RESUMO
BACKGROUND: Despite multiple exposure to HIV-1, some individuals remain uninfected. This resistance has been associated with homozygosity for a 32 base pair deletion in the gene for the CCR5 receptor. This variant occurs frequently in Caucasians but is extremely rare in Asians or Africans. OBJECTIVE: To identify variations in CCR5 receptor gene that affect susceptibility to HIV infection in non-Caucasians. METHODS: CCR5 coding region polymorphisms were screened in three groups of Vietnamese subjects: 47 HIV-1 infected intravascular drug users, 50 highly HIV-1-exposed but seronegative intravascular drug users and 37 HIV-1-unexposed seronegative individuals. DNA was analysed by denaturing high performance liquid chromatography; this was followed by examination of the biochemical and HIV coreceptor properties of the coding regions. RESULTS: Five CCR5 coding region variants were identified in this Vietnamese population. The S185R, I254T and C269F mutations have not been previously described; G106R and R223Q have already been found in other Asian populations, but the functional properties of G106R is not known. These variants differed in biochemical and HIV coreceptor properties. S185R and I254T variants had receptor and coreceptor activities comparable to that of the wild type, whereas C269F and G106R behaved differently. This latter pair are poorly expressed at the cell surface, weakly bind macrophage inflammatory protein 1beta (CCL4) and RANTES (CCL5), and display reduced HIV-1 coreceptor efficiency. CONCLUSIONS: Among the five CCR5 variants found in this Vietnamese population, G106R and C269F displayed significant modifications of their receptor and coreceptor properties, which may contribute to susceptibility to HIV-1 infection and/or disease progression within this population.
Assuntos
Infecções por HIV/genética , HIV-1/genética , Receptores CCR5/genética , Camboja , Linhagem Celular , Quimiocina CCL4 , Quimiocina CCL5/metabolismo , Quimiocinas CC/metabolismo , DNA Viral/genética , Genes Virais/genética , Predisposição Genética para Doença/genética , Infecções por HIV/complicações , Soronegatividade para HIV/genética , Heterozigoto , Humanos , Proteínas Inflamatórias de Macrófagos/metabolismo , Mutação , Polimorfismo Genético/genética , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/genética , VietnãRESUMO
OBJECTIVE: To identify mechanisms of resistance to HIV-1 infection in exposed uninfected individuals. DESIGN: We examined in-vitro cell susceptibility to HIV-1 infection in highly exposed Vietnamese intravascular drug users (IDU) who, despite a history of more than 10 years of drug use and a high prevalence of other blood-borne viral infections, remain apparently HIV uninfected. METHODS: Forty-five exposed uninfected IDU and 50 blood donors were included in the study. Peripheral blood mononuclear cells (PBMC) or CD4 cell susceptibilities to HIV infection were evaluated using three HIV-1 isolates with different tropisms. Polymerase chain reaction analysis of HIV-1-DNA replication intermediates was used to characterize the restriction of HIV-1 replication in CD4 cells. Homologous CD8 cells were mixed with infected CD4 cells to evaluate their role in virus suppression. RESULTS: We observed a relative resistance to PBMC infection with HIV-1 in 21 out of 45 exposed uninfected IDU, but only in five out of 50 unexposed controls (P < 0.001). PBMC resistance was related either to an inhibition of HIV-1 replication in CD4 cells or to CD8 cell-mediated viral suppression. HIV-1 replication in CD4 cells was restricted at the early stages of the viral cycle. CONCLUSION: Reduced PBMC susceptibility to HIV-1 infection was associated with resistance to infection in exposed uninfected IDU. Distinct mechanisms are involved in in-vitro resistance and may contribute to the apparent protection from HIV-1 transmission in this systemically exposed population.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Soronegatividade para HIV/imunologia , HIV-1/fisiologia , Abuso de Substâncias por Via Intravenosa , Adulto , Estudos de Casos e Controles , Quimiocinas/biossíntese , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Receptores CCR5/metabolismo , Vietnã , Replicação ViralRESUMO
We addressed the role of innate immunity in the protection against HIV-1 infection by studying NK cell function in 37 Vietnamese intravascular drug users (IDUs), who appeared to remain HIV-1 uninfected despite many years of high-risk exposure (exposed uninfected, EU), 10 IDUs who underwent seroconversion and 28 unexposed blood donors. Main results were: NK cell lytic activities against both the NK-susceptible K562 cell line and the NK-resistant Daudi cell line were significantly augmented in EU IDUs compared with either controls or seroconverters before or after seroconversion; NK cells producing the cytokines IFN-gamma and TNF-alpha and the beta chemokines CCL3, CCL4, and CCL5 were also increased in the EU IDUs, either after in vitro activation or without stimulation. The finding of an enhanced NK cell function in EU IDUs, especially compared with IDUs who became HIV-1 infected, supports the hypothesis that NK cells contribute to the protection against HIV-1 infection.