RESUMO
Systems biological analysis has recently revealed how innate immune variants as well as gut microbiota impact the individual response to immunization. HIV-infected (HIV+) patients have a worse response rate after standard vaccinations, possibly due to the immune exhaustion, increased gut permeability and microbial translocation. In the last decade, dendritic cells (DC)-based immunotherapy has been proposed as an alternative approach to control HIV plasma viral load, however clinical trials showed a heterogeneity of immunization response. Hypothesizing that host genetics may importantly affects the outcome of immunotherapy in HIV+ patients, genetic polymorphisms' distribution and gene expression modulation were analyzed in a phase I/II clinical trial of DC-based immunotherapy according to immunization response, and quality of vaccine product (DC). Polymorphisms in genes previously associated with progression of HIV infection to AIDS (i.e.: PARD3B, CCL5) contribute to a better response to immunotherapy in HIV+ individuals, possibly through a systemic effect on host immune system, but also directly on vaccine product. Genes expression profile after immunization correlates with different degrees of immune chronic activation/exhaustion of HIV+ patients (i.e. PD1, IL7RA, EOMES), but also with anti-viral response and DC quality (i.e.: APOBEC3G, IL8, PPIA), suggested that an immunocompetent individual would have a better vaccine response. These findings showed once more that host genetics can affect the response to DC-based immunotherapy in HIV+ individuals, contributing to the heterogeneity of response observed in concluded trials; and it can be used as predictor of immunization success.
Assuntos
Vacinas contra a AIDS/imunologia , Células Dendríticas/imunologia , Infecções por HIV/terapia , Interações entre Hospedeiro e Microrganismos/genética , Imunoterapia/métodos , Vacinas contra a AIDS/administração & dosagem , Desaminase APOBEC-3G/genética , Desaminase APOBEC-3G/metabolismo , Adulto , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/patogenicidade , HIV-1/fisiologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Polimorfismo Genético/imunologia , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
Host genome is still poorly investigated in the context of vaccine or immunotherapy, however recently findings emphasized that it may affect the response to those treatments. In our retrospective study we evaluated the effect of HIV-1 genetic restriction factors on the response to dendritic cell (DC)-based immunotherapy in a Brazilian cohort of HIV positive (HIV+) patients that underwent a phase I clinical trial in 2004. Genomic DNA from 18 HIV+ individuals that underwent DC-based immunotherapy was analyzed for selected polymorphisms known to be associated with susceptibility to HIV-1 infection and/or AIDS progression. Allelic and genotypic distribution of the 22 polymorphisms was evaluated considering the response to the treatment. The rs11884476 SNP in PARD3B resulted associated with good response to immune treatment according to an over-dominant model. Even if functional effect of this variation is still unknown, our data suggested that it could play a role in the control of viral replication. Our findings, being aware of the limitation represented by the small number of subjects analyzed, suggest that genetic factors involved in AIDS progression could affect the response to immunotherapy, reinforcing the idea that deeper investigation on host genetic variations will be fundamental for a rational vaccine development.