Use of mouse to model HIV disease: lack of CD4 cell depletion in SCID-hu mice infected by a rev-independent HIV-1

We studied the effects of Rev/RRE replacement by the heterologous RNA posttranscriptional control element CTE on HIV-1 replication using SCID-hu mice. Two infectious HIV-1 molecular clones were studied, containing intact or deleted nef genes in addition to the Rev/RRE replacement. The nef+ and nef- Rev-independent viruses established infection with kinetics similar to the nef NL4-3. Interestingly, no CD4 depletion was observed within the human lymphoid tissues after infection by the Rev-independent viruses after 6 weeks (endpoint of the experiment). This is in contrast to the infection by both wild type and the nef viruses, which lead to CD4 depletion after 3 and 6 weeks, respectively. Therefore, replacement of the Rev/RRE regulatory axis may generate viruses with altered biological properties in vivo. A Rev-independent SIVmac infectious molecular clone was also generated by similar methods. This virus replicates less efficiently, has lower infectivity in rhesus PBMCs, and has a stable genotype. The Rev-independent SIV is studied in macaques to elucidate the role of Rev in pathogenesis. In another line of experiments, we have generated transgenic mice expressing the human CXCR4 gene. These mice are currently studied to understand the restriction process in primary mouse cells and animals. Research sponsored in part by the National Cancer Institute, DHHS, under contract with ABL.

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