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. 2013 Oct 24;155(3):540-51.
doi: 10.1016/j.cell.2013.09.020. Epub 2013 Oct 24.

Replication-competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure

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Replication-competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure

Ya-Chi Ho et al. Cell. .
Free PMC article

Abstract

Antiretroviral therapy fails to cure HIV-1 infection because latent proviruses persist in resting CD4(+) T cells. T cell activation reverses latency, but <1% of proviruses are induced to release infectious virus after maximum in vitro activation. The noninduced proviruses are generally considered defective but have not been characterized. Analysis of 213 noninduced proviral clones from treated patients showed 88.3% with identifiable defects but 11.7% with intact genomes and normal long terminal repeat (LTR) function. Using direct sequencing and genome synthesis, we reconstructed full-length intact noninduced proviral clones and demonstrated growth kinetics comparable to reconstructed induced proviruses from the same patients. Noninduced proviruses have unmethylated promoters and are integrated into active transcription units. Thus, it cannot be excluded that they may become activated in vivo. The identification of replication-competent noninduced proviruses indicates that the size of the latent reservoir-and, hence, the barrier to cure-may be up to 60-fold greater than previously estimated.

Figures

Figure 1
Figure 1. Characterization of non-induced proviruses
Figure 2
Figure 2. Mapping of large internal deletions in non-induced proviruses
Figure 3
Figure 3. Growth kinetics of reconstructed non-induced viruses
Figure 4
Figure 4. LTR activity of non-induced proviruses
Figure 5
Figure 5. Integration sites of non-induced proviruses
Figure 6
Figure 6. CpG methylation of non-induced proviruses
Figure 7
Figure 7. Quantification of intact non-induced proviruses

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