RESUMEN

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.

Asunto(s)

Anticuerpos Neutralizantes/sangre , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Estudios de Cohortes , Femenino , VIH-1/inmunología , Humanos , Lactante , Transmisión Vertical de Enfermedad Infecciosa , Masculino , Vacunación

RESUMEN

Broad and potent neutralizing antibodies (bnAbs) with multiple epitope specificities evolve in HIV-1-infected children. Herein, we studied two antiretroviral-naive chronically HIV-1 clade C-infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, with potent plasma bnAbs. Elite plasma neutralizing activity was observed since the initial sampling at 78 months of age in AIIMS_330 and persisted throughout, while in AIIMS_329 it was seen at 90 months of age, after which the potency decreased over time. We evaluated potential viral characteristics associated with the varied immune profiles by generating single genome-amplified pseudoviruses. The AIIMS_329 viruses generated from the 90-month time point were neutralization sensitive to bnAbs and contemporaneous plasma antibodies, while viruses from the 112-month and 117-month time points were resistant to most bnAbs and contemporaneous plasma. AIIMS_329 viruses developed resistance to plasma neutralizing antibodies (nAbs) plausibly by N160 glycan loss and V1 and V4 loop lengthening. The viruses generated from AIIMS_330 (at 90 and 117 months) showed varied susceptibility to bnAbs and autologous contemporaneous plasma antibodies, while the viruses of the 112-month time point, at which the plasma nAb specificities mapped to the V2 glycan, V3 glycan, and CD4 binding site (CD4bs), were resistant to contemporaneous plasma antibodies as well as to most bnAbs. Chimeric viruses were constructed from 90-month-time-point PG9-sensitive AIIMS_329 and AIIMS_330 viruses with swapped V1V2 regions of their respective evolved viruses (at 112 and 117 months), which led to higher resistance to neutralization by PG9 and autologous plasma antibodies. We observed the evolution of a viral pool in the AIIMS_330 donor comprising plasma antibody neutralization-sensitive or -resistant diverse autologous viruses that may have contributed to the development and maintenance of elite neutralizing activity.IMPORTANCE Herein, we report the longitudinal development of bnAbs in a pair of chronically HIV-1 clade C-infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, who acquired the infection by vertical transmission. The plasma from both donors, sharing a similar genetic makeup and infecting virus, showed the evolvement of bnAbs targeting common epitopes in the V2 and V3 regions of the envelope, suggesting that bnAb development in these twins may perhaps be determined by specific sequences in the shared virus that can guide the development of immunogens aimed at eliciting V2 and V3 bNAbs. Characterization of the neutralization-sensitive and -resistant viruses coevolving with bNAbs in the contemporaneous AIIMS_330 plasma provides information toward understanding the viral alterations that may have contributed to the development of resistance to bnAbs. Further longitudinal studies in more monozygotic and dizygotic twin pairs will help in delineating the role of host and viral factors that may contribute to the development of bnAbs.

Asunto(s)

Anticuerpos Neutralizantes/sangre , Enfermedades en Gemelos/virología , Infecciones por VIH/inmunología , VIH-1/inmunología , Niño , Progresión de la Enfermedad , Enfermedades en Gemelos/inmunología , Epítopos/metabolismo , Anticuerpos Anti-VIH/sangre , Humanos , Estudios Longitudinales , Gemelos Monocigóticos

