Independent Effects of Genetic Variations in Mannose-Binding Lectin Influence the Course of HIV Disease: The Advantage of Heterozygosity for Coding Mutations

• Published in: The Journal of Infectious Diseases Vol. 198; no. 1; pp. 72 - 80
• Main Authors: Catano, Gabriel, Agan, Brian K., Kulkarni, Hemant, Telles, Vanessa, Marconi, Vincent C., Dolan, Matthew J., Ahuja, Sunil K.
• Format: Journal Article
• Language: English
• Published: Chicago, IL The University Chicago Press 01.07.2008; University of Chicago Press
• Subjects: Adult; AIDS; Alleles; Biological and medical sciences; Cohort Studies; Disease progression; Fundamental and applied biological sciences. Psychology; Genetic Predisposition to Disease; Genotype; Genotypes; Haplotypes; Heterozygote; HIV; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - metabolism; HIV-1; HIV/AIDS; Human immunodeficiency virus 1; Human viral diseases; Humans; Infectious diseases; Lectins; Mannose-Binding Lectin - genetics; Mannose-Binding Lectin - immunology; Mannose-Binding Lectin - metabolism; Medical genetics; Medical sciences; Microbiology; Mutation; Pathogenesis; Polymorphism, Genetic; Promoter Regions, Genetic - genetics; Skin tests; T lymphocytes; Time Factors; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Infection; Immunopathology; Lectin; Microbiology; Viral disease; Genetics; AIDS; Mannose; Mutation; Immune deficiency
• ