Low-level HIV replication versus latency: identifying the source of viral rebounds during treatment interruption
Richard Jefferys, TAG
In HIV research, there is a persistent and vigorous debate around the question of whether or not viral replication persists in the face of successful antiretroviral therapy. During a plenary session at the International AIDS Conference in Mexico City back in August, Bob Siliciano made a compelling argument that, in most cases, antiretroviral therapy completely shuts down virus production. 
Now, a new paper in PNAS provides additional support for this view. 
Beda Joos and colleagues evaluated a staggering 1,753 genetic sequences from the envelope region of HIV, sampled over the course of a treatment interruption trial known as SSITT (Swiss-Spanish Intermittent Treatment Trial). The study design involved a series of two-week treatment breaks followed by a prolonged interruption (therapy was subsequently reinitiated according to the CD4 and viral load thresholds used in current treatment guidelines).
The researchers used the sequence data to plot the relationships between the different viruses, using a technique called phylogenetic analyses. For each study participant analyzed, the sequences were used to define “the most recent common ancestor” (MRCA), which is the virus sequence from which all the others derived. Viruses that appeared during treatment interruptions (TIs) were then compared to the MRCA, to see if the sequences suggested that there had been ongoing replication and evolution while the study participants were on ART. The results showed that the rebounding viruses during TI were actually more distant from the MRCA than the viruses detected when the participants first entered the study. The researchers conclude: “the striking lack of a temporal relationship between rebounding virus and pretreatment viruses strongly suggests that rebounding virus originates from reactivated, latently infected cells rather than from a cellular pool or compartment engaged in low-level replication.”
Source: TAG basic science blog (20 November 2008)
- Siliciano R. HIV persistence on patients on HAART: re-evaluating prospects for eradication. XVII Intl AIDS Conference, 3-8 August 2008, Mexico City.
- Joosa B et al. HIV rebounds from latently infected cells, rather than from continuing low-level replication. PNAS October 28, 2008 vol. 105 no. 43 16725-16730