Human herpesvirus 8 (HHV-8) or Kaposi's sarcoma-associated herpesvirus (KSHV) is a newly discovered herpesvirus. HHV-8 is a member of the lymphoproliferative human γ2-herpesvirus family (genus Rhadinovirus) which was first identified by representation difference analysis of Kaposi's sarcoma (KS) tissue from an AIDS patient in 1994 by Chang and others. HHV-8 is associated with a variety of malignancies including all forms of KS, body cavity lymphomas, and multicentric Castleman's Disease (MCD).

Advances in virus entry (includes both herpesviruses and others) have been made by the use of virus specific target cells and analyzing different stages of the virus infectious process, critical signaling cascades induced by the virus, and those cellular signals that benefit the virus infection. However, there is very little research performed on the effect of such oncogenic signals on virus entry.

KS is a neoplasm of vascular origin arising as multiple independent lesions, and over time, can progress into a nodular tumor localizing in skin and visceral organs including the gastro-intestinal tract and lungs. Cancers arise owing to the accumulation of mutations in critical genes that alter normal programs of cell proliferation, differentiation, and death. In a recently concluded study (Akula et al, 2004, In Press), we demonstrated for the first time, the ability of Raf to enhance HHV-8 infection of cells. This is a very interesting observation: the two arms for the increase in HHV-8 load in KS is hypothesized to be the micro-environment provided by the aberrant growth factor production and a productive HHV-8 infection. Our work demonstrates the ability of oncoprotein Raf to influence both these arms significantly. Our present research is focused on delineating the Raf and associated oncogenic signaling in HHV-8 entry leading to a productive infection and pathogenesis. Recently, Raf has been targeted as a novel therapeutic strategy in cancer biology. Hence, the long term goals will be aimed at developing anti-viral therapies based on targeting the Raf kinase cascade.

The journey of understanding the virus entry into target cells is far from complete. HHV-8 entry into cells involves the orchestration of a very complex array of molecules and events that remains to be delineated. In addition to the project outlined above, we are also examining the role of target cell molecules in HHV-8 entry process.

Hamden, K. E., Bryan, B. A., Ford, P. W., Xie, C., Li, Q., and Akula, S. M. 2005. Spectroscopic Analysis of Kaposi's Sarcoma-Associated Herpesvirus Infected Cells by Raman Tweezers. J. Virol. Methods (In Press).

Whitman, A. G., Dyson, O. F., Ford, P. W., and Akula, S .M. 2005. Raf/MEK/ERK signaling: Implications in the infection and pathogenesis of viruses associated with AIDS. Gene Ther. Mol. Biol. 9: 51-60.

Whitman, A. G., Bryan, A. B., Dyson, O. F., Patel, K. D., Ramasamy, D., Anatharaman, S., Reber, A. J., and Akula, S. M. 2005. AIDS related viruses, their association with leukemia, and Raf signaling. Current HIV Res. 3:319-327.

Ford, P. W., Hamden, K. E., Whitman, A. G., Bryan, B. A., Chintalgattu, V., McCubrey, J. A., Dyson, O. F., and Akula, S. M. 2005. Cigarette Smoke Concentrate Inhibits Kaposi's Sarcoma-Associated Herpesvirus Infection. Virus Res. 114: 172-176.

Akula, S. M., Hamden, K. H., Whitman, A. G., Ford, P. W., and McCubrey, J. A. 2005. Raf Induces Expression of Vascular Endothelial Growth Factor in Kaposi's Sarcoma-Associated Herpesvirus Infected Human B cells. Blood 105: 4516-4522.

Bryan, B. A., Dyson, O. F., McCubrey, J. A., and Akula, S. M. 2005. Biology of Kaposi's Sarcoma-Associated Herpesvirus. Frontiers in Bioscience 10: 2882-2891.

Hamden, K. H., Ford, P. W., Whitman, A. G., McCubrey, J. A., and Akula, S. M. 2004. Raf induced Vascular Endothelial Growth Factor Augments Kaposi's Sarcoma-Associated Herpesvirus (KSHV/HHV-8) Infection. J. Virol 78: 13381-13390.

Ford, P. W., Hamden, K. H., Whitman, A. G., McCubrey, J. A., and Akula, S. M. 2004. Vascular Endothelial Growth Factor augments Human Herpesvirus-8 (HHV-8/KSHV) Infection. Cancer Biol. Ther. 3: 876-881.

Akula, S. M., Ford, P. W., Whitman, A. G., Hamden, K. H., Shelton, J. G., and McCubrey, J. A. 2004. Raf promotes human herpesvirus-8 (HHV-8/KSHV) infection. Oncogene 23: 5227-5241.

Akula, S. M., Pramod, N. P., Sharma-Walia, N, Wang, F-Z., Fegley, B., and Chandran, B. 2003. Kaposi's Sarcoma-Associated Herpesvirus (KSHV/HHV-8) Infection of Human Fibroblast Cells Occurs Through Endocytosis. J. Virol. 77: 7978-7990.

Wang, F-Z., Akula, S. M., Sharma-Walia, N., Zeng, L., and Chandran, B. 2003. Human herpesvirus envelope glycoprotein gB mediates cell adhesion via its RGD sequence. J. Virol. 77: 3131-3147.

Pramod, N. P., Akula, S. M., Zien, C., Vieira, J., and Chandran, B. 2003. Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) induces PI3-K-PKC- ζ-MEK-ERK signaling pathway via integrin α3β1 in the target cells early during infection: implications in infectivity. J. Virol. 77: 1524-1539.

Akula, S. M., Pramod, N. P., Wang, F-Z., and Chandran, B. 2002. Integrin alpha3beta1 (CD 49c/29) is a cellular receptor for Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) entry into the target cells. Cell 108: 407-419.

Akula, S. M., Pramod, N. P., Wang, F-Z., and Chandran,B. 2001. Human herpesvirus 8 envelope associated glycoprotein B interacts with heparan sulfate-like moieties. Virology 284: 235-249.

Akula, S. M., Wang, F-Z, Vieira, J., and Chandran, B. 2001. Human herpesvirus 8 interaction with target cells involves heparan sulfate. Virology 282: 245-255.