The study investigates the presence and characteristics of noninduced proviruses in the latent reservoir of HIV-1, which are proviruses that do not produce infectious virus after maximum in vitro activation. The authors analyzed 213 noninduced proviral clones from treated patients and found that while most (88.3%) had identifiable defects, 11.7% had intact genomes and normal long terminal repeat (LTR) function. Using direct sequencing and genome synthesis, they reconstructed full-length intact noninduced proviral clones and demonstrated comparable growth kinetics to reconstructed induced proviruses from the same patients. These intact noninduced proviruses have unmethylated promoters and are integrated into active transcription units, suggesting they could be activated in vivo. The identification of replication-competent noninduced proviruses indicates that the size of the latent reservoir may be up to 60-fold greater than previously estimated, increasing the barrier to HIV-1 cure. The study provides insights into the extent of the challenge posed by the latent reservoir and suggests novel strategies to target intact noninduced proviruses.The study investigates the presence and characteristics of noninduced proviruses in the latent reservoir of HIV-1, which are proviruses that do not produce infectious virus after maximum in vitro activation. The authors analyzed 213 noninduced proviral clones from treated patients and found that while most (88.3%) had identifiable defects, 11.7% had intact genomes and normal long terminal repeat (LTR) function. Using direct sequencing and genome synthesis, they reconstructed full-length intact noninduced proviral clones and demonstrated comparable growth kinetics to reconstructed induced proviruses from the same patients. These intact noninduced proviruses have unmethylated promoters and are integrated into active transcription units, suggesting they could be activated in vivo. The identification of replication-competent noninduced proviruses indicates that the size of the latent reservoir may be up to 60-fold greater than previously estimated, increasing the barrier to HIV-1 cure. The study provides insights into the extent of the challenge posed by the latent reservoir and suggests novel strategies to target intact noninduced proviruses.