Role of Rev regulation in HIV replication and pathogenesis

HIV production depends on the viral Rev protein binding to RRE, whereas expression of the type D retroviruses depends on the viral CTE RNA element interaction with cellular factor(s). To understand the role of Rev regulation in virus replication and pathogenesis, we replaced Rev/RRE by the posttranscriptional control element (CTE) of the simian type D retroviruses. The CTE can support replication of the Rev/RRE-deficient HIV-1 and SIV in primary lymphocytes. These viruses have a lower replicative capacity and infectivity and have a stable genotype in primary lymphocytes. Evaluation of the replicative capacity of the Rev-independent HIV viruses in the SCID-hu mouse system revealed lower virus load and lack of CD4 cell depletion independent of the presence of Nef. The replacement of the Rev/RRE regulatory axis may generate viruses with altered biological properties and may allow the production of attenuated nonpathogenic viral strains. Rev is a shuttling protein. Its function depends on appropriated and precise nucleocyoplamic trafficking. Several factors affecting steps in Rev trafficking inhibit Rev function and HIV replication. We identified a nuclear export signal in RanBPI that shares export pathway, while CTE-directed export and expression is distinct. Research sponsored by the National Cancer Institute, DHHS, under contract with ABL.

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