TY - JOUR
T1 - XReplication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure
AU - Ho, Ya Chi
AU - Shan, Liang
AU - Hosmane, Nina N.
AU - Wang, Jeffrey
AU - Laskey, Sarah B.
AU - Rosenbloom, Daniel I.S.
AU - Lai, Jun
AU - Blankson, Joel N.
AU - Siliciano, Janet D.
AU - Siliciano, Robert F.
N1 - Funding Information:
We thank all study participants. We thank S. Alireza Rabi, Gregory Laird, and Drs. Stuart Ray and Joel Pomerantz for critical advice; Linda Alston for patient recruitment; David Walker for advice on CpG methylation; and Dr. Gautam Sahu for PCR suggestions. This work was supported by amfAR as part of the amfAR Research Collaboration on HIV Eradication (ARCHE) and also by the Martin Delaney CARE and DARE Collaboratories (National Institutes of Health [NIH] Grants AI096113 and AI096109), by NIH Grant AI043222, by the Johns Hopkins Center for AIDS Research, and by the Howard Hughes Medical Institute. Y.-C.H. is a Howard Hughes Medical Institute International Student Research Fellow.
PY - 2013/10/24
Y1 - 2013/10/24
N2 - 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. PaperFlick
AB - 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. PaperFlick
UR - http://www.scopus.com/inward/record.url?scp=84886769508&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2013.09.020
DO - 10.1016/j.cell.2013.09.020
M3 - Article
C2 - 24243014
AN - SCOPUS:84886769508
SN - 0092-8674
VL - 155
SP - 540
JO - Cell
JF - Cell
IS - 3
ER -