RESUMEN

Broadly neutralizing antibodies (bNAbs) have demonstrated protective effects against HIV-1 in primate studies and recent human clinical trials. Elite neutralizers are potential candidates for isolation of HIV-1 bNAbs. The coexistence of bNAbs such as BG18 with neutralization-susceptible autologous viruses in an HIV-1-infected adult elite controller has been suggested to control viremia. Disease progression is faster in HIV-1-infected children than in adults. Plasma bNAbs with multiple epitope specificities are developed in HIV-1 chronically infected children with more potency and breadth than in adults. Therefore, we evaluated the specificity of plasma neutralizing antibodies of an antiretroviral-naive HIV-1 clade C chronically infected pediatric elite neutralizer, AIIMS_330. The plasma antibodies showed broad and potent HIV-1 neutralizing activity with >87% (29/33) breadth, a median inhibitory dilution (ID50) value of 1,246, and presence of N160 and N332 supersite-dependent HIV-1 bNAbs. The sorting of BG505.SOSIP.664.C2 T332N gp140 HIV-1 antigen-specific single B cells of AIIMS_330 resulted in the isolation of an HIV-1 N332 supersite-dependent bNAb, AIIMS-P01. The AIIMS-P01 neutralized 67% of HIV-1 cross-clade viruses, exhibited substantial indels despite limited somatic hypermutations, interacted with native-like HIV-1 trimer as observed in negative stain electron microscopy, and demonstrated high binding affinity. In addition, AIIMS-P01 neutralized the coexisting and evolving autologous viruses, suggesting the coexistence of vulnerable autologous viruses and HIV-1 bNAbs in the AIIMS_330 pediatric elite neutralizer. Such pediatric elite neutralizers can serve as potential candidates for isolation of novel HIV-1 pediatric bNAbs and for understanding the coevolution of virus and host immune response.IMPORTANCE More than 50% of the HIV-1 infections globally are caused by clade C viruses. To date, there is no effective vaccine to prevent HIV-1 infection. Based on the structural information of the currently available HIV-1 bNAbs, attempts are under way to design immunogens that can elicit correlates of protection upon vaccination. Here, we report the isolation and characterization of an HIV-1 N332 supersite-dependent bNAb, AIIMS-P01, from a clade C chronically infected pediatric elite neutralizer. The N332 supersite is an important epitope and is one of the current HIV-1 vaccine targets. AIIMS-P01 potently neutralized the contemporaneous and autologous evolving viruses and exhibited substantial indels despite low somatic hypermutations. Taken together with the information on infant bNAbs, further isolation and characterization of bNAbs contributing to the plasma breadth in HIV-1 chronically infected children may help provide a better understanding of their role in controlling HIV-1 infection.

Asunto(s)

Anticuerpos Neutralizantes/uso terapéutico , VIH-1/inmunología , Adulto , Antirretrovirales , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Evolución Biológica , Niño , Epítopos/inmunología , Femenino , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/virología , Seropositividad para VIH , Humanos , Masculino , Pruebas de Neutralización , Vacunación , Viremia , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología

RESUMEN

BACKGROUND: Information from Ayurveda meeting the analytical challenges of modern technology is an area of immense relevance. Apart from the cerebral task of bringing together two different viewpoints, the question at the pragmatic level remains 'who benefits whom'. OBJECTIVE: The aim is to highlight the challenges in integration of information (Ayurvedic) and technology using test examples of Nuclear Magnetic Resonance (NMR) metabolomics and anti-HIV-1 potential of select Ayurvedic medicinal plants. The other value added objective is implications and relevance of such work for Ayurveda. MATERIALS AND METHODS: Six medicinal plants (Azadirachta indica, Tinospora cordifolia, Swertia chirata, Terminalia bellerica, Zingiber officinale and Symplocos racemosa) were studied using high resolution proton NMR spectroscopy based metabolomics and also evaluated for anti-HIV-1 activity on three pseudoviruses (ZM53 M.PB12, ZM109F.PB4, RHPA 4259.7). RESULTS: Of the six plants, T. bellerica and Z. officinale showed minimum cell cytotoxicity and maximum anti-HIV-1 potential. T. bellerica was effective against all the three HIV-1 pseudoviruses. Untargeted NMR profiling and multivariate analyses demonstrated that the six plants, all of which had different Ayurvedic pharmacological properties, showed maximum differences in the aromatic region of the spectra. CONCLUSION: The work adds onto the list of potential plants for anti-HIV-1 drug molecules. At the same time, it has drawn attention to the different perspectives of Ayurveda and Western medicine underscoring the inherent limitations of conceptual bilinguism between the two systems, especially in the context of medicinal plants. The study has also highlighted the potential of NMR metabolomics in study of plant extracts as used in Ayurveda.

