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In HIV-infected patients, interruption of antiretroviral therapy (ART) is promptly followed by viral rebound. Where does this rebounding virus come from? Does it arise from expansion of viral populations that were replicating at low levels during ART, or from reactivation of latently infected cells? To address this question, investigators analyzed viral strains obtained before and during structured treatment interruptions (TIs) among 20 participants in the Swiss-Spanish Intermittent Treatment Trial.
After having undetectable viral loads (<50 copies/mL) for ≥6 months, the patients underwent four TI cycles (2 weeks off, then 8 weeks on ART), followed by a fifth TI of indefinite duration. Longitudinal clonal evolutionary studies were conducted on 1753 gp120 C2-V3-C3 region sequences of viruses obtained from these patients during a median of 6.5 years.
Strains that emerged during the 2-week TIs were relatively homogeneous, consistent with an oligoclonal or monoclonal origin. These viruses appeared to be of early ancestry within individuals and did not show evidence of ongoing evolution. Viral diversity during TIs was notably lower than that seen before ART initiation and remained so for a lengthy period, suggesting creation of an evolutionary roadblock. TIs did not provoke a shift from CCR5 to CXCR4 coreceptor usage.
Joos B et al. HIV rebounds from latently infected cells, rather than from continuing low-level replication. Proc Natl Acad Sci U S A 2008 Oct 28; 105:16725.
Comment
Relatively little ongoing viral evolution was seen in patients who achieved undetectable viral loads on ART. Moreover, the rate of genetic diversification in viruses that emerged during ART interruption was slowed. Together, these findings provide reassurance that in individuals who achieve long-term viral suppression with ART, drug resistance is unlikely to emerge, and that even if ART is interrupted, the relative rate of viral evolution will be limited, provided that drugs with similar half-lives are stopped simultaneously.