is often impaired in cancer cells with constitutively activated NF-kappaB.
Giam’s results suggest that the antisense protein of HTLV-1, HBZ, which downregulates NF-kappaB and HTLV-1 trans-activation by Tax, would mitigate or prevent Tax-induced senescence. This prediction has been borne out experimentally: Tax promotes robust HTLV-1 replication, potent NF-kappaB activation, and senescence, while HBZ attenuates Tax-driven viral replication and NF-kappaB activation to allow for the proliferation of infected cells and persistent infection. His laboratory’s data support the notion that inactivation of the senescence checkpoint facilitates chronic NF-kappaB hyperactivation, a critical step in leukemia development.
His current efforts are concentrated on understanding how chronic NF-kappaB activation induces cellular senescence and how the senescence checkpoint becomes impaired in cancer cells whose NF-kappaB signaling pathway is chronically activated. He is also establishing cell-free systems to elucidate the mechanism by which Tax activates IKKs and is investigating the role of HBZ in HTLV-1 viral latency. For more information about Giam and his research program, see http://www.usuhs.mil/faculty/chouzengiam-mic.html.
A captioned videocast of the lecture and award presentation has been archived on the NIH Videocasting website; to view the videocast, click here.
Anne Arthur is the technical laboratory manager, HIV Drug Resistance Program.