Replication of primate lentiviruses within macrophages may play a fundamental role in the pathogenic manifestations of lentivirus infection. Monocytotropism may be important in viral transmission, in viral persistence and in maintenance of viral burden. Macrophages are terminally differentiated and non-dividing cells. Although onco-retroviruses require host cell mitosis for nuclear localization of viral DNA and provirus establishment, lentiviruses such as HIV have evolved a specific mechanism which allows provirus establishment in non-dividing cells. This property of HIV is governed by the nucleophilic virion proteins gag matrix (MA) and vpr, which facilitate nuclear localization of viral DNA in non-dividing macrophages. HIV variants containing mutations in gag MA and vpr nucleophilic sequences are attenuated for replication in macrophages but are unaffected for replication in proliferating host cells such as activated lymphocytes. The object of this proposal is to examine the importance of macrophages for lentivirus-induced disease by examining transmissibility, tissue tropism, persistence and pathogenicity of HIV and SIV variants which lack the ability to replicate within cells of macrophage lineage. Specifically, the applicant proposes to: 1) derive non-monocytotropic HIV-1, HIV-2 and SIV variants by the introduction of single and combined mutations in gag MA, vpr and vpx nucleophilic functions and examine phenotype of these viruses in dividing (activated T cells) and in non- dividing (macrophages) primary cell systems; 2) define pathogenic properties of monocytotropic and non-monocytotropic SIVmac and SIVagm in rhesus and pig-tailed macaques respectively; 3) define mucosal transmissibility of monocytotropic and non-monocytotropic SIVmc and SIVagm in rhesus and pig-tailed macaques respectively; and 4) define the relative importance of monocytotropic nucleophilic functions for pathogenic manifestations of HIV-1 and HIV-2 in the SCID-hu model. It is expected that these studies will define the role of the macrophage in lentivirus transmission, persistence and pathogenicity and will also define a function for the vpr and vpx genes of primate lentiviruses.
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