Prevalence and Clinical Significance of HIV Drug Resistance Mutations by Ultra-Deep Sequencing in Antiretroviral-Naïve Subjects in the CASTLE Study

CASTLE compared the efficacy of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-naïve subjects from 5 continents.Determine the baseline rate and clinical significance of TDR mutations using ultra-deep sequencing (UDS) in ARV-naïve subjects in CASTLE.A case control study was performed on baseline samples for all 53 subjects with virologic failures (VF) at Week 48 and 95 subjects with virologic successes (VS) randomly selected and matched by CD4 count and viral load. UDS was performed using 454 Life Sciences/Roche technology.Of 148 samples, 141 had successful UDS (86 subtype B, 55 non-B subtypes). Overall, 30.5% of subjects had a TDR mutation at baseline; 15.6% only had TDR(s) at <20% of the viral population. There was no difference in the rate of TDRs by B (30.2%) or non-B subtypes (30.9%). VF (51) and VS (90) had similar rates of any TDRs (25.5% vs. 33.3%), NNRTI TDRs (11.1% vs.11.8%) and NRTI TDRs (24.4% vs. 25.5%). Of 9 (6.4%) subjects with M184V/I (7 at <20% levels), 6 experienced VF. 16 (11.3%) subjects had multiple TAMs, and 7 experienced VF. 3 (2.1%) subjects had both multiple TAMs+M184V, and all experienced VF. Of 14 (9.9%) subjects with PI TDRs (11 at <20% levels): only 1 experienced virologic failure. The majority of PI TDRs were found in isolation (e.g. 46I) at <20% levels, and had low resistance algorithm scores.Among a representative sample of ARV-naïve subjects in CASTLE, TDR mutations were common (30.5%); B and non-B subtypes had similar rates of TDRs. Subjects with multiple PI TDRs were infrequent. Overall, TDRs did not affect virologic response for subjects on a boosted PI by week 48; however, a small subset of subjects with extensive NRTI backbone TDR patterns experienced virologic failure

Treatment of HIV-1 Infection with Combination Therapy: Antiretroviral Agents and Biological Response Modifiers

While nucleoside antiretroviral agents are effective in delaying disease progression in human immunodeficiency virus (HIV - infected individuals. their activity is limited in magnitude and duration. Therefore, approaches to attacking HIV via combination therapies have recently been under investigation. In particular, since HIV infection dysregulates and destroys the immune system. it is logical to develop therapeutic approaches that would both restore the immune response and have direct antiviral activity. Preliminary evaluations of the combination of zidovudine wilh interferon alpha (IFN-α) have demonstrated enhanced antiviral. antitumour and immunomodulatory activity. Other promising approaches include antiretroviral therapy with interleukin (IL) -2, and IFN-α wilh IL-2. The clinical research pertaining to these combinations of antiretrovirals and biological response modifiers is reviewed

Abnormal Levels of Some Biomarkers of Immune Activation Despite Very Early Treatment of Human Immunodeficiency Virus.

BackgroundDespite early antiretroviral therapy (ART), ART-suppressed people with human immunodeficiency virus (HIV) (PWH) remain at higher risk for infections and infection-related cancers than the general population. The immunologic pathways that remain abnormal in this setting, potentially contributing to these complications, are unclear.MethodsART-suppressed PWH and HIV-negative controls, all cytomegalovirus seropositive and enriched for HIV risk factors, were sampled from an influenza vaccine responsiveness study. PWH were stratified by timing of ART initiation (within 6 months of infection [early ART] vs later) and nadir CD4+ T-cell count among later initiators. Between-group differences in kynurenine-tryptophan (KT) ratio, interferon-inducible protein 10, soluble CD14 and CD163, soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor were assessed after confounder adjustment.ResultsMost participants (92%) were male, reflecting the demographics of early-ART initiators in San Francisco. Most biomarkers were higher among later-ART initiators. Participants in the early-ART group achieved near-normal soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor levels, but substantially higher KT ratio than those without HIV after confounder adjustment (P = .008). Soluble CD14, soluble CD163, and interferon-inducible protein 10 trended similarly.ConclusionsWhile early-ART initiators restore near-normal levels of many inflammatory markers, the kynurenine pathway of tryptophan catabolism remains abnormally high. Because this pathway confers adaptive immune defects and predicts tuberculosis and cancer progression, this it may contribute to persistent risks of these complications in this setting

Advanced Astrophysics Discovery Technology in the Era of Data Driven Astronomy

Astrophysics is at the threshold of a new epoch in which increasinglycomplex, heterogeneous datasets will challenge our existing information infrastructure and traditional approaches to analysis. The rapid advancement of graphics processing units, compact field programmable gate arrays and dedicated artificial intelligence accelerator chips is now permitting the use of scientific methods, processes and algorithms to extract knowledge and insights from structured and unstructured data in ways never before seen. Miniaturization of spacecraft architectures and supporting infrastructure is opening new observing strategies and new discovery spaces for science. The community is just beginning to awaken to these imminent challenges as evidenced by their relative lack of emphasis in the New Worlds, New Horizons ASTRO2010 decadal survey, in the ExoPAG Science Analysis Group 11 report andin the formulation of the WFIRST Data Challenge. We suggest that the Astrophysics Science Division (ASD), which has clearly recognized this new epoch of rapidly evolving information technology, could be more affirmative in its approach. We offer a modest structural solution