Vav2 Is an Activator of Cdc42, Rac1, and RhoA

Vav and Vav2 are members of the Dbl family of proteins that act as guanine nucleotide exchange factors (GEFs) for Rho family proteins. Whereas Vav expression is restricted to cells of hematopoietic origin, Vav2 is widely expressed. Although Vav and Vav2 share highly related structural similarities and high sequence identity in their Dbl homology domains, it has been reported that they are active GEFs with distinct substrate specificities toward Rho family members. Whereas Vav displayed GEF activity for Rac1, Cdc42, RhoA, and RhoG, Vav2 was reported to exhibit GEF activity for RhoA, RhoB, and RhoG but not for Rac1 or Cdc42. Consistent with their distinct substrate targets, it was found that constitutively activated versions of Vav and Vav2 caused distinct transformed phenotypes when expressed in NIH 3T3 cells. In contrast to the previous findings, we found that Vav2 can act as a potent GEF for Cdc42, Rac1, and RhoA in vitro. Furthermore, we found that NH(2)-terminally truncated and activated Vav and Vav2 caused indistinguishable transforming actions in NIH 3T3 cells that required Cdc42, Rac1, and RhoA function. In addition, like Vav and Rac1, we found that Vav2 activated the Jun NH(2)-terminal kinase cascade and also caused the formation of lamellipodia and membrane ruffles in NIH 3T3 cells. Finally, Vav2-transformed NIH 3T3 cells showed up-regulated levels of Rac-GTP. We conclude that Vav2 and Vav share overlapping downstream targets and are activators of multiple Rho family proteins. Therefore, Vav2 may mediate the same cellular consequences in nonhematopoietic cells as Vav does in hematopoietic cells

Improved adherence to modern antiretroviral therapy among HIV-infected injecting drug users

OBJECTIVES: Adherence to antiretroviral therapy (ART) among injection drug users (IDU) is often sub-optimal, yet little is known about changes in patterns of adherence since the advent of highly active antiretroviral therapy in 1996. We sought to assess levels of optimal adherence to ART among IDU in a setting of free and universal HIV care. METHODS: Data was collected through a prospective cohort study of HIV-positive IDU in Vancouver, British Columbia. We calculated the proportion of individuals achieving at least 95% adherence in the year following initiation of ART from 1996 to 2009. RESULTS: Among 682 individuals who initiated ART, the median age was 37 (31–44) years with 248 (36.4%) female participants. The proportion achieving at least 95% adherence increased over time from 19.3% in 1996 to 65.9% in 2009 (Cochrane-Armitage test for trend: p < 0.001). In a logistic regression model examining factors associated with 95% adherence, initiation year was statistically significant (Odds Ratio = 1.08, 95% Confidence Interval: 1.03–1.13, p < 0.001 per year after 1996) after adjustment for a range of drug use variables and other potential confounders. CONCLUSIONS: The proportion of IDU achieving at least 95% adherence during the first year of ART has consistently increased over a 13-year period. Although improved tolerability and convenience of modern ART regimens likely explain these positive trends, by the end of the study period a substantial proportion of IDU still had sub-optimal adherence demonstrating the need for additional adherence support strategies