Mannose-Binding Lectin in Susceptibility and Progression of HIV-1 Infection in Children

Abstract

Background Mannose-binding lectin (MBL; encoded by MBL-2) is a circulating pattern-recognition molecule that recognizes microbial carbohydrate motifs, leading to complement activation and cell lysis. Mutations in the MBL-2 promoter and of the MBL-2 gene exon 1 result in reduced protein levels and increased susceptibility to infection. We have investigated the effect of MBL-2 polymorphisms on susceptibility and progression of HIV-1 infection in children. Patients and methods One-hundred and twenty-eight children, aged 2–16 years were recruited. MBL-2 genotypes were determined by PCR and heteroduplex analyses. Serum MBL levels were measured by ELISA. Comparison of genotypes (A=wild type, 0=variant alleles) and protein levels between groups was performed using χ2, Mann–Whitney U or Kruskal–Wallis tests. Results Children were classified according to the Centers for Disease Control and Prevention clinical classification: A, B or C (mildly symptomatic [ n=39], moderately symptomatic [ n=58] or severely symptomatic AIDS [ n=31]) or immune category 1 ( n=77), 2 ( n=46) or 3 ( n=5). Analysis of MBL-2 genotypes with respect to clinical classification yielded minimal differences. However, patients in immunological categories 2 and 3 (<25% CD4+ T cells) were more likely to have MBL-2 variant alleles ( P=0.01). We further explored MBL status with respect to disease progression. Only 1/10 long-term non-progressors (LTNPs) had an MBL-2 mutation (A/D) with a corresponding protein level of 611 ng/ml. Conclusions MBL deficiency was more frequent in patients with severe disease as assessed by CD4+ T-cell status. MBL-2 variants may be less frequent in children classified as LTNPs. MBL analysis could be useful in identifying children with slow disease progression and, consequently, may not require immediate antiretroviral treatement.

Host Genetic Impact on Infectious Diseases among Different Ethnic Groups

“…MBL‐2 promoter and MBL‐2 exon 1 genetic variations resulted in decreased protein levels and increased HIV susceptibility. [ 183 ] Polymorphisms in the promoter region are likely to affect gene transcription and disrupt the normal functioning of the gene, resulting in increased disease susceptibility. In addition, polymorphisms in the exon region that code for the protein would have the same effect.…”

MBL Deficiency as Risk of Infection and Autoimmunity

“…In search of the effect of MBL-2 polymorphisms on susceptibility and progression of HIV-1 infection in children, Dzwonek et al (2006) observed MBL deficiency more frequently in patients with severe disease. The study suggested that MBL-2 variants may be less frequent in children classified as long-term non-progressors (LTNPs) and hence MBL analysis can be useful in identifying children with slow disease progression and, consequently, may not require immediate antiretroviral treatment (Dzwonek et al 2006). Production of HIV in the presence of the mannosidase I inhibitor deoxymannojirimycin (dMM) significantly enhanced binding of HIV to MBL and increased MBL neutralization of an M-tropic HIV primary isolate.…”