AIDS:
28 March 2003 - Volume 17 - Issue 5 - pp 779-780
Correspondence
MBL2 encodes a multichain serum lectin called mannose-binding protein (MBP), an important effector of innate immunity. MBP binds specific carbohydrate residues present on some virus, bacteria and yeast by activating the complement system on the pathogens or assisting phagocytosis by macrophages. Saifuddin et al. [1] recently demonstrated that MBP is able to bind the HIV-1 glycoprotein complex gp120-gp41 in vitro.
Three dominant missense mutations that result in reduced serum levels of MBP protein have been described in the first exon of the gene [2].
We evaluated the frequency of the polymorphisms in the first exon of the MBL2 gene in an HIV-1-infected pediatric Brazilian cohort, sampled from impoverished areas in the proximity of Recife (Pernambuco, Brazil). The population was derived from an admixture of African, Caucasian and native American populations estimated, respectively, at 44, 34 and 22% [3].
A total of 114 HIV-1-infected children, aged from 3 to 8 years, were enrolled for this study. Twenty-seven Guthrie cards were collected from HIV-1-exposed but uninfected children, matched for age and sex. All of these children were born to HIV-1-positive mothers who had not undergone any antiretroviral therapy during pregnancy, and had not undergone caesarean section to prevent transmission, because the diagnosis was made after delivery. A total of 165 uninfected and unexposed children, from the same population, were employed as controls after informed consent.
DNA was extracted by using standard laboratory techniques [4,5]. MBL2 genotyping was performed by melting temperature assay [6]. As described by Garred et al. [7] the three MBL2 variants were grouped together as allele 0, whereas the wild-type allele was called A. Allele frequencies were calculated by direct gene counting and the differences analysed by the chi-square test using 2 × 2 contingency tables. The relative risk was calculated according to Woolf's formula [8].
The 0 allele was significantly more frequent in 114 HIV-1-infected children (0.29) than in 165 HIV-1-unexposed and uninfected children (0.20) (P = 0.0155). The 0 allele frequency in the 27 HIV-1-exposed but uninfected children was 0.19 (Table 1).
MBL2 genotype frequencies are in accordance with Hardy-Weinberg equilibrium for the three populations. The frequency of the A/A homozygotes was significantly higher in healthy controls (0.67) than in HIV-1-exposed and infected children (0.54) (P = 0.0318). The A/A frequency in exposed but uninfected children (0.70) was similar to the healthy controls. When we compared HIV-1-infected children and HIV-1-exposed but uninfected children we did not find any statistically significant difference in either the allelic or the genotype frequencies, probably because of the low number of the former population.
The presence of the allele 0 confers a relative risk of 1.37 (95% confidence limits 1.02-1.84) for HIV-1 infection through vertical transmission.
We found an association between the presence of the mutated MBL2 allele (allele 0) and HIV-1 infection in perinatally exposed children. The allele 0 has a dominant negative effect on MBP serum levels as a result of the incorrect assembly of MBP subunits in the collagen-like domain that make the protein more vulnerable to degradation by metalloproteinases [9]. In heterozygous individuals the serum level of the protein was reduced five to 10 times, whereas in 0/0 homozygotes the level of the protein was undetectable [2,7,10]. Our data are similar to those obtained by Garred et al. in a cohort of homosexual men [7]. In fact they have observed significantly higher frequencies of 0/0 homozygotes in HIV-1-infected patients when compared with high-risk controls.
Furthermore, we hypothesized that MBP is more important in newborns for its role as 'ante-antibody' [11]. In newborns the acquired immune response is not fully developed, and a decreased MBP serum level is an important risk factor for HIV-1 infection; in fact children carriers of the allele 0 (both homozygous and heterozygous) showed an increased risk of HIV-1 infection.
In their study, Garred et al. [7] also demonstrated a correlation between MBL2 allelic variants and a more rapid progression to death in seroconverters, whereas in a more recent study Maas et al. [12] showed that carriers of MBL2 allelic variants progressed more slowly to AIDS and death. Unfortunately, no information on disease progression was available to us for the Brazilian HIV-1-infected children, but the findings of Boniotto et al. [13] with respect to an Italian pediatric population seem to confirm a dual role for MBP in HIV-1-exposed children.
In conclusion, our results suggest that lower MBP serum levels may be an important risk factor for HIV-1 vertical transmission.
References
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13.Boniotto M, Crovella S, Pirulli D, Scarlatti G, Spano' A, Vatta L, et al. Polymorphisms in the MBL2 promoter correlated with risk of HIV-1 vertical transmission and AIDS progression. Genes Immun 2000, 1:346-348.#m AcknowledgementsThe authors wish to thank Dr Edvaldo Souza (paediatrician), Dr Ruben Maggi (director of the Instituto Materno Infantil do Pernambuco), and Dr Josemar Mello (head of the immunology laboratory at the Instituto Materno Infantil do Pernambuco) for their valuable support.
© 2003 Lippincott Williams & Wilkins, Inc.