ABSTRACT
BACKGROUND The time of progression towards AIDS can vary greatly among seropositive patients, and may be associated with host genetic variation. The NR1I2 (PXR) gene, a ligand-activated transcription factor, regulates the transcription immune pathway genes and can therefore be targets of viral replication mechanisms influencing time of progression to AIDS. OBJECTIVE To verify the association of single nucleotide polymorphisms (SNPs) rs3814057, rs6785049, rs7643645, and rs2461817 in the NR1I2 (PXR) gene with progression to AIDS in HIV-1 infected patients. METHODS Blood samples were obtained from 96 HIV-1 positive individuals following informed consent. DNA was isolated and genotyped through real time polymerase chain reaction (PCR) for the presence of SNPs in the NR1I2. Questionnaires on socio-demographic features and behaviors were answered and time of progression to AIDS was estimated based on medical chart analysis. FINDINGS Patients with the GG genotype for rs7643645 were shown to be related with a more rapid disease progression when compared to GA and AA genotypes. This result was maintained by the Multivariate Cox Regression considering sex, ethnicity, and presence of HLA-B*57, HLA-B*27, and CCR5del32 polymorphisms. MAIN CONCLUSIONS Recent studies reported the expression of the nuclear receptors in T-Lymphocytes, suggesting their possible role in the immune response. In addition, nuclear receptors have been shown to inhibit the HIV replication, although no such mechanism has been thoroughly elucidated to date. This is the first time an association between NR1I2 polymorphism and time of progression to AIDS is reported and supports an apparent relationship between the gene in the immune response and identifies another genetic factor influencing AIDS progression.
Subject(s)
Humans , Male , Female , Adult , Acquired Immunodeficiency Syndrome/genetics , Acquired Immunodeficiency Syndrome/pathology , Disease Progression , Polymorphism, Genetic , GenotypeABSTRACT
Background: Although most HIV-1 infections in Brazil are due to subtype B, Southern Brazil has a high prevalence of subtype C and recombinant forms, such as CRF31_BC. This study assessed the impact of viral diversity on clinical progression in a cohort of newly diagnosed HIV-positive patients. Methods: From July/2004 to December/2005, 135 HIV-infected patients were recruited. The partial pol region was subtyped by phylogeny. A generalized estimating equation (GEE) model was used to examine the relationship between viral subtype, CD4+ T cell count and viral load levels before antiretroviral therapy. Hazard ratio (Cox regression) was used to evaluate factors associated with viral suppression (viral load < 50 copies/mL at six months). Results: Main HIV-1 subtypes included B (29.4%), C (28.2%), and CRF31_BC (23.5%). Subtypes B and C showed a similar trend in CD4+ T cell decline. Comparison of non-B (C and CRF31_BC) and B subtypes revealed no significant difference in the proportion of patients with viral suppression at six months (week 24). Higher CD4+ T cell count and lower viral load were independently associated with viral suppression. Conclusion: No significant differences were found between subtypes; however, lower viral load and higher CD4+ T cell count before therapy were associated with better response.
Introdução: Embora a maioria das infecções de HIV-1 no Brasil seja devido ao subtipo B, o Sul do Brasil apresenta uma alta prevalência do subtipo C e formas recombinantes, como CRF31_BC. Este estudo avaliou o impacto da diversidade viral na evolução clínica em uma coorte de pacientes HIV-positivos recém diagnosticados. Métodos: De julho/2004 a dezembro/2005, 135 pacientes anti-HIV reagentes foram recrutados. A região pol parcial foi subtipada por filogenia. Um modelo de equação de estimativa generalizada (GEE) foi utilizado para examinar a relação entre subtipo viral, contagem de células CD4 e níveis de carga viral pré-terapia antirretroviral. Hazard ratio (regressão de Cox) foi utilizada para avaliar os fatores associados à supressão viral (carga viral < 50 cópias/mL em seis meses). Resultados: Os principais subtipos de HIV-1 incluíram B (29,4%), C (28,2%) e CRF31_BC (23,5%). Os subtipos B e C apresentaram uma tendência semelhante no declínio de células CD4. Quando comparados os subtipos não B (C e CRF31_BC) e B, não houve diferença significativa na proporção de pacientes com supressão viral aos seis meses (24 semanas). CD4 mais alto e carga viral mais baixa demonstraram associação independente com supressão viral. Conclusão: Não houve diferença significativa entre os subtipos; entretanto, viremia mais baixa e CD4 mais alto pré-terapia mostraram associação com melhor resposta.