Studies on the host factors essential for HIV-1life cycle to develop novel anti-HIV drugs

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Replication of human immunodeficiency virus type 1 (HIV-1) depends on host cell factors, but only a limited number of such proteins have been reported. Through the use of expression cloning method, we established and analyzed two mutant human cell clones derived from 293T cells, C611 and YD4, which are resistant to HIV-1 infection, but permissive to murine leukemia virus (MLV) infection. Quantitative polymerase chain reaction (qPCR) studies revealed that C611 cells had a post-entry block prior to the completion of reverse transcription, whereas in YD4 cells viral DNA entered the nucleus, but failed to be integrated in the cellular genome. The genetic phenotype of these blocks appeared to be recessive, because hybridization between the mutant and parental cells restored the susceptibility to HIV-1 infection. Of note, the defects were not complemented by known cofactors, and hence these mutant cells are expected to be useful for identifying new cellular cofactors of HIV-1 infection.Beside this, we made different types of experiments and found 3 additional host factors, acting either positively or negatively for HIV-1 infection. They include the Arp2/3 complex which appears to be important for early step of primate lentivirus and vaccinia IMV infection, and two negative regulators,NAF-1 and HEXIM1.As to CXCR4 antagonists, we have completed the screening and selection of the candidates through in vitro studies and they have been subjected to animal studies using mice model. Amongst them, KRH-3955 is considered best at this moment and the whole story will be reported.