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Our lab is focused on characterizing the biologic and biochemical function(s) of the regulatory protein Nef from HIV-1 and SIV. Using a molecular genetic approach we determine whether specific Nef functions are important for viral replication. To determine whether these functions are critical for development of disease, we utilize the SIV/rhesus macaque model for simian AIDS.

We have discovered that a cellular serine-threonine kinase, p21-activated kinase (PAK), associates and with and activates both HIV-1 and SIV Nef. Our studies using SIV Nef mutants indicate that there is a strong correlation between the ability of SIV Nef to associate with PAK and the induction of high viral loads and disease in SIV-infected rhesus macaques. We are mapping the domains of both HIV-1 and SIV Nef that are important for PAK association and activation.

Selected Publications: Sawai, E.T., Hamza, S., Ye, M., Shaw, K., and Luciw, P.A. Pathogenic Conversion of Live-attenuated Simian Immunodeficiency Virus (SIV) Vaccines is Associated with Expression of Truncated Nef. J. Virol., 74:2038-2045, 2000.

Mandell, C.P., Reyes, R.A., Cho, K., Sawai, E.T., Fang, A.L., Schmidt, K.A., and Luciw, P.A. SIV/HIV nef Recombinant virus (SHIVnef) infection of rhesus macaques and simian AIDS. Virology 265:235-251, 1999.

Brown, A., Wang, X., Sawai, E., Cheng-Mayer, C. Activation of the PAK-related kinase by Human Immunodeficiency Virus type 1 Nef in Primary Human Peripheral Blood Lymphocytes and Macrophages Leads to Phosphorylation of a PIX-p95 Complex. J. Virol. 73: 9899-9907, 1999.

Khan, I.H., Sawai, E.T., Antonio, E., Weber, C.J., Mandell, C.P., Montbriand, P.M., and Luciw, P.A. Role of the SH3-ligand domain of Simian Immunodeficiency Virus Nef in interaction with Nef-associated kinase (NAK) and simian AIDS in rhesus macaques. J. Virol. 72: 5820-5830, 1998.

Sawai, E.T., Cheng-Mayer, C., and Luciw, P.A. Nef and the Nef-associated Kinase. Research in Virology. 148:47-52, 1997.

Sawai, E.T., Khan, I.H., Montbriand, P.M., Peterlin, B.M., Cheng-Mayer, C., and Luciw, P.A. Activation of PAK by HIV and SIV Nef: Importance for AIDS in SIV-infected Rhesus Macaques, Current Biology 6: 1519-1527, 1996.

Lu, X., Wu, X., Plemenitas, A., Yu, H., Sawai, E.T., Abo, A., and Peterlin, B.M. Rac1 and CDC42 are implicated in the activation of the Nef-associated kinase and replication of HIV. Current Biology, 6: 1677-1684, 1996.

Sawai, E.T., Baur, A.S., Peterlin, B.M., Levy, J.A., and Cheng-Mayer, C. A conserved domain and membrane targeting of Nef from HIV and SIV are required for association with a cellular serine kinase activity. J. Biol. Chem. 270:1539-1543, 1995.

Baur, A.S., Sawai, E.T., Dazin, P., Fantl, W.J., Cheng-Mayer, C, and Peterlin, B.M. HIV-1 Nef leads to inhibition or activation of T cells depending on its intracellular localization. Immunity 1: 373-384, 1994.

Sawai, E.T., Baur, A., Struble, H., Peterlin, B.M., Levy, J.A., and Cheng-Mayer, C. Human Immunodeficiency Virus type 1 Nef associates with a cellular serine kinase in T lymphocytes. Proc. Natl. Acad. Sci. USA. 91:1539-1543, 1994.