The von Hippel-Lindau Cullin-RING E3 ubiquitin ligase regulates APOBEC3 cytidine deaminases.

The 7 members of the A3 family of cytidine deaminases (A3A to A3H) share a conserved catalytic activity that converts cytidines in single-stranded (ss) DNA into uridines, thereby inducing mutations. After their initial identification as cell-intrinsic defenses against HIV and other retroviruses, A3s were also found to impair many additional viruses. Moreover, some of the A3 proteins (A3A, A3B, and A3H haplotype I) are dysregulated in cancer cells, thereby causing chromosomal mutations that can be selected to fuel progression of malignancy. Viral mechanisms that increase transcription of A3 genes or induce proteasomal degradation of A3 proteins have been characterized. However, only a few underlying biological mechanisms regulating levels of A3s in uninfected cells have been described. Here, we characterize that the von Hippel-Lindau tumor suppressor (pVHL), via its CRLpVHL, induces degradation of all 7 A3 proteins. Two independent lines of evidence supported the conclusion that the multiprotein CRLpVHL complex is necessary for A3 degradation. CRLpVHL more effectively induced degradation of nuclear, procancer A3 (A3B) than the cytoplasmic, antiretroviral A3 (A3G). These results identify specific cellular factors that regulate A3s post-translationally.

Antiretrovial (ARV) drug utilisation in Harare.

OBJECTIVE: To investigate ARV utilisation in Harare in order to gather necessary data to help in the formulation of treatment guidelines to be used in Zimbabwe. DESIGN: A cross sectional study. SETTING: Doctors' rooms and retail pharmacy outlets. SUBJECTS: 68 primary care physicians, 80 pharmacists and 92 patients. MAIN OUTCOME MEASURES: Number of physicians prescribing antiretroviral agents (ARVs) and pharmacists stocking ARVs. Type of ARV utilised, cost to the patient and information on ARV available. RESULTS: Out of the 68 private practitioners interviewed 18 were prescribing ARVs during the period of study. There were 92 patients on ARVs whose mean age was 35 +/- 5 years and consuming an average total of 17 tablets daily. Thirteen out of the 18 doctors had access to laboratory facilities to determine CD4 counts and viral load. The rest were using other approaches to treat and manage HIV/AIDS patients. About a quarter, 27.0%, of the retail pharmacists stocked ARVs. The majority, 82.0%, of the patients appeared to be on Zidovudine (AZT) mainly in combination with other drugs. The most popular combination was that of AZT, Lamivudine (3TC) and Indinavir prescribed to 29.0% of the patients, followed by that of Didanosine (DDI) and hydroxyurea prescribed to 17% of patients. At least 17% of the patients were on AZT monotherapy. There was no significant difference (p = 0.06) in the number of tablets consumed by patients who had other conditions secondary to HIV infection. Only 39 out of the 92 patients reported untoward experiences with ARVs. The major problem being associated gastro-intestinal disturbance which accounted for 56% of the reports. It was not possible to ascertain adherence. CONCLUSION: There appeared to be therapeutic anarchy in the private sector in Harare in the way ARVs were being used. Patients need to be told that deciding to take one of the combinations means making a serious commitment to the drugs on schedule if they want to enjoy the benefit. At the same time there is need to develop and publicize HIV/AIDS treatment guidelines and effective Information, Education and Communication (IEC) materials specific to Zimbabwe.