ABSTRACT
RESUMEN Introduction: Variants in genes encoding for HIV-1 co-receptors and their natural ligands have been individually associated to natural resistance to HIV-1 infection. However, the simultaneous presence of these variants has been poorly studied. Objective: To evaluate the association of single and multilocus haplotypes in genes coding for the viral co-receptors CCR5 and CCR2, and their ligands CCL3 and CCL5, with resistance or susceptibility to HIV-1 infection. Materials and methods: Nine variants in CCR5-CCR2, two SNPs in CCL3 and two in CCL5 were genotyped by PCR-RFLP in 35 seropositive (cases) and 49 HIV-1-exposed seronegative Colombian individuals (controls). Haplotypes were inferred using the Arlequin software, and their frequency in individual or combined loci was compared between cases and controls by the chi-square test. A p' value <0.05 after Bonferroni correction was considered significant. Results: Homozygosis of the human haplogroup (HH) E was absent in controls and frequent in cases, showing a tendency to susceptibility. The haplotypes C-C and T-T in CCL3 were associated with susceptibility (p'=0.016) and resistance (p'<0.0001) to HIV-1 infection, respectively. Finally, in multilocus analysis, the haplotype combinations formed by HHC in CCR5-CCR2, T-T in CCL3 and G-C in CCL5 were associated with resistance (p'=0.006). Conclusion: Our results suggest that specific combinations of variants in genes from the same signaling pathway can define an HIV-1 resistant phenotype. Despite our small sample size, our statistically significant associations suggest strong effects; however, these results should be further validated in larger cohorts.
ABSTRACT Introducción. Algunas variantes en genes que codifican los correceptores del HIV-1 y sus ligandos se han asociado individualmente a la resistencia natural frente a dicha infección. Sin embargo, su presencia simultánea ha sido poco estudiada. Objetivo. Evaluar la asociación de haplotipos individuales y multilocus en genes que codifican los correceptores virales CCR5 y CCR2 y sus ligandos CCL3 y CCL5 con la resistencia o la propensión a la infección por el HIV-1. Materiales y métodos. Nueve variantes en CCR5-CCR2, dos en CCL3 y dos en CCL5 fueron genotipificadas mediante reacción en cadena de la polimerasa de polimorfismos de longitud de fragmentos de restricción (Restriction Fragment Length Polymorphism-PCR-RFLP) en 35 individuos seropositivos (casos) y 49 seronegativos expuestos (controles) de Colombia. Los haplotipos se infirieron utilizando el programa Arlequín, y su frecuencia individual o combinada se comparó en los casos y los controles mediante la prueba de ji al cuadrado. Se consideró significativo un valor de p'<0,05 después de la corrección de Bonferroni. Resultados. La homocigosis del haplogrupo humano (HH) E estaba ausente en los controles y era frecuente en los casos, es decir, con tendencia hacia la propensión. Los haplotipos C-C y T-T en CCL3 se asociaron con la propensión (p'=0,016) y la resistencia (p'<0,0001), respectivamente. Por último, en el análisis multilocus, el haplotipo combinado formado por HHC en CCR5-CCR2, T-T en CCL3 y G-C en CCL5 se asoció con la resistencia (p'=0,006). Conclusión. Los resultados de este estudio sugieren que ciertas combinaciones específicas de variantes en los genes de una misma vía de señalización pueden definir un fenotipo resistente al HIV-1. Aunque el tamaño de la muestra era pequeño, las asociaciones estadísticamente significativas sugieren un efecto considerable; sin embargo, estos resultados deben validarse en cohortes de mayor tamaño.
Subject(s)
Humans , Haplotypes/genetics , HIV Infections/microbiology , HIV Infections/epidemiology , HIV-1/immunology , Receptors, CCR5/genetics , Polymorphism, Single Nucleotide/genetics , Immunity, Innate/immunology , Phenotype , HIV Infections/genetics , Cohort Studies , HIV-1/genetics , HIV-1/chemistry , Colombia , Polymorphism, Single Nucleotide/physiology , Genotype , Immunity, Innate/physiologyABSTRACT
HIV-1 Tat is considered to be one of key players to facilitate monocyte entry into the CNS, which is characteristic feature of AIDS-related encephalitis and dementia. This study was performed to determine the regulatory function of superoxide dismutase (SOD) on the HIV-1 Tat-induced signaling pathways leading to NF-kappaB activation, expression of adhesion molecules, and monocyte adhesion in CRT-MG human astroglioma cells by using cell-permeable SOD. When cell-permeable SOD was added to the culture medium of CRT-MG cells, it rapidly entered the cells in dose- and time-dependent manners. Treatment of astrocytes with cell-permeable SOD led to decrease in Tat-induced ROS generation as well as NF-kappaB activation. Cell-permeable SOD inhibited the activation of MAP kinases including ERK, JNK and p38 by HIV-1 Tat. Treatment of CRT-MG cells with cell-permeable SOD significantly inhibited protein and mRNA levels of ICAM-1 and VCAM-1 up-regulated by HIV-1 Tat, as measured by Western blot analysis and RT-PCR. Furthermore, enhanced adhesiveness of monocyte to astrocyte by HIV-1 Tat was significantly abrogated by pretreatment with cell-permeable SOD fusion proteins. These data indicate that SOD has a regulatory function for HIV-1 Tat-induced NF-kappaB activation in astrocytes and suggest that cell-permeable SOD can be used as a feasible therapeutic agent for regulation of ROS-related neurological diseases.
Subject(s)
Humans , Astrocytes/enzymology , Cell Adhesion/physiology , Cell Membrane Permeability , Gene Products, tat/pharmacology , HIV Infections/metabolism , HIV-1/chemistry , Monocytes/cytology , Signal Transduction , Superoxide Dismutase/geneticsABSTRACT
The HIV-1 genetic variation in 60 infected Malaysian intravenous drug users (IDU) was studied by comparison of the nucleotide sequences and their predicted amino acid sequences in the V3 loop of the external glycoprotein gp120. In this study, HIV-1 B, C and E subtypes were identified among Malaysian IDU, with HIV-1 B being the predominant subtype (91.7%). HIV-1 C and HIV-1 E were minority subtypes among Malaysian IDU. Analysis of the amino acid alignment of the C2-V3 region of the env gene suggests a genetic relationship between Thai and Malaysian B and E subtype strains. This study serves as a baseline for monitoring HIV-1 genetic diversity and spread in Malaysia.
Subject(s)
Adult , Amino Acid Sequence , Base Sequence , Genetic Variation , HIV Envelope Protein gp120/chemistry , HIV Infections/complications , HIV-1/chemistry , Humans , Malaysia , Male , Molecular Sequence Data , Peptide Fragments/chemistry , Phylogeny , Polymerase Chain Reaction , Risk Factors , Substance Abuse, Intravenous/complicationsABSTRACT
Esta revisäo aborda recentes descobertas dque esclareceram a natureza das moléculas acessórias obrigatoriamente utilizadas pelo HIV para infectar células humanas, elucidando mecanismos de resistência à infecçäo e abrindo perspectivas de novos alvos para drogas e vacinas. Um ano após a descoberta do HIV, a molécula CD4 foi identificada como receptor primário utilizado no processo de infecçäo dos linfócitos T. Entretanto, há mais de uma década se sabia que só esta molécula näo era suficiente e que o HIV precisava de moléculas adicionais, ou co-receptores, para permitir a infecçäo da célula-alvo. Em 1996, vários grupos de pesquisa descobriram que receptores para citocinas, das quais bem caracterizadas...