Residual HIV Replication Persists in Some Patients During Suppressive Antiretroviral Therapy
A recently published study provides additional in vivo evidence that residual viral replication persists in patients on highly suppressive therapies and that viral rebound is fueled by this cryptic replication. This means that, at least in some patients, standard antiretroviral therapy is not fully suppressive.
There is currently evidence to support the existence of at least 2 distinct reservoirs during therapeutic suppression of HIV replication :
-latently-infected lymphocytes ;
-a reservoir of low-level ongoing replication.
Episomal HIV-1 cDNAs detection is a valid surrogate marker of recently infected cells. Episomal HIV-1 genomes are a dynamic marker for recent infection and are representative of a reservoir in which HIV-1 is actively replicating, while proviral genomes are predominantly archival and defective.
The approach that was used (1) is to amplily env from episomes and also target 1-LTR circles that are approximately ten times more abundant than 2-LTR circles, resulting in a much greater sensitivity of detection.
The authors compared envelope sequences to define the phylogenetic relationships between episomal and proviral genomes prior to rebound in patients on ART to RNA genomes of viruses that emerged upon therapy interruption. During the treatment period, patients were suppressed by a combination of 2 nRTIs and at least one PI.
In some patients, there was tight intermingling of rebound RNA and episomal sequences demonstrating very close genetic similarity supporting the conclusion that viral rebound originated from a reservoir in which viral replication was ongoing. Plylogenetic analysis of viral env sequences in individuals who interrupted therapy indicated that plasma viremia originated from a cryptic viral reservoir as identified by episomal sequences.
Consequently, in the majority of patients, rebounding virus was highly similar to episomal sequences that existed prior to treatment interruption, but were not closely related to proviral sequences present at the same sampling time. It is therefore more likely that the rebounding virus is derived from actively replicating virus.
1-Sharkey M, Babic DZ, Greenough T, Gulick R, Kuritzkes DR, Stevenson M. Episomal Viral cDNAs Identify a Reservoir That Fuels Viral Rebound after Treatment Interruption and That Contributes to Treatment Failure. PLoS Pathogens 2011; 7(2): e1001303
Key words: hiv persistence, hiv reservoirs, ongoing replication