Analysis of CCR5, CCR2, SDF1 and RANTES gene polymorphisms in subjects with HIV-related PML and not determined
Franca R Guerini1, Serena Delbue, Milena Zanzottera
1Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi Foundation IRCCS, S. Maria Nascente, Milan, Italy. fguerini@dongnocchi.it
Abstract:
Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV), a human polyomavirus that can lytically infect and destroy the oligodendrocites in immunosuppressed individuals. After the introduction of highly active antiretroviral therapy (HAART) for AIDS treatment, a PML-like leukoencephalopathy, known as non-determined leukoencephalopathy (NDLE), has also been observed. Since a number of host genetic factors have been identified as having an impact on susceptibility to HIV-1 infection and in the progression to AIDS and death, in this work we analysed the pattern of distribution of different chemokine and chemokine receptor polymorphisms that seem to be involved in HIV+ neurological diseases. The CCR5, RANTES, CCR2 and SDF1 genes were molecularly analysed in 84 HIV+ HAART treated subjects: 55 without neurological disorders (HIV+), 12 HIV+ NDLE and 17 HIV+ PML patients. The RANTES -403 G/A polymorphism was significantly associated with NDLE. These data suggest that mutation of the RANTES allele can predispose to the induction of demyelination similarly to what has been observed in Multiple Sclerosis (MS) and may suggest a possible explanation for the development of leukoencephalopathy without detection of JCV.
Insights
Genetic variations in the RANTES gene are linked to non-determined leukoencephalopathy (NDLE) in HIV+ patients. This finding may explain demyelination in the central nervous system (CNS) without JC virus (JCV) detection.
Area of Science:
- Neuroimmunology
- Virology
- Genetics
Background:
- Progressive Multifocal Leukoencephalopathy (PML) is a fatal CNS demyelinating disease caused by JC virus (JCV) in immunosuppressed individuals.
- Highly active antiretroviral therapy (HAART) for AIDS has led to the observation of PML-like non-determined leukoencephalopathy (NDLE).
- Host genetic factors influence susceptibility to HIV-1 infection and disease progression.
Purpose of the Study:
- To investigate the association between chemokine and chemokine receptor gene polymorphisms and neurological disorders in HIV+ patients.
- To analyze the distribution patterns of CCR5, RANTES, CCR2, and SDF1 gene polymorphisms in HIV+ individuals with and without neurological complications.
Main Methods:
- Molecular analysis of CCR5, RANTES, CCR2, and SDF1 genes.
- Study population included 84 HIV+ HAART-treated subjects: 55 HIV+ without neurological disorders, 12 HIV+ with NDLE, and 17 HIV+ with PML.
- Statistical analysis to identify significant associations between gene polymorphisms and neurological conditions.
Main Results:
- The RANTES -403 G/A polymorphism showed a significant association with NDLE.
- No significant associations were found for other analyzed polymorphisms (CCR5, CCR2, SDF1) with NDLE or PML.
Conclusions:
- The RANTES -403 G/A polymorphism may predispose individuals to demyelination, potentially explaining leukoencephalopathy development in the absence of JCV.
- These findings suggest a genetic component in the pathogenesis of NDLE and highlight the role of RANTES in CNS inflammatory and demyelinating processes.
