This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Drug resistance to the existing pool of anti-HIV therapies continues to rise. Continued success in the repression of HIV replication in infected individuals will require the development of new inhibitors that are effective against drug-resistant strains of virus. Drugs that target novel areas of virus replication have the greatest probability to be effective against such viruses. The proposed work focuses on the large viral DNA (vDNA) complexes formed during early HIV-1 infection of cells- the reverse transcription and preintegration complexes (RTCs and PICs). These complexes facilitate synthesis of viral DNA and its transport into the nucleus of cells. The first step toward the development of new inhibitors is to determine the composition of these complexes. The viral proteins associated with RTCs and PICs are not consistent with their size, suggesting they contain additional cellular components. Our long-term goal is to aid in the development of new HIV-1 inhibitors by determining how RTCs and PICs assemble and mediate nuclear transport of vDNA in dividing and non-dividing cells. The objective of the proposed studies is to identify and characterize novel cellular components of HIV-1 vDNA complexes that play an essential role in HIV-1 replication. We have developed novel methods to purify these complexes and we have successfully detected viral components by mass spectrometry. Using these methods we will identify novel host proteins that are critical for HIV-1 replication. Successful completion of these studies will contribute to the understanding of early events of HIV replication and discover new targets for antiviral therapies.
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