RESUMO
BACKGROUND: Antiretroviral therapy (ART) saved millions from HIV-1 infection and AIDS, but some patients do not experience adequate CD4+ T cells gain despite achieving viral suppression. The genetic component of this condition is not yet completely elucidated. OBJECTIVE: To identify predictive genetic markers of immune response to ART. METHODS: Case-control study. Out of 176 HIV-infected patients recruited in the city of Recife, Northeast Brazil, 67 patients with no immunologic response were the cases and the remaining 109 patients who responded were the controls. A set of 94 selected single nucleotide polymorphisms (SNPs) involved in antiretroviral drugs pharmacodynamic pathways and immune system homeostasis were genotyped, while the remaining 48 were ancestry informative markers (AIMs) for controlling for eventual hidden population structure. RESULTS: Male patients were overrepresented in non-responder group (p=0.01). Non-responders also started with lower absolute CD4+ T cell counts (p<0.001). We found five SNPs significantly associated with the outcome, being three more frequent in non-responders than responders: rs2243250 (IL4) A allele (p=0.04), rs1128503 (ABCB1) A allele (p=0.03) and rs707265 (CYP2B6) A allele (p=0.02), whereas the other two were less frequent in non-responders: rs2069762 (IL2) C allele (p=0.004) and rs4646437 (CYP3A4) A allele (p=0.04). CONCLUSION: Some significant univariate associations remained independently associated at multivariate survival analysis modeling, such as pre-treatment CD4+ T cells counts, IL2 and ABCB1 genotypes, and use of protease inhibitors, yielding a predictive model for the probability for immune response. More studies are needed to unravel the genetic basis of ART immunological non-response.
Assuntos
Antirretrovirais/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Sistema Imunitário/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/imunologia , Adolescente , Adulto , Terapia Antirretroviral de Alta Atividade , Brasil , Contagem de Linfócito CD4 , Feminino , Frequência do Gene , Estudos de Associação Genética , Marcadores Genéticos , Humanos , Fenômenos Imunogenéticos/efeitos dos fármacos , Fenômenos Imunogenéticos/genética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Estatísticas não Paramétricas , Carga Viral , Adulto JovemRESUMO
ABSTRACT Background: Antiretroviral therapy (ART) saved millions from HIV-1 infection and AIDS, but some patients do not experience adequate CD4+ T cells gain despite achieving viral suppression. The genetic component of this condition is not yet completely elucidated. Objective: To identify predictive genetic markers of immune response to ART. Methods: Case-control study. Out of 176 HIV-infected patients recruited in the city of Recife, Northeast Brazil, 67 patients with no immunologic response were the cases and the remaining 109 patients who responded were the controls. A set of 94 selected single nucleotide polymorphisms (SNPs) involved in antiretroviral drugs pharmacodynamic pathways and immune system homeostasis were genotyped, while the remaining 48 were ancestry informative markers (AIMs) for controlling for eventual hidden population structure. Results: Male patients were overrepresented in non-responder group (p = 0.01). Non-responders also started with lower absolute CD4+ T cell counts (p < 0.001). We found five SNPs significantly associated with the outcome, being three more frequent in non-responders than responders: rs2243250 (IL4) A allele (p = 0.04), rs1128503 (ABCB1) A allele (p = 0.03) and rs707265 (CYP2B6) A allele (p = 0.02), whereas the other two were less frequent in non-responders: rs2069762 (IL2) C allele (p = 0.004) and rs4646437 (CYP3A4) A allele (p = 0.04). Conclusion: Some significant univariate associations remained independently associated at multivariate survival analysis modeling, such as pre-treatment CD4+ T cells counts, IL2 and ABCB1 genotypes, and use of protease inhibitors, yielding a predictive model for the probability for immune response. More studies are needed to unravel the genetic basis of ART immunological non-response.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Polimorfismo de Nucleotídeo Único/imunologia , Antirretrovirais/farmacologia , Sistema Imunitário/efeitos dos fármacos , Brasil , Marcadores Genéticos , Análise Multivariada , Estudos Retrospectivos , Estatísticas não Paramétricas , Contagem de Linfócito CD4 , Carga Viral , Terapia Antirretroviral de Alta Atividade , Fenômenos Imunogenéticos/efeitos dos fármacos , Fenômenos Imunogenéticos/genética , Estudos de Associação Genética , Frequência do GeneRESUMO
Mapping single nucleotide polymorphisms (SNPs) in genes potentially involved in immune responses may help understand the pathophysiology of infectious diseases in specific geographical regions. In this context, we have aimed to analyze the frequency of immunogenetic markers, focusing on genes CD209 (SNP -336A/G), FCγRIIa (SNP -131H/R), TNF-α (SNP -308A/G) and VDR (SNP Taq I) in two populations of the Espirito Santo State (ES), Brazil: general and Pomeranian populations. Peripheral blood genomic DNA was extracted from one hundred healthy individuals of the general population and from 59 Pomeranians. Polymorphic variant identification was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). SNP genotype frequencies were in Hardy-Weinberg Equilibrium. There was no statistically significant difference in allelic and genotypic distributions between the two populations studied. Statistically significant differences were observed for SNP genotype distribution in genes CD209, TNF-α and VDR when comparing the ES populations with other Brazilian populations. This is the first report of CD209, FcγRIIa, TNF-α and VDR allelic frequencies for the general and Pomeranian populations of ES.
