Survival of the Fittest: Positive Selection of CD4+ T Cells Expressing a Membrane-Bound Fusion Inhibitor Following HIV-1 Infection

Although a variety of genetic strategies have been developed to inhibit HIV replication, few direct comparisons of the efficacy of these inhibitors have been carried out. Moreover, most studies have not examined whether genetic inhibitors are able to induce a survival advantage that results in an expansion of genetically-modified cells following HIV infection. We evaluated the efficacy of three leading genetic strategies to inhibit HIV replication: 1) an HIV-1 tat/rev-specific small hairpin (sh) RNA; 2) an RNA antisense gene specific for the HIV-1 envelope; and 3) a viral entry inhibitor, maC46. In stably transduced cell lines selected such that >95% of cells expressed the genetic inhibitor, the RNA antisense envelope and viral entry inhibitor maC46 provided the strongest inhibition of HIV-1 replication. However, when mixed populations of transduced and untransduced cells were challenged with HIV-1, the maC46 fusion inhibitor resulted in highly efficient positive selection of transduced cells, an effect that was evident even in mixed populations containing as few as 1% maC46-expressing cells. The selective advantage of the maC46 fusion inhibitor was also observed in HIV-1-infected cultures of primary T lymphocytes as well as in HIV-1-infected humanized mice. These results demonstrate robust inhibition of HIV replication with the fusion inhibitor maC46 and the antisense Env inhibitor, and importantly, a survival advantage of cells expressing the maC46 fusion inhibitor both in vitro and in vivo. Evaluation of the ability of genetic inhibitors of HIV-1 replication to confer a survival advantage on genetically-modified cells provides unique information not provided by standard techniques that may be important in the in vivo efficacy of these genes

Evolution and plasticity of photosynthetic thermal tolerance, specific leaf area and leaf size: congeneric species from desert and coastal environments

• We examined whether increased high temperature photosynthetic thermal tolerance (PT), reduced specific leaf area (SLA) and reduced leaf size represent correlated and convergent adaptations for recently diverged Encelia, Salvia, Atriplex and Eriogonumcongeneric species pairs from contrasting thermal and water environments (the Mojave Desert and coastal California). We also studied whether variation in PT is associated with inducible small heat shock protein expression (sHsp). • Traits were measured in a common environment (CE) and in the field to partition effects of phenotypic plasticity and genetic divergence. • We found little evidence for convergent adaptation of PT (CE measurements). Field measurements revealed significant plasticity for PT, which was also associated with increased sHsp expression. Compared to coastal congeners desert species had lower SLA in the CE. These differences were magnified in the field. There was a negative correlation between SLA and PT. Desert species also tended to have smaller leaves both in the CE and in the field. • SLA and leaf size reductions represent repeated evolutionary divergences and are perhaps convergent adaptations for species radiating into the desert, while PT is highly plastic and shows little evidence for convergent adaptation in the congeneric species pairs we studied