RESUMEN

Progression of human immunodeficiency virus type-1 (HIV-1) infection in children is faster than adults. HIV-1 subtype C is responsible for more than 50% of the infections globally and more than 90% infections in India. To date, there is no effective vaccine against HIV-1. Recent animal studies and human Phase I trials showed promising results of the protective effect of anti-HIV-1 broadly neutralizing antibodies (bnAbs). Interaction between CD4 binding site (CD4bs) on the HIV-1 envelope glycoprotein and CD4 receptor on the host immune cells is the primary event leading to HIV-1 infection. The CD4bs is a highly conserved region, comprised of a conformational epitope, and is a potential target of bnAbs such as VRC01 that is presently under human clinical trials. Recombinant scFvs can access masked epitopes due to their small size and have shown the potential to inhibit viral replication and neutralize a broad range of viruses. Pediatric viruses are resistant to many of the existing bnAbs isolated from adults. Therefore, in this study, pooled peripheral blood mononuclear cells from 9 chronically HIV-1 subtype C infected pediatric cross-neutralizers whose plasma antibodies exhibited potent and cross-neutralizing activity were used to construct a human anti-HIV-1 scFv phage library of 9 × 108 individual clones. Plasma mapping using CD4bs-specific probes identified the presence of CD4bs directed antibodies in 4 of these children. By extensive biopanning of the library with CD4bs-specific antigen RSC3 core protein, we identified two cross-neutralizing scFv monoclonals 2B10 and 2E4 demonstrating a neutralizing breadth and GMT of 77%, 17.9 µg/ml and 32%, 51.2 µg/ml, respectively, against a panel of 49 tier 1, 2 and 3 viruses. Both scFvs competed with anti-CD4bs bnAb VRC01 confirming their CD4bs epitope specificity. The 2B10 scFv was effective in neutralizing the 7 subtype C and subtype A pediatric viruses tested. Somatic hypermutations in the VH gene of scFvs (10.1-11.1%) is comparable with that of the adult antibodies. These cross-neutralizing CD4bs-directed scFvs can serve as potential reagents for passive immunotherapy. A combination of cross-neutralizing scFvs of diverse specificities with antiretroviral drugs may be effective in suppressing viremia at an early stage of HIV-1 infection and prevent disease progression.

RESUMEN

Several B cell defects are reported in HIV-1 infected individuals including variation in B cell subsets, polyclonal B cell activation and exhaustion, with broadly neutralizing antibodies elicited in less than 10-20% of the infected population. HIV-1 disease progression is faster in children than adults. B Lymphocyte Stimulator (BLyS), expressed on dendritic cells (DCs), is a key regulator of B cell homeostasis. Understanding how DCs influence B cell phenotype and functionality (viral neutralization), thereby HIV-1 disease outcome in infected children, is important to develop interventional strategies for restoration of B cell function. In this study, a total of 38 vertically transmitted HIV-1 infected antiretroviral therapy (ART) naïve children and 25 seronegative controls were recruited. Based on the CD4 counts and years post-infection, infected children were categorized as long-term non-progressors (LTNPs) (n = 20) and progressors (n = 18). Eight of these progressors were followed up at 6-12 months post-ART. Percentages (%) of DCs, B cell subsets, and expression of BLyS on DCs were analyzed by flow-cytometry. Plasma levels of B cell growth factors were measured by ELISA and viral neutralization activity was determined using TZM-bl assay. Lower (%) of myeloid DCs (mDCs), plasmacytoid DCs, and high expression of BLyS on mDCs were observed in HIV-1 infected progressors than seronegative controls. Progressors showed lower % of naive B cells, resting memory B cells and higher % of mature activated, tissue-like memory B cells as compared to seronegative controls. Higher plasma levels of IL-4, IL-6, IL-10, and IgA were observed in progressors vs. seronegative controls. Plasma levels of IgG were high in progressors and in LTNPs than seronegative controls, suggesting persistence of hypergammaglobulinemia at all stages of disease. High plasma levels of BLyS in progressors positively correlated with poor viral neutralizing activity. Interestingly on follow up, treatment naïve progressors, post-ART showed increase in resting memory B cells along with reduction in plasma BLyS levels that correlated with improvement in viral neutralization. This is the first study to demonstrate that reduction in plasma BLyS levels correlates with restoration of B cell function, in terms of viral neutralization in HIV-1-infected children.

RESUMEN

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.

