Christina Kitchen, Department of Biostatistics, UCLA.
Location:
Thursday, April 7, 2011
4:00pm - 5:00pm
1216 SAS Hall, NCSU
Abstract: Careful examination of viral dynamics during treatment can provide important insights into HIV pathogenesis. Here, we examined viral evolution during and after enfuvirtide (T-20) treatment with an objective of defining the characteristics of viral evolution during advanced HIV immunodeficiency. First we examined the viral quasispecies from 9 patients who experienced incomplete viral suppression on an enfuvirtide-based regimen, and who subsequently interrupted enfuvirtide (ENF) while remaining on a stable background regimen (ENF "partial treatment interruption"). An average of 8 clones were sequenced from 3 time points: pre-ENF, post-ENF failure and post-ENF interruption. We utilized a Bayesian hierarchical phylogenetic model to assess the evolutionary relatedness of the virus that emerged after ENF interruption to the strains sequenced before initiation of ENF and strains sequenced before the interruption, Previously we found that during partial treatment interruption of ENF the envelope gene product gp41 continues to evolve and the loss of drug resistance-associated mutations is due to back mutation and not the recall of archived strains. It is unknown how ENF therapy may affect the selective pressure of other envelope gene regions involved in viral entry such as gp120. To aid in understanding the evolution of both gene regions we extended our Bayesian hierarchical phylogenetic model to allow for the simultaneous estimation of both gene regions and to test the hypothesis of independent evolution between the regions. The hierarchical approach allows for the simultaneous estimation of overall trends across patients and genes and for pooling of information. Examination of both gene regions yielded a Bayes Factor of 1427 in the comparison of the continued evolution hypothesis over the re-emergence of archived strains hypothesis. Analysis of only the gp41 gene region yielded a Bayes Factor of 30.2 of the evolution hypothesis over re-emergence suggesting that the borrowed strength of pooled estimates gave overwhelming support of continued evolution over re-emergence of archived strains. This gives further evidence that the loss of resistance-associated mutations seen after approximately 16 weeks post T20 interruption are a consequence of back-mutation and forward evolution in both gp120 and gp41. To more fully examine the role of resistance on viral virulence we conducted 454 sequencing on 18 treatment-experienced patients with a history of enfuvirtide treatment failure who are no longer taking enfuvirtide and to which enfuvirtide was added to a stable regimen for four weeks. 454-based pyrosequencing of the HIV-1 gp41 HR1 region was performed on plasma virus on a weekly basis. Our data support the hypothesis that resistance mutations attenuate HIV-1 pathogenicity and cytopathicity in vivo. This is in agreement with previous observations from our group suggesting that enfuvirtide results in durable immunologic benefit even in the presence of high-level enfuvirtide resistance, and implicate decreased HIV-1 virulence (capacity to cause CD4+ T cell loss) as the principal mechanism underlying the sustained benefit.
