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Natural products continue to be a useful source of new leads for the pharmaceutical industry. Actinomycetes are prolific producers of natural products and one strategy to increase the possibility of discovering novel chemical entities is to screen actinomycetes considered 'rare' in the environment and previously under-represented in natural product screening collections. We describe a method using bacteriophage as a marker to detect these actinomycetes in environmental samples. This method allows samples to be pre-screened for the presence of target actinomycetes before lengthy isolation programmes are undertaken.

HIV infection is an independent risk factor for end-stage kidney disease in HIV-positive patients of black ethnicity. Highly effective antiretroviral therapy has allowed these patients to be considered for kidney transplantation (KT). We report the outcomes of KT in a national observational cohort study. We retrospectively identified HIV-positive patients who had undergone KT up to December, 2010, through all 25 UK KT centres and major HIV clinics, and included follow-up until December, 2011. Patient characteristics, treatments, and complications were described. Patient and graft survival rates and cumulative incidence of acute rejection were estimated with Kaplan-Meier and Nelson-Aalen analyses. 35 HIV-positive KT recipients (median age 40 years, 66% male, 74% black ethnicity) were identified. At the time of KT, all patients were stable on antiretroviral therapy with undetectable HIV RNA and median CD4 cell count of 366 cells per mL. Patient survival at both 1 and 3 years was 91·3%, and graft survival was 91·3% and 84·7%, respectively. In the first year after KT, blood concentrations of calcineurin inhibitors (CNI) were frequently outside the therapeutic reference range. At 1 year after KT, the cumulative incidence of acute allograft rejection was 48%, and the median estimated glomerular filtration rate 61 mL/min/1·73 m2 (IQR 46–78). Although HIV viraemia and HIV disease progression were uncommon, renal complications were relatively frequent. Our study corroborates the feasibility of KT in HIV-positive patients. Co-administration of antiretroviral therapy and CNI is challenging, and sub-therapeutic CNI concentrations may contribute to the high rate of acute allograft rejection. The optimum immune suppression strategy in this population remains to be refined. King's College London.

The prognosis of human immunodeficiency virus (HIV) has been dramatically improved over the years owing to more widespread access and earlier use of antiretroviral drug therapy. Consequently, HIV-positive patients are no longer dying from AIDS related illnesses but increasingly are experiencing non-infectious complications such as end-stage kidney disease (ESKD). The prevalence of ESKD among 7,307 black HIV-positive patients in the UK CHIC cohort increased from 0.44% in 2000/2001 to 1.09% in 2010/2011. Kidney transplantation was increasingly used to treat ESKD. Among those suitable for transplantation, survival on dialysis and post-kidney transplantation was similar (89% and 85% at five years, respectively, p=0.53). 97 HIV-positive kidney transplant recipients were identified in the United Kingdom. Of those that met the study criteria (n=78), 34% received a kidney allograft from a living donor and the median follow-up period was 31 (19, 55) months. Patient survival at 1 and 3 years post-KT was excellent at 97·3% and 94·8%, respectively, and the corresponding graft survival rates were 97.3% and 90.0%. Delayed graft function was encountered in 16 patients (21%), all of whom had received a kidney from a deceased donor. The cumulative incidence of allograft rejection (AR) at 1 year was 58% and 21% among patients on ciclosporin (CsA) and tacrolimus (Tac) respectively. Choice of calcineurin inhibitor (CNI) was significantly associated with AR (hazard ratio for Tac vs. CsA 0.25 [95% CI 0.11, 0.57], p=0.001). Complex drug interactions complicated post-transplant management of HIV/KT recipients. CNI doses for patients who received ritonavir-boosted protease inhibitor (PI) containing cART were significantly lower throughout the first year post-KT (30~fold for ciclosporin, 100~fold for tacrolimus) compared to those receiving PI-sparing antiretroviral regimens. By week 4 post-transplant, more than half of the patients in both CNI groups had achieved target trough concentrations i.e. 50% Tac vs 57% for CsA. Patients in whom mycophenolate (MMF) concentrations were routinely measured experienced significantly reduced cumulative incidence of latent virus infections, even after adjusting for cytomegalovirus prophylaxis (20% vs 84% respectively, p=0.0001). In conclusion, these data presented in this thesis demonstrate the increasing burden of ESKD despite the widespread use of cART. Findings corroborate the feasibility of kidney transplantation in HIV-positive patients albeit with a high rate of delayed graft function and allograft rejection. Poor allograft outcomes may have been complicated by suboptimal immunotherapy owing to the pharmacokinetic interactions between antiretroviral and immunosuppressant drugs. The use of tacrolimus may be the preferred CNI for use in KT in HIV-positive individuals, and monitoring of mycophenolate drug concentrations may be beneficial in this patient population.