Asunto(s)

Sitios de Unión/inmunología , Antígenos CD4/metabolismo , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Anticuerpos de Cadena Única/inmunología , Anticuerpos Neutralizantes/inmunología , Afinidad de Anticuerpos , Mapeo Epitopo , Anticuerpos Anti-VIH/genética , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/virología , Humanos , Pruebas de Neutralización , Biblioteca de Péptidos , Unión Proteica/inmunología , Anticuerpos de Cadena Única/genética

RESUMEN

Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been extensively tested against pesudoviruses of diverse strains. We generated and characterized HIV-1 primary isolates from antiretroviral naïve infected Indian children, and determined their susceptibility to known NAbs. All the 8 isolates belonged to subtype-C and were R5 tropic. Majority of these viruses were resistant to neutralization by NAbs, suggesting that the bnAbs, known to efficiently neutralize pseudoviruses (adult and pediatric) of different strains, are less effective against pediatric primary isolates. Interestingly, AIIMS_329 isolate displayed high susceptibility to neutralization by PG9 and PG16bnAbs, with IC50 titer of 1.3 and 0.97µg/ml, suggesting exposure of this epitope on this virus. All isolates except AIIMS_506 were neutralized by contemporaneous plasma antibodies. Our findings suggest that primary isolates, due to close resemblance to viruses in natural infection, should be used to evaluate NAbs as effective vaccine candidates in both children and adults.

Asunto(s)

Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Adolescente , Secuencia de Aminoácidos , Anticuerpos Neutralizantes/inmunología , Recuento de Linfocito CD4 , Niño , Preescolar , Enfermedad Crónica , Epítopos/inmunología , Femenino , Genotipo , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/epidemiología , Infecciones por VIH/metabolismo , VIH-1/clasificación , VIH-1/genética , Humanos , India/epidemiología , Masculino , Pruebas de Neutralización , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Fenotipo , Filogenia , Unión Proteica , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismo , Carga Viral

RESUMEN

Disease progression in HIV-1 infected children is faster than in adults. Less than 5% of the infected children maintain stable CD4 counts beyond 7 years of infection and are termed long-term nonprogressors (LTNPs). Delineating the host immune response in antiretroviral naïve (ART) and treated HIV-1 infected children at different disease stages will help in understanding the immunopathogenesis of the disease.A total of 79 asymptomatic, perinatally HIV-1 infected children (50 ART naïve and 29 ART treated) and 8 seronegative donors were recruited in this study. T- and B-cell activation PCR arrays were performed from the cDNA, using total RNA extracted from the peripheral blood mononuclear cells (PBMCs) of 14 HIV-1 infected children at different stages of the disease. The differentially expressed genes were identified. Quantitative RT-PCR was performed for the (interleukin-8) IL-8 gene and its transcriptional mediators, that is, SHP2, GRB2, and IL-8R (IL-8 receptor/CXCR1). Plasma levels of IL-8 were measured by flow cytometry.Gene array data revealed a higher expression of IL-8 in the ART naïve HIV-1 infected progressors and in ART nonresponders than LTNPs and ART responders, respectively. Quantitative RT-PCR analysis demonstrated a significant higher expression of IL-8 (P < 0.001), its receptor CXCR1 (P = 0.03) and the upstream signaling molecule SHP2 (P = 0.04) in the progressors versus LTNPs. Plasma levels of IL-8 were significantly higher in progressors versus LTNPs (P < 0.001), and ART nonresponders versus ART responders (P < 0.001). A significant negative correlation of plasma levels of IL-8 with CD4 counts (cells/µL) was observed in HIV-1 infected ART naïve subjects (r = -0.488; P < 0.001), while the IL-8 levels positively correlated with viral load in the ART treated children (r = 0.5494; P < 0.001). ART naïve progressors on follow up demonstrated a significant reduction in the mRNA expression (P = 0.05) and plasma levels of IL-8 (P = 0.05) post 6 months of ART initiation suggesting the beneficial role of ART therapy in reducing inflammation in infected children.Our data suggest that IL-8 may serve as a potential prognostic marker in adjunct with CD4 counts to monitor disease progression in the HIV-1 infected children and the efficacy of ART.

Asunto(s)

Progresión de la Enfermedad , Infecciones por VIH/inmunología , VIH-1/inmunología , Interleucina-8/biosíntesis , Adolescente , Antirretrovirales/uso terapéutico , Recuento de Linfocito CD4 , Niño , Preescolar , ADN Circular , Femenino , Proteína Adaptadora GRB2/inmunología , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/inmunología , Infecciones por VIH/tratamiento farmacológico , Humanos , Lactante , Interleucina-8/inmunología , Leucocitos Mononucleares , Masculino , ARN Mensajero , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Interleucina-8A/biosíntesis , Receptores de Interleucina-8A/inmunología , Carga Viral

