Rates of shutdown of HIV-1 into latency: Roles of the LTR and tat/rev/vpu gene region

CEM T-cells chronically infected with most HIV-1 isolates gradually cease virus production over a 4-6 week period. This is due to slow shutdown of virus replication in the majority of the cells, leading to latent infections. We identified one HIV-1 isolate (HIV₂₁₃) which shut down into latency at a rate much slower than most HIV strains, requiring more than 12 weeks for the majority of the cells to become nonproductive. This indicated that genes of the virus influence the rate of shutting down, or alternatively, the length of time chronically infected cells produce virus. The viral gene(s) influencing differential rates of shutdown were mapped using chimeric viruses composed of the HIV₂₁₃ genome substituted with various restriction fragments from HIV(MCK), which rapidly progresses into latency. We found that the 3' region of the LTR was the major determinant influencing the rate of shutdown, but the tat/rev/vpu region also slightly influenced this phenotype. These data show that at least these two genomic regions can influence the duration of virus production in chronically infected cells and that polymorphisms in these regions result in phenotypically divergent viruses which go into latency at different rates. It is also possible that this viral property may be an important determinant or clinical outcomes.