Assuntos
Genes/imunologia , Variação Genética , Fenômenos Imunogenéticos/genética , Brasil , Primers do DNA/genética , Frequência do Gene , Genes/genética , Marcadores Genéticos/imunologia , Alemanha Oriental/etnologia , Humanos , Polônia/etnologia , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
This review of the immunogenetics of cord blood transplantation attempts to highlight the connections between classical studies and conclusions of the tissue transplantation field as a scholarly endeavor, exemplified by the work of Professor Hoecker, with the motivations and some recent and key results of clinical cord blood transplantation. The authors review the evolution of understanding of transplantation biology and find that the results of the application of cord blood stem cells to Transplantation Medicine are consistent with the careful experiments of the pioneers in the field, from the results of tumor and normal tissue transplants, histocompatibility immunogenetics, to cell and molecular biology. Recent results of the National Cord Blood Program of the New York Blood Center describe the functioning in cord blood transplantation of factors, well known in transplantation immunogenetics, like the Fl anti-parent effect and the tolerance-like status of donors produced by non-inherited maternal HLA antigens. Consideration of these factors in donor selection strategies can improve the prognosis of transplantation by characterizing "permissibility" in HLA-incompatible transplantation thereby increasing the probability of survival and reducing the likelihood of leukemic relapse.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Antígenos HLA/genética , Antígenos HLA/imunologia , Histocompatibilidade/imunologia , Fenômenos Imunogenéticos/imunologia , Imunologia de Transplantes/imunologia , Histocompatibilidade/genética , Humanos , Fenômenos Imunogenéticos/genética , Imunologia de Transplantes/genéticaRESUMO
This review of the immunogenetics of cord blood transplantation attempts to highlight the connections between classical studies and conclusions of the tissue transplantation field as a scholarly endeavor, exemplified by the work of Professor Hoecker, with the motivations and some recent and key results of clinical cord blood transplantation. The authors review the evolution of understanding of transplantation biology and find that the results of the application of cord blood stem cells to Transplantation Medicine are consistent with the careful experiments of the pioneers in the field, from the results of tumor and normal tissue transplants, histocompatibility immunogenetics, to cell and molecular biology. Recent results of the National Cord Blood Program of the New York Blood Center describe the functioning in cord blood transplantation of factors, well known in transplantation immunogenetics, like the Fl anti-parent effect and the tolerance-like status of donors produced by non-inherited maternal HLA antigens. Consideration of these factors in donor selection strategies can improve the prognosis of transplantation by characterizing "permissibility" in HLA-incompatible transplantation thereby increasing the probability of survival and reducing the likelihood of leukemic relapse.
Assuntos
Humanos , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Antígenos HLA/genética , Antígenos HLA/imunologia , Histocompatibilidade/imunologia , Fenômenos Imunogenéticos/imunologia , Imunologia de Transplantes/imunologia , Histocompatibilidade/genética , Fenômenos Imunogenéticos/genética , Imunologia de Transplantes/genéticaRESUMO
Rhoptry proteins have been extensively shown to be important in invasion and parasitophorous vacuole (PV) formation. This work evaluates the immunogenicity and protective efficacy of Plasmodium vivax RAP2 in the non-human Aotus primate model, when expressed as a recombinant molecule in E. coli and formulated in Freund and Alum hydroxide adjuvants. Our results show that rPvRAP2 is immunogenic in both formulations, finding a trend of higher cytokine levels in immunized monkeys, specially in IL-4 levels (using Freund's adjuvant) and IL-5 (using Alum hydroxide). RAP2 is suggested as a P. vivax-vaccine candidate since immunized monkeys exhibited lower parasitemias than control groups after being experimentally challenged with the P. vivax VCG-I strain.