RESUMEN

Dissecting antibody specificities in the plasma of HIV-1 infected individuals that develop broadly neutralizing antibodies (bNAbs) is likely to provide useful information for refining target epitopes for vaccine design. Several studies have reported CD4-binding site (CD4bs) antibodies as neutralization determinants in the plasma of subtype B-infected individuals; however there is little information on the prevalence of CD4bs specificities in HIV-infected individuals in India. Here, we report on the presence of CD4bs antibodies and their contribution to virus neutralization in the plasma from a cohort of HIV-1 infected Indian individuals. Plasma from 11 of the 140 HIV-1 infected individuals (7.9%) studied here exhibited cross-neutralization activity against a panel of subtype B and C viruses. Analyses of these 11 plasma samples for the presence of CD4bs antibodies using two CD4bs-selective probes (antigenically resurfaced HXB2gp120 core protein RSC3 and hyperglycosylated JRFLgp120 mutant ΔN2mCHO) revealed that five (AIIMS 617, 619, 627, 642, 660) contained RSC3-reactive plasma antibodies and only one (AIIMS 660) contained ΔN2mCHO-reactive antibodies. Plasma antibody depletion and competition experiments confirmed that the neutralizing activity in the AIIMS 660 plasma was dependent on CD4bs antibodies. To the best of our knowledge, this is the first study to report specifically on the presence of CD4bs antibodies in the plasma of a cohort of HIV-1 infected Indian donors. The identification of CD4bs dependent neutralizing antibodies in an HIV-1 infected Indian donor is a salient finding of this study and is supportive of ongoing efforts to induce similar antibodies by immunization.

Asunto(s)

Anticuerpos Neutralizantes/inmunología , Sitios de Unión de Anticuerpos , Antígenos CD4/inmunología , Infecciones por VIH/inmunología , Adolescente , Adulto , Anticuerpos Neutralizantes/química , Femenino , Anticuerpos Anti-VIH/inmunología , VIH-1/inmunología , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

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.

Asunto(s)

Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Adulto , Anciano , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Femenino , Genotipo , Humanos , India , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo

RESUMEN

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.

Asunto(s)

Carcinoma de Células Escamosas/genética , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP2E1/genética , Neoplasias Esofágicas/genética , Anciano , Carcinoma de Células Escamosas/epidemiología , Neoplasias Esofágicas/epidemiología , Carcinoma de Células Escamosas de Esófago , Genotipo , Humanos , Incidencia , India/epidemiología , Persona de Mediana Edad , Riesgo

RESUMEN

BACKGROUND: Several studies have reported association between animal contact and some cancer types, including lymphohaematopoietic, colon, pancreatic and neurological malignancies. We aimed to investigate the association between animal contact and risk of oesophageal squamous cell carcinoma (ESCC) in a case-control study in Kashmir, India, area with a relatively high incidence of ESCC. METHODS: We recruited 703 histologically confirmed ESCC cases and 1664 controls individually matched to the cases for age, sex and district of residence. Information, including on animal contact, was obtained in face-to-face interviews using a structured questionnaire. Conditional logistic regression models were used to calculate ORs and 95% CIs. RESULTS: As compared with no contact with animals, daily close contact was associated with an increased risk of ESCC (OR 5.99; 95% CI 3.86 to 9.31) in models adjusted for several potential confounding factors, including multiple indicators of socioeconomic status. This association persisted in subgroups following stratification by a composite wealth score and occupation. Irregular contact with animals was not associated with ESCC risk. The association between duration of animal contact and ESCC risk was mixed; however, contact for more than 50 years was associated with an increased risk (OR 3.10; 95% CI 1.53 to 6.26). Frequency (p for trend, 0.001) and duration (p for trend, <0.001) of animal contact showed dose-response association with ESCC risk. CONCLUSIONS: Our results suggest an association between long-term and daily close contact with animals and ESCC. This association needs to be investigated in further studies.

Asunto(s)

Crianza de Animales Domésticos , Carcinoma de Células Escamosas/etiología , Exposición a Riesgos Ambientales/efectos adversos , Neoplasias Esofágicas/etiología , Ganado , Anciano , Animales , Estudios de Casos y Controles , Carcinoma de Células Escamosas de Esófago , Femenino , Humanos , India , Entrevistas como Asunto , Modelos Logísticos , Masculino , Persona de Mediana Edad , Enfermedades Profesionales/etiología , Exposición Profesional/efectos adversos , Ocupaciones , Factores de Riesgo , Clase Social , Encuestas y Cuestionarios , Factores de Tiempo