Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure.
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.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ya-Chi
YC
Ho
Liang
L
Shan
Nina N
NN
Hosmane
Jeffrey
J
Wang
Sarah B
SB
Laskey
Daniel I S
DI
Rosenbloom
Jun
J
Lai
Joel N
JN
Blankson
Janet D
JD
Siliciano
Robert F
RF
Siliciano
D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D019175:DNA Methylation; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics*; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D011533:Proviruses / Q000235:genetics; D016415:Sequence Alignment; D017735:Virus Latency