RESUMO
We investigated the effect of RANTES polymorphisms on human immunodeficiency virus type 1 (HIV-1) disease progression in an urban population of Uganda. HIV-positive individuals homozygous for the INT1.1C polymorphism, which had been associated previously with low RANTES expression, were less likely to die than were those with other genotypes (hazard ratio, 0.53 [95% confidence interval, 0.33-0.83]; P=.007). This report of a non-human leukocyte antigen genetic association with HIV-1 and/or acquired immunodeficiency syndrome disease progression in an African population reveals a genetic effect different from that reported elsewhere for African Americans and may impact therapeutic strategies targeting the RANTES pathway in HIV infection.
Assuntos
Quimiocina CCL5/genética , Soropositividade para HIV/genética , Soropositividade para HIV/mortalidade , Polimorfismo Genético , Estudos de Coortes , Soronegatividade para HIV , Soropositividade para HIV/fisiopatologia , Homozigoto , Humanos , Análise de Regressão , Análise de Sobrevida , Resultado do Tratamento , UgandaRESUMO
Schliekelman et al. have provided a model to quantify the speed at which HIV-resistance haplotypes can become enriched in a susceptible population through a delay in the onset of AIDS, permitting greater lifetime reproduction and the selection of AIDS-delaying haplotypes. But we question their conclusion that there could be a rapid evolution of resistance to AIDS onset in some African populations if the current HIV epidemic persists, as this depends on an untested assumption: that variant forms of the chemokine-receptor-5 (CCR5) gene impart selective advantages or disadvantages in Africa that are comparable to those reported for African Americans. Here we test this premise in a large Ugandan population, and find that CCR5 variants are not associated with HIV/AIDS disease risk in Africa--the origin and centre of the current AIDS pandemic. This gene may therefore not be subject to rapid evolutionary change as a result of the HIV epidemic in Africa.
Assuntos
Síndrome da Imunodeficiência Adquirida/genética , Predisposição Genética para Doença/genética , Receptores CCR5/genética , Síndrome da Imunodeficiência Adquirida/epidemiologia , Síndrome da Imunodeficiência Adquirida/virologia , Alelos , População Negra/genética , Progressão da Doença , Evolução Molecular , Frequência do Gene , Variação Genética/genética , HIV-1/classificação , HIV-1/isolamento & purificação , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Modelos Genéticos , Regiões Promotoras Genéticas/genética , Receptores CCR2 , Receptores de Quimiocinas/genética , Análise de Regressão , Seleção Genética , Uganda/epidemiologia , População Branca/genéticaRESUMO
The CD45 antigen is essential for normal antigen receptor-mediated signalling in lymphocytes, and different patterns of splicing of CD45 are associated with distinct functions in lymphocytes. Abnormal CD45 splicing has been recognized in humans, caused by a C77G transversion in the gene encoding CD45 (PTPRC). Recently the C77G polymorphism has been associated with multiple sclerosis and increased susceptibility to HIV-1 infection. These studies suggest that the regulation of CD45 splicing may be critical for the proper function of the immune system. Because of these data we examined the frequency of the C77G allele in African and Asian populations from countries with high or low prevalence of HIV infection. Here we report that the variant CD45 C77G allele is absent in African populations. We further show that populations living in the Pamir mountains of Central Asia have a very high prevalence of the C77G variant.