Search

Broadly neutralizing antibodies (bnAbs) develop in a subset of HIV-1 infected individuals over 2–3 years of infection. Infected infants develop plasma bnAbs frequently and as early as 1-year post-infection suggesting factors governing bnAb induction in infants are distinct from adults. Understanding viral characteristics in infected infants with early bnAb responses will provide key information about antigenic triggers driving B cell maturation pathways towards induction of bnAbs. Herein, we evaluate the presence of plasma bnAbs in a cohort of 51 HIV-1 clade-C infected infants and identify viral factors associated with early bnAb responses. Plasma bnAbs targeting V2-apex on the env are predominant in infant elite and broad neutralizers. Circulating viral variants in infant elite neutralizers are susceptible to V2-apex bnAbs. In infant elite neutralizers, multivariant infection is associated with plasma bnAbs targeting diverse autologous viruses. Our data provides information supportive of polyvalent vaccination approaches capable of inducing V2-apex bnAbs against HIV-1. [ABSTRACT FROM AUTHOR]

Polymorphisms in glutathione-S-transferases (GSTs), the phase II xenobiotic detoxifying enzymes, have been associated with increased cancer risk. In this study, we assessed the association of functional polymorphisms in GSTM1 and GSTT1 with esophageal cancer in Kashmir, India, an area with a high incidence of esophageal squamous cell carcinoma (ESCC). We analyzed genotypes of GSTM1 and GSTT1 using a multiplex PCR in 492 pairs of ESCC cases and individually matched controls. The associations between polymorphisms in these genes and ESCC risk were examined by conditional logistic regression models adjusted for multiple potential confounders. In addition, the interaction between these genes and several environmental exposures with regard to ESCC risk was assessed. Our results showed an association between the GSTT1 null genotype and ESCC risk (odds ratio (OR) = 1.58; 95 % confidence interval (CI) 1.04-2.39). Although GSTM1 alone was not associated with ESCC risk, individuals with the GSTM1/ GSTT1 genotype showed an inverse relation with ESCC risk (OR = 0.55; 95 % CI 0.32-0.93), compared to GSTM1/ GSTT1 individuals. We found a significant interaction between the GSTT1 and GSTM1 genotypes with regard to ESCC risk ( P = 0.001); however, there were no interactions between environmental factors and GSTT1 and GSTM1 genotypes. This study indicates that GSTT1 null genotype is associated with ESCC risk in Kashmiri population. The association between GSTM1 and ESCC risk needs further investigations. Interactions of these genotypes with environmental exposures should be examined in multicentric studies with bigger sample sizes. [ABSTRACT FROM AUTHOR]

The study analyzed the relationship between genetic polymorphisms of phase I xenobiotic metabolizing enzymes, cytochromes P450 ( CYP) 1A1 and CYP2E1 and esophageal squamous cell carcinoma (ESCC) in Kashmir, India. The different genotypes of CYP1A1 and CYP2E1 were analyzed by polymerase chain reaction and restriction fragment length polymorphism in 526 ESCC cases and equal number of matched controls. Conditional logistic regression models were used to assess the association of various genotypes with ESCC, gene-gene, and gene-environment interactions. High risk of ESCC was found in participants who carried CYP1A1 Val/Val genotype (OR = 2.87; 95 % CI = 1.00-8.44) and the risk increased in such individuals when c1/c1 of CYP2E1 genotype was also present (OR = 5.68; 95 % CI = 1.09-29.52). Risk due to CYP1A1 Val/Val genotype was further enhanced (OR = 8.55; 95 % CI = 1.86-42.20) when the analysis was limited to ever smokers. Participants who carried CYP2E1 c1/c2 genotype showed an inverse relation (OR = 0.27; 95 % CI = 0.17-0.43) with ESCC. The inverse association of CYP2E1 c1/c2 genotype was retained when CYP1A1 Ile/Ile was also present (OR = 0.18; 95 % CI = 0.09-0.32), as well as when analysis was limited to ever smokers (OR = 0.45; 95 % CI = 0.23-0.90). Significant interaction was found between CYP1A1 (Val/Val) and CYP2E1 (c1/c1) genotypes (OR = 1.30; 95 % CI = 1.12-1.51; P = 0.001) and between CYP1A1 (Val/Val) and smoking (OR = 1.31; 95 % CI = 1.01-1.69; P = 0.043). The study suggests CYP1A1 Val/Val and CYP2E1 c1/c1 genotypes are significantly associated with ESCC risk. [ABSTRACT FROM AUTHOR]

More than 50% of HIV-1 infection globally is caused by subtype_C viruses. Majority of the broadly neutralizing antibodies (bnAbs) targeting HIV-1 have been isolated from non-subtype_C infected donors. Mapping the epitope specificities of bnAbs provides useful information for vaccine design. Recombinant antibody technology enables generation of a large repertoire of monoclonals with diverse specificities. We constructed a phage recombinant single chain variable fragment (scFv) library with a diversity of 7.8 × 108 clones, using a novel strategy of pooling peripheral blood mononuclear cells (PBMCs) of six select HIV-1 chronically infected Indian donors whose plasma antibodies exhibited potent cross neutralization efficiency. The library was panned and screened by phage ELISA using trimeric recombinant proteins to identify viral envelope specific clones. Three scFv monoclonals D11, C11 and 1F6 selected from the library cross neutralized subtypes A, B and C viruses at concentrations ranging from 0.09 μg/mL to 100 μg/mL. The D11 and 1F6 scFvs competed with mAbs b12 and VRC01 demonstrating CD4bs specificity, while C11 demonstrated N332 specificity. This is the first study to identify cross neutralizing scFv monoclonals with CD4bs and N332 glycan specificities from India. Cross neutralizing anti-HIV-1 human scFv monoclonals can be potential candidates for passive immunotherapy and for guiding immunogen design. [ABSTRACT FROM AUTHOR]