Low Inducibility of Latent Human Immunodeficiency Virus Type 1 Proviruses As a Major Barrier to Cure

The latent reservoir for human immunodeficiency virus type 1 (HIV-1) in resting CD4+ T cells is a major barrier to cure. The dimensions of the reservoir problem can be defined with 2 assays. A definitive minimal estimate of the frequency of latently infected cells is provided by the quantitative viral outgrowth assay (QVOA), which detects cells that can be induced by T-cell activation to release infectious virus. In contrast, the intact proviral DNA assay (IPDA) detects all genetically intact proviruses and provides a more accurate upper limit on reservoir size than standard single-amplicon polymerase chain reaction assays which mainly detect defective proviruses. The frequency of cells capable of initiating viral rebound on interruption of antiretroviral therapy lies between the values produced by the QVOA and the IPDA. We argue here that the 1-2-log difference between QVOA and IPDA values in part reflects that the fact that many replication-competent proviruses are not readily induced by T-cell activation. Findings of earlier studies suggest that latently infected cells can be activated to proliferate in vivo without expressing viral genes. The proliferating cells nevertheless retain the ability to produce virus on subsequent stimulation. The low inducibility of latent proviruses is a major problem for the shock-and-kill strategy for curing HIV-1 infection, which uses latency-reversing agents to induce viral gene expression and render infected cells susceptible to immune clearance. The latency-reversing agents developed to date are much less effective at reversing latency than T-cell activation. Taken together, these results indicate that HIV-1 eradication will require the discovery of much more effective ways to induce viral gene expression.