CRYSTALLOGRAPHIC ANALYSIS OF HIV-1 VIF IN COMPLEX WITH HUMAN HOST PROTEINS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The World Health Organization estimates 30-36 million persons are infected worldwide with the HIV-1 virus. Nearly as many individuals have died from AIDS since 1981. Although significant progress has been made in the development of new anti-viral therapies, new classes of drugs are required due to the emergence of drug resistance. Here we propose to determine the crystal structure of the HIV-1 factor Vif, which is essential for viral infectivity due to its ability to inactivate the innate immune factor APOBEC3G in CD4+ T cells. Vif functions in the infected host cell by recruiting APOBEC3G to a Cullin Ring Ligase (CRL) complex where the anti-viral factor undergoes polyubiquitination, and subsequent degradation by the 26S proteasome. The C-terminal 72 amino acids of Vif are necessary and sufficient to interact with the elongin (Elo)B and EloC proteins of the CRL via a divergent BC-box motif. We have prepared crystals of a ternary complex comprising the C-terminus of Vif bound to the human EloB/C proteins. In the short term, we require rapid access to synchrotron radiation to: (i) screen the numerous small crystals we have prepared at home in order to guide optimization efforts; and (ii) to collect native data for possible molecular replacement using the known EloB/C coordinates. The interaction between Vif and EloB/C represents a potentially novel target for new HIV-1 therapeutics. As such, this work has the potential to benefit public health.