RESUMO
BACKGROUND: A polymorphism at position -589 in the interleukin 4 (IL-4) promoter region was recently described as being associated with the presence of syncytium-inducing CXCR4 using (X4) HIV-1 variants. OBJECTIVE: To study the IL-4 promoter polymorphism -589T in relation to HIV-1 disease progression and acquisition of X4 HIV-1 variants. DESIGN AND METHODS: Retrospective longitudinal study among 342 HIV-1-infected homosexual men who participated in the Amsterdam Cohort study. Polymerase chain reaction was used in combination with restriction analysis to identify IL-4 promoter genotypes. RESULTS: Carriers of the -589T allele (either -589 C/T heterozygotes or -589 T/T homozygotes), showed comparable progression to AIDS [relative hazard (RH), 0.94; P = 0.71], and survival (RH IL-4 -589 C/T or T/T, 0.94; P = 0.69) as carriers of the -589 C/C genotype (the reference group). In contrast to a previous study, we found that the -589T polymorphism was associated with a delayed acquisition of X4 HIV-1 variants (RH, 0.56; P = 0.02 for IL-4 -589 C/T or T/T) and a reduced number of CCR5 expressing memory CD4 T cells. CONCLUSION: In the Amsterdam Cohort of homosexual men with HIV infection, the IL-4 -589T promoter polymorphism was associated with a delayed acquisition of X4 variants but did not affect overall disease progression.
Assuntos
Infecções por HIV/genética , HIV-1/genética , Interleucina-4/genética , Polimorfismo Genético/genética , Receptores CXCR4/genética , Linfócitos T CD4-Positivos/metabolismo , Estudos de Coortes , Progressão da Doença , Genótipo , Homossexualidade Masculina , Humanos , Estudos Longitudinais , Masculino , Regiões Promotoras Genéticas , Estudos RetrospectivosRESUMO
Previously, we established a murine model, that involves the engraftment of fully allogeneic T cell depleted donor bone marrow cells in sublethally irradiated and single dose anti-CD3 treated recipient mice. These mice developed permanent stable multilineage mixed chimerism and donor-specific tolerance without graft-versus-host disease. Recently, we have shown that donor-specific tolerance is not induced and/or maintained by clonal anergy, neither by a Th1/Th2 shift, nor by suppressor or other regulatory processes. In the present study, we investigated whether clonal deletion plays a role in tolerance induction in our model. We studied the kinetics of TCRVbeta8(+) T cells in BALB/c (H-2L(d+))-->dm2 (H-2L(d-)) chimeras, in which combination of mouse strains TCRVbeta8 predominates the anti-donor response. We found that TCRVbeta8(+) T cells were specifically deleted. To our surprise, this deletion was also found in mixed chimeras, thymectomized prior to the conditioning regimen. We conclude that clonal deletion plays a role in the establishment and maintenance of donor-specific tolerance, and that the thymus is not required for this process. In addition, confocal laser-scanning microscopy clearly showed the presence of abundant amounts of donor T cells and some donor antigen presenting cells in the small intestine in thymectomized chimeras and not in other organs, suggesting that T cell selection might take place in this organ in the absence of the thymus.
Assuntos
Transplante de Medula Óssea/imunologia , Deleção Clonal , Linfócitos T/imunologia , Timo/imunologia , Tolerância ao Transplante/imunologia , Animais , Quimera/imunologia , Tolerância Imunológica , Intestino Delgado/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Pele , Timectomia , Fatores de Tempo , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
The presence of only non-syncytium-inducing beta-chemokine receptor 5-restricted (R5/NSI) human immunodeficiency virus type 1 (HIV-1) in an infected individual has been associated with long-term asymptomatic survival. However, the majority of R5/NSI HIV-1-infected individuals do progress to AIDS. Here, we compared the replicative capacity and cytopathicity of R5/NSI HIV-1 variants that were isolated early and late in the clinical course from 7 long-term asymptomatic individuals and 7 individuals with progressive HIV-1 infection. R5/NSI HIV-1 cytopathicity in vitro directly correlated with in vitro replication. HIV-1 variants obtained early and late during long-term asymptomatic HIV infection from the same individual were equally cytopathic. In contrast, HIV-1 variants obtained during late-stage progressive HIV infection were more cytopathic than viruses obtained early in infection from the same individuals. Our data indicate that the cytopathicity of HIV-1 variants may increase with progression to disease.
Assuntos
Efeito Citopatogênico Viral , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , HIV/fisiologia , HIV/patogenicidade , Receptores CCR5/metabolismo , Células Cultivadas , Progressão da Doença , Infecções por HIV/patologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Fito-Hemaglutininas/farmacologia , Replicação ViralRESUMO
In approximately half of human immunodeficiency virus (HIV) type 1-infected individuals, the development of CXC chemokine receptor 4-using, syncytium-inducing (SI) virus variants precedes a rapid progression to acquired immunodeficiency syndrome (AIDS). In other individuals, only CC chemokine receptor 5-using (R5), non-SI (NSI) virus variants are present throughout infection. These individuals may be either long-term survivors (LTSs) or rapid progressors. The basis for this variable disease progression in individuals with only R5 virus variants is not yet fully understood. In this study, the beta-chemokine sensitivity of biological HIV-1 clones isolated from 13 individuals who harbored only R5, NSI virus variants (7 LTSs and 6 progressors) was investigated. We found a statistically significant decrease in sensitivity of virus variants to RANTES (regulated on activation, normally T cell-expressed and -secreted) neutralization during the course of progressive infection, but not during follow-up of LTSs. Our data suggest that a role exists for RANTES neutralization sensitivity of HIV-1 in AIDS pathogenesis.
Assuntos
Quimiocina CCL5/imunologia , Variação Genética , Infecções por HIV/imunologia , Sobreviventes de Longo Prazo ao HIV , HIV-1/imunologia , Receptores CCR5/metabolismo , Progressão da Doença , Genótipo , Células Gigantes/fisiologia , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , HIV-1/patogenicidade , Humanos , Testes de NeutralizaçãoRESUMO
Studies in humans have provided evidence that CD8(+) T cells exhibit distinct phenotypical and functional properties dependent on virus specificity. It is not known how these T-cell phenotypes develop over the course of infection. Dynamics and properties of T cells specific for human immunodeficiency virus (HIV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) in HIV infection were investigated in relation to viral load. In rapid progressors, HIV-specific CD8(+) T cells were less differentiated early in infection and did not develop a more differentiated phenotype. In slow progressors, perforin expression of HIV-specific CD8(+) T cells slightly increased over time. HIV and EBV loads were detectable in all individuals, while CMV load could not be detected. Thus, in individuals with progressive HIV infection, HIV-specific T cells are less differentiated already early in infection. This apparent block in differentiation may be partly caused by chronic viremia or lack of CD4(+) T-cell help.