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Numerous clinical studies have reported T20-resistance mutations [1,10,11,13-20]. One clinical trial that enrolled 17 patients was used to track the evolution of sequence changes in HR1 and HR2 that are associated with T20-resistance . Mutations in HR1 (amino acids 36–45) were noted in all patients. Isolates from 6 of 17 patients also developed the subsequent S138A change in HR2. It was proposed that the S138A mutation represents a compensatory mutation that increases T20-resistance, particularly when it co-exists with mutations at position 43 in HR1. Interestingly, careful analysis of the published results revealed a SIM-DKY variant in one of the patients after 24 weeks of therapy. This mutant resembles the T20-dependent GIA-SKY variant that we described . However, little additional information is available, as not all mutations were tested in a molecular HIV-1 clone and analyzed for possible drug-resistance and drug-dependence. Studies that reported combined HR1/HR2 changes are summarized in Table 1.
Another clinical trial study analyzed amino acid changes in the gp41 region of Env over a 40–72 week period in 4 patients that received T20 on top of an optimized antiviral regimen . Three of the four patients initially developed T20-resistance mutations in the HR1 region and subsequently developed HR2 mutations. HR1 mutations occurred in the amino acid region 36–45 (G36D/E, N42T, N43D and L45M), whereas S138A was again the main mutation observed in HR2. Although they did not perform molecular recloning experiments, it can be concluded that compensatory changes in HR2 develop frequently within the course of T20 therapy.
Two very recent 2007 studies reported interesting compensatory changes in HR2 within the virus population of patients on T20 therapy [17,21]. The first study describes five treatment-experienced patients that were analyzed for Env sequences prior to T20 therapy and at the point of virologic failure . The same double mutant that we reported , GIA-SKY, was isolated from one patient and confirmed to be highly resistant to T20. However, drug-dependence was not tested. In fact, all patients developed both HR1 and HR2 mutations, including the S138A change in HR2, which was seen in combination with the N43D mutation in HR1 in one patient.
In the second study, Env sequences were analyzed during the course of T20-therapy in 5 patients . The N43D mutation in HR1 provided resistance to T20, but at a large fitness cost (92% decreased infectivity was measured). An interesting compensatory mutation in HR2 (E137K) restored the infectivity defect and further increased resistance to T20.
Thus, mutations in HR1 at residue 43 trigger a response in HR2 at residue 137 (E137K) or 138 (S138A). Interestingly, these HR1 and HR2 amino acid residues are juxtaposed in the post-fusion 6-helix bundle structure . The introduction of N43D in HR1 introduces a negatively charged aspartic acid (D), which may be unfavorable in the formation of the 6-helix bundle as it approaches the negatively charged glutamic acid (E) at position 137. The compensatory HR2 mutation introduces a positively charged lysine (K) or a neutral charged alanine (A), which will avoid the repulsion and thus restore virus infectivity.
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