In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 53, No. 7 ( 2009-07), p. 2816-2823
Kurzfassung:
The gp41-encoding sequence of the env gene contains in two separate regions the Rev-responsive elements (RRE) and the alternative open reading frame of the second exon of the regulatory protein Rev. The binding of Rev to the RRE allows the transport of unspliced/singly spliced viral mRNAs out of the nucleus, an essential step in the life cycle of human immunodeficiency virus type 1 (HIV-1). In this study, we have investigated whether the fusion-inhibitor enfuvirtide (ENF) can induce mutations in Rev and if these mutations correlate with the classical ENF resistance gp41 mutations and with viremia and CD4 cell count. Specific Rev mutations were positively associated with ENF treatment and significantly correlated with classical ENF resistance gp41 mutations. In particular, a cluster was observed for the Rev mutations E57A (E57A rev ) and N86S rev with the ENF resistance gp41 mutations Q40H (Q40H gp41 ) and L45M gp41 . In addition, the presence at week 48 of the E57A rev correlates with a significant viremia increase from baseline to week 48 and with a CD4 cell count loss from baseline to week 48. By modeling the RRE structure, we found that the Q40 gp41 and L45 gp41 codons form complementary base pairs in a region of the RRE involved in Rev binding. The conformation of this Rev-binding site is disrupted when Q40H gp41 and L45M gp41 occur alone while it is restored when both mutations are present. In conclusion, our study shows that ENF pressure may also affect both Rev and RRE structures and can provide an excellent example of compensatory evolution. This highlights the multiple roles of ENF (and perhaps other entry inhibitors) in modulating the correct interplay between the different HIV-1 genes and proteins during the HIV-1 life cycle.
Materialart:
Online-Ressource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/AAC.01067-08
Sprache:
Englisch
Verlag:
American Society for Microbiology
Publikationsdatum:
2009
ZDB Id:
1496156-8
SSG:
12
SSG:
15,3
