Integrated Human Immunodeficiency Virus Type 1 Proviral DNA (HIV-1 Proviral DNA)

Integrated HIV-1 proviral DNA is the double-stranded DNA form of the Human Immunodeficiency Virus type 1 that has been covalently inserted into the host cell's chromosomal DNA by the viral enzyme integrase (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350464/). This integrated genome serves as a permanent template for the production of new viral particles and is the primary barrier to a functional cure for HIV/AIDS (Frontiers in Microbiology, https://www.frontiersin.org/articles/10.3389/fmicb.2019.00522/full). While antiretroviral therapy (ART) effectively suppresses active viral replication, it does not eliminate the proviral DNA, which can persist in a latent state within long-lived resting CD4+ T cells for decades (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449130/). Therapeutic strategies targeting the provirus include "shock and kill" approaches using latency-reversing agents to induce viral expression for immune clearance, "block and lock" methods to permanently silence transcription, and direct excision of the viral genome using gene-editing technologies like CRISPR/Cas9, such as EBT-101 (Excision BioTherapeutics, https://www.excision.bio/ebt-101). Monitoring the reservoir size and the intactness of the proviral DNA using assays like the Intact Proviral DNA Assay (IPDA) is essential for evaluating the success of these curative interventions (Nature, https://www.nature.com/articles/s41586-019-0898-8). A significant challenge in targeting the provirus is the high degree of sequence diversity and the presence of defective proviruses that complicate both therapeutic targeting and accurate measurement (Journal of Virology, https://journals.asm.org/doi/10.1128/jvi.01334-23).

Other names

HIV-1 provirusIntegrated HIV-1 DNAHIV-1 latent reservoirHIV-1 proviral genome

Therapeutic strategies include gene editing for direct excision or inactivation of the proviral sequence, transcriptional activation (shock and kill) to induce viral expression and subsequent immune clearance, and transcriptional silencing (block and lock) to permanently suppress viral rebound (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449130/; Excision BioTherapeutics, https://www.excision.bio/ebt-101).