P20-05. Emergence of HIV-1 circulatory recombinant forms (CRFs) and unique recombinant forms (URFs) in North India: functional and pathogenic implications

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Molecular Epidemiology of HIV-1 Subtypes in India: Origin and Evolutionary History of the Predominant Subtype C

This thesis describes the translational genomics of HIV-1subtype C in India from its origin to therapeutic response with the aim to improve our knowledge for better therapeutic and preventive strategies to combat HIV/AIDS. In a systemic approach, we identified the molecular phylogeny of HIV-1 subtypes circulating in India and the time to most recent common ancestors (tMRCA) of predominant HIV-1 subtype C strains. Additionally, this thesis also studied drug resistance mutations in children, adolescents and adults, the role of host factors in evolution of drug resistance, and population dynamics of viremia and viral co-receptor tropism in perinatal transmission. Finally, the long term therapeutic responses on Indian national first-line antiretroviral therapy were also studied. In Paper I, we reported an increase in the HIV-1 recombinant forms in the HIV-1 epidemiology using a robust subtyping methodology. While the study confirmed HIV- 1 subtype C as a dominant subtype, its origin was dated back to the early 1970s from a single or few genetically related strains from South Africa, whereafter, it has evolved independently. In Paper II, the lethal hypermutations due to the activity of human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (hA3G) was significantly associated with antiretroviral therapy (ART) failure in Indian HIV-1 subtype C patients. The presence of M184I and M230I mutations were observed due to the editing of hA3G in the proviral compartment but stop codons were also found in the open reading frames and the same drug resistance mutations were absent in plasma virus. Therefore, it is unlikely that the viral variants which exhibit hypermutated sequences and M184I and/or M230I will mature and expand in vivo and hence are unlikely to have any clinical significance. The high concordance of drug resistance genotyping in the plasma and proviral compartments in therapy-naïve patients, gives weight to the idea of using whole blood for surveillance of drug resistance mutations which precludes logistic challenges of cold chain transport. In Papers III and IV, we identified a substantial proportion of HIV-1 subtype C perinatally-infected older children who had a high burden of plasma viremia but also had high CD4+ T-cell counts. In addition, older children with HIV-1 subtype C infection presented a high prevalence of predicted X4 and R5/X4 tropic strains which indicates that HIV-1 subtype C strains required longer duration of infection and greater disease progression to co-receptor transition from R5- to X4-tropic strains (IV). Our studies also indicate that transmitted drug resistance is low among Indian HIV-1 infected children, adolescents (III) and adults (II). In Paper V, in a longitudinal cohort study, a good long-term response to the Indian national first-line therapy for a median of nearly four years with 2.8% viral failure, indicating the overall success of the Indian ART program. Our study also showed that three immunologically well patients with virological rebound and major viral drug resistance mutations (M184V, K103N and Y181C) during one study visit had undetectable viral load at their next visit. These findings suggest that use of multiple parameters like patients’ immunological (CD4+ T-cell count), virological (viral load) and drug resistance data should all be used to optimize the treatment switch to second line therapy. In conclusion, this translational genomics study enhances our knowledge about the HIV-1 subtype C strains circulating in India which are genetically distinct from prototype African subtype C strains. Considerably more research using appropriate models need to be performed to understand the phenotypic and biological characteristics of these strains to guide efficient disease intervention and management strategies

Absolute photoionization cross section measurements of the Kr I-isoelectronic sequence

Photoionization spectra have been recorded in the 4s, 4p and 3d resonance regions for the Kr Iisoelectronic sequence using both the dual laser produced plasma technique (at DCU) to produce photoabsorption spectra, and the merged ion beam and synchrotron radiation technique (at ASTRID) to measure absolute photoionization cross sections. Profile parameters are compared for the 4s − np resonances of Rb+ and Sr2+. Many new 4p " ns, md transitions are identified with the aid of Hartree-Fock calculations, and consistent quantum defects are observed for the various ns and md Rydberg series. Absolute single and double photoionization cross sections recorded in the 3d region for Rb+ and Sr2+ ions show preferential decay via double photoionization. This is only the second report where both the DLP technique and the merged beam technique have been used simultaneously to record photoionization spectra, and the advantages of both techniques (i.e. better resolution in the case of DLP and values for absolute photoionization cross sections in the case of the merged beam technique) are highlighted

Drug resistance in non-B subtype HIV-1: Impact of HIV-1 reverse transcriptase inhibitors

Human immunodeficiency virus (HIV) causes approximately 2.5 million new infections every year, and nearly 1.6 million patients succumb to HIV each year. Several factors, including cross-species transmission and error-prone replication have resulted in extraordinary genetic diversity of HIV groups. One of these groups, known as group M (main) contains nine subtypes (A-D, F-H and J-K) and causes ∼95% of all HIV infections. Most reported data on susceptibility and resistance to anti-HIV therapies are from subtype B HIV infections, which are prevalent in developed countries but account for only ∼12% of all global HIV infections, whereas non-B subtype HIV infections that account for ∼88% of all HIV infections are prevalent primarily in low and middle-income countries. Although the treatments for subtype B infections are generally effective against non-B subtype infections, there are differences in response to therapies. Here, we review how polymorphisms, transmission efficiency of drug-resistant strains, and differences in genetic barrier for drug resistance can differentially alter the response to reverse transcriptase-targeting therapies in various subtypes

Retraction Note: Gold Nanoparticles‑enabled Efficient Dual Delivery of Anticancer Therapeutics to HeLa cells

The editors have retracted their article Gold Nanoparticles-enabled Efficient Dual Delivery of Anticancer Therapeutics to HeLa cells. Concerns were brought to the attention of the Editors with respect to apparent inappropriate manipulation of the data in seven of the nine panels shown in Figure 7. The Editors no longer have confidence in the data reported in this Article

Trends in autoionization of Rydberg states converging to the 4s threshold in the Kr-Rb⁺-Sr²⁺ isoelectonic sequence: theory and experiment

We have measured the photoabsorption spectra of the Kr-like ions Rb+ and Sr2+ at photon energies corresponding to the excitation of 4s-np resonances using, the dual laser plasma photoabsorption technique. Dramatic changes in the line profiles, with increasing ionization and also proceeding along the Rydberg series of each ion, are observed and explained by the trends in 4s-transition amplitudes computed within a framework of configuration-interaction Pauli-Fock calculations. Total photoionization cross sections show very good agreement with relative absorption data extracted from the measured spectra

A System for Information Management in BioMedical Studies—SIMBioMS

Summary: SIMBioMS is a web-based open source software system for managing data and information in biomedical studies. It provides a solution for the collection, storage, management and retrieval of information about research subjects and biomedical samples, as well as experimental data obtained using a range of high-throughput technologies, including gene expression, genotyping, proteomics and metabonomics. The system can easily be customized and has proven to be successful in several large-scale multi-site collaborative projects. It is compatible with emerging functional genomics data standards and provides data import and export in accepted standard formats. Protocols for transferring data to durable archives at the European Bioinformatics Institute have been implemented

A Direct Comparison of Two Densely Sampled HIV Epidemics: The UK and Switzerland

Phylogenetic clustering approaches can elucidate HIV transmission dynamics. Comparisons across countries are essential for evaluating public health policies. Here, we used a standardised approach to compare the UK HIV Drug Resistance Database and the Swiss HIV Cohort Study while maintaining data-protection requirements. Clusters were identified in subtype A1, B and C pol phylogenies. We generated degree distributions for each risk group and compared distributions between countries using Kolmogorov-Smirnov (KS) tests, Degree Distribution Quantification and Comparison (DDQC) and bootstrapping. We used logistic regression to predict cluster membership based on country, sampling date, risk group, ethnicity and sex. We analysed >8,000 Swiss and >30,000 UK subtype B sequences. At 4.5% genetic distance, the UK was more clustered and MSM and heterosexual degree distributions differed significantly by the KS test. The KS test is sensitive to variation in network scale, and jackknifing the UK MSM dataset to the size of the Swiss dataset removed the difference. Only heterosexuals varied based on the DDQC, due to UK male heterosexuals who clustered exclusively with MSM. Their removal eliminated this difference. In conclusion, the UK and Swiss HIV epidemics have similar underlying dynamics and observed differences in clustering are mainly due to different population sizes