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To construct SIV/HIV-2 chimeras (SHIV) that replicate in vivo. These would be valuable tools to elucidate the mechanism by which HIV-2 can bypass protection conferred by live attenuated SIV vaccines.Novel SHIV were constructed to express either the vpx, vpr, tat, rev and env genes (SHIV-2isyenv) or the gag and pol genes (SHIV-2isygag/pol) of the infectious molecular clone HIV-2isy in an SIVmac backbone. The replication of SHIV-2isyenv and SHIV-2isygag/pol were evaluated on selected cell lines and peripheral blood mononuclear cells (PBMC) in vitro. In addition, their infectivity was assessed in vivo.Virus stocks of SHIV-2isyenv and SHIV-2isygag/pol were prepared in vitro. For SHIV-2isygag/pol both the 5′ and 3′ boundaries of the chimeric construct were critical for infectivity in vitro. The growth of each chimera on T cell lines in vitro mirrors that of the parental viruses donating the envelope gene. On PBMCs SHIV-2isyenv replicated well on human and simian PBMC whereas SHIV-2isygag/pol replicated to detectable levels on human PBMC only. In vivo, SHIV-2isyenv virus was isolated from one of two cynomolgus macaques challenged intravenously. SHIV-2isygag/pol was isolated from one of two cynomolgus macaques and both rhesus macaques challenged intravenously.This is the first report of SIV/HIV-2 chimeras that are infectious in macaques. Moreover, this is the first report of an infectious chimera in which both SIV gag and pol have been replaced with the equivalent regions of an HIV isolate.