Polymorphisms in the MBL2 promoter correlated with risk of HIV-1 vertical transmission and AIDS progression

Genetic Service, IRCCS Burlo Garofolo and Chair of Genetics, University of Trieste, Via dell'Istria 65/1, 34137 Trieste, Italy.
Genes and Immunity (Impact Factor: 2.91). 07/2000; 1(5):346-8. DOI: 10.1038/sj.gene.6363685
Source: PubMed


We investigated the polymorphisms of the promoter region of the MBL2 gene, which codifies for the Mannose-binding protein (MBP). The study population included 90 children with vertically acquired HIV-infection, further divided on the basis of the disease rate, 27 HIV exposed-uninfected children, and 74 healthy control subjects matched for ethnic origin to evaluate the MBP involvement in the risk of HIV-1 infection and to assess the role of the MBP promoter in AIDS progression. A region of 380 bp in the promoter of the MBL2 gene was analysed by PCR and direct sequencing of both DNA strands. We found that the polymorphism at position -550 influences the risk of HIV-infection and AIDS progression. Also a 6 bp deletion at position -328 was correlated with HIV-1 infection. This study indicates that the promoter of the MBL2 gene influences vertical transmission of HIV and the course of perinatal infection.

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Available from: Sergio Crovella, Mar 10, 2014
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    • "Deficiency in MBL protein, which is mainly due to reduced gene expression and poor oligomerization, has been linked with increased susceptibility to HIV (Boniotto et al., 2000; Garred et al., 2006). We describe MBL2 genetic variation among Zimbabweans and discuss their possible role in differential susceptibility to HIV infection in utero. "
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    ABSTRACT: Abstract Mannose binding lectin (MBL) is a pathogen pattern recognition protein involved in antimicrobial activities. Variation in MBL2 gene has been extensively implicated in differential outcomes of infectious diseases in studies conducted outside Africa, but virtually very little is known on the role of this candidate gene in the African continent. We investigated human genetic variations in MBL2 in a Zimbabwean pediatric population and their putative associations with HIV infection in perinatally exposed children. One hundred and four children aged 7 to 9 years comprising 68 perinatally exposed to HIV (32 who were born infected and 36 who were uninfected) and 36 unexposed controls were recruited. DNA samples were genotyped for MBL2 polymorphisms using PCR-RFLP and sequencing. HIV infected children had markedly variable and significantly lower mean height (p=0.03) and weight (p=0.005) when compared to the uninfected children. Using all samples, frequencies for MBL2 genetic variants for the Zimbabwean population were calculated. Twelve single nucleotide polymorphisms were observed and minor alleles occurred with the following frequencies: -550C>G (G: 0.02), -435G>A (A: 0.08), -428A>C (C: 0.39), -394A>G (A: 0.39), -328AGAGAA ins/del (AGAGAA ins: 0.44), -245G>A (A: 0.05), -221C>G (C: 0.12), -111A>T (T: 0.10), -70C>T (C: 0.46), +4C>T (C: 0.45), novel -595G>A (A: 0.02), and 170G>A (0.24). We found that the MBL2 +4T variant displayed a trend for association with reduced risk of HIV transmission from mother-to-child but the remaining vast majority of the genetic markers did not show a significant association. We conclude (1) the MBL2 gene is highly polymorphic in the Zimbabwean population, and (2) MBL2 genetic variation does not appear to play a major role in influencing the risk of mother-to-child HIV transmission in our study sample. These observations contest the hitherto significant role of this candidate gene for HIV transmission from mother-to-child in non-African populations and thus, further speak to the limits of extrapolating genomic association studies directly to the African populations from studies conducted elsewhere. It is hoped that more OMICS research in a diverse set of African countries can shed further light on the putative role (or the lack thereof ) of this candidate gene in HIV transmission in the continent, a major global health burden in Africa.
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    ABSTRACT: Background: Mannose-binding lectin (MBL-2) allele variants are associatedwithdeficienciesininnateimmunityandhavebeenfound to be correlated with HIV infection in adults and children. Objective: We tested whether MBL-2 variants among infants born to HIV-positive mothers have an increased susceptibility to HIV. Design: MBL-2 allele variants were measured among 225 infants born to HIV-positive mothers enrolled in a trial in Durban, South Africa. Mothers of 108 infants were randomly assigned to receive vitamin A and -carotene supplementation and 117 to receive pla- cebo.InfantswerefollowedwithregularHIVteststodeterminerates of mother-to-child HIV transmission. Results: A high proportion of infants were either homozygous (10.7%) or heterozygous (32.4%) for MBL-2 variants. MBL-2 vari- antswithintheplaceboarmwereassociatedwithanincreasedriskof HIV transmission (odds ratio: 3.09; 95% CI: 1.21, 7.86); however,
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    ABSTRACT: The overall hypothesis of this thesis project was that bleomycin hydrolase (BLMH) has biologically specific and unique functions in the central nervous system (CNS). BLMH is a multifaceted papain superfamily cysteine protease that has importance in drug metabolism. The physiological functions of this protease are unknown as are factors regulating its expression. Immunohistochemical examination of B6.129Blmhtm1Geh/J null and control animals showed no gross abnormalities; however, marked global astrogliosis was observed in the null aged animals. To define the role of BLMH in the brain, the behavioral phenotype of hybrid [129S6-Blmhtm1Geh/J X B6.129 Blmhtm1Geh/J]F1 null and littermate controls was characterized using multiple behavioral paradigms. Deletion of Blmh was found to result in deficits among young animals in water maze probe trials. Retention of target platform location during the probe trials requires both learning and memory as well as sensory and locomoter skills. No overt sensory or motor deficits were noted in Blmh null F1 hybrids. The profile of BLMH expression and its regulation in the CNS was studied next. Inducible transcription of BLMH was evaluated in the context of a putative role in the processing of MHC I epitopes. BLMH was found to be differentially regulated in microglia and astrocytes. In microglia, Blmh protein was significantly induced by gamma interferon or tumor necrosis factor a, whereas in astrocytes, no change in protein expression was observed. Treatment of microglial derived cell lines with both gamma interferon and tumor necrosis factor a revealed synergistic effects between the cytokines. BLMH protein induction was accompanied by increased Blmh mRNA. These results suggest that cell specific regulation of BLMH is an important control mechanism for this protease. These data also provide further evidence for a targeted immune related biological function for BLMH. It is concluded that BLMH potentially has multiple unique and biologically important functions within the brain.
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