HIV-1 Drug Resistance Testing From Proviral DNA: Methods, Dynamics, and Clinical Utility
Genotypic resistance testing of HIV-1 DNA in peripheral blood mononuclear cells is increasingly used for patients with virological suppression on antiretroviral therapy, where plasma RNA may be undetectable. This Clinical Microbiology Reviews article explains how proviral DNA dynamics differ from plasma virus, why NGS is particularly suited for detecting minority drug-resistance mutations archived in the cellular reservoir, and the clinical scenarios where PBMC-based testing adds value. The review notes a critical time lag between plasma and PBMC compartments that affects test sensitivity.
The original study
Genotypic Resistance Testing of HIV-1 DNA in Peripheral Blood Mononuclear Cells.
- Authors
- Chu C, Armenia D, Walworth C, Santoro MM, Shafer RW
- Journal
- Clinical microbiology reviews
- Type
- Journal Article, Review, Research Support, N.I.H., Extramural
- PMID
- 36102816
Original abstract
HIV-1 DNA exists in nonintegrated linear and circular episomal forms and as integrated proviruses. In patients with plasma viremia, most peripheral blood mononuclear cell (PBMC) HIV-1 DNA consists of recently produced nonintegrated virus DNA while in patients with prolonged virological suppression (VS) on antiretroviral therapy (ART), most PBMC HIV-1 DNA consists of proviral DNA produced months to years earlier. Drug-resistance mutations (DRMs) in PBMCs are more likely to coexist with ancestral wild-type virus populations than they are in plasma, explaining why next-generation sequencing is particularly useful for the detection of PBMC-associated DRMs. In patients with ongoing high levels of active virus replication, the DRMs detected in PBMCs and in plasma are usually highly concordant. However, in patients with lower levels of virus replication, it may take several months for plasma virus DRMs to reach detectable levels in PBMCs. This time lag explains why, in patients with VS, PBMC genotypic resistance testing (GRT) is less sensitive than historical plasma virus GRT, if previous episodes of virological failure and emergent DRMs were either not prolonged or not associated with high levels of plasma viremia. Despite the increasing use of PBMC GRT in patients with VS, few studies have examined the predictive value of DRMs on the response to a simplified ART regimen. In this review, we summarize what is known about PBMC HIV-1 DNA dynamics, particularly in patients with suppressed plasma viremia, the methods used for PBMC HIV-1 GRT, and the scenarios in which PBMC GRT has been used clinically.