Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration

Citation: Cardozo EF, Andrade A, Mellors JW, Kuritzkes DR, Perelson AS, Ribeiro RM. Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration. PLoS Pathog. 2017 Jul 5;13(7):e1006478. doi: 10.1371/journal.ppat.1006478. eCollection 2017 Jul. PMID: 28678879; PMCID: PMC5513547 

Access full article:

https://www.ncbi.nlm.nih.gov/pubmed/28678879

The kinetics of HIV-1 decay under treatment depends on the class of antiretrovirals used. Mathematical models are useful to interpret the different profiles, providing quantitative information about the kinetics of virus replication and the cell populations contributing to viral decay. We modeled proviral integration in short- and long-lived infected cells to compare viral kinetics under treatment with and without the integrase inhibitor raltegravir (RAL). We fitted the model to data obtained from participants treated with RAL-containing regimes or with a four-drug regimen of protease and reverse transcriptase inhibitors. Our model explains the existence and quantifies the three phases of HIV-1 RNA decay in RAL-based regimens vs. the two phases observed in therapies without RAL. Our findings indicate that HIV-1 infection is mostly sustained by short-lived infected cells with fast integration and a short viral production period, and by long-lived infected cells with slow integration but an equally short viral production period. We propose that these cells represent activated and resting infected CD4+ T-cells, respectively, and estimate that infection of resting cells represent ~4% of productive reverse transcription events in chronic infection. RAL reveals the kinetics of proviral integration, showing that in short-lived cells the pre-integration population has a half-life of ~7 hours, whereas in long-lived cells this half-life is ~6 weeks. We also show that the efficacy of RAL can be estimated by the difference in viral load at the start of the second phase in protocols with and without RAL. Overall, we provide a mechanistic model of viral infection that parsimoniously explains the kinetics of viral load decline under multiple classes of antiretrovirals.

Categories

CRS
Topics

Clinical Trials

A5274: REMEMBER, Reducing Early Mortality and Early...

This study is being done in people who are starting HIV treatment and who live in areas where the TB infection rate is high. The...

Read More

A5384: A Phase II, Randomized, Open-Label Trial of a...

Study Description A5384 is a trial for people who have or might have tuberculous meningitis (TBM). TBM is an infectious disease...

Read More

NWCS 445: Novel Biomarkers to Shorten TB Treatment

Objectives: Primary: To develop a highly predictive algorithm that identifies TB patients who will be cured by treatment...

Read More

A5322: Long-Term Follow-up of Older HIV-infected Adults in...

The A5322 protocol is a long-term observational study, with a planned series of analyses of data to be collected from an...

Read More

HPTN083: A Phase 2b/3 Double Blind Safety and Efficacy Study...

HPTN 083 is a study being done to evaluate the efficacy of the long-acting injectable agent, cabotegravir (CAB LA), for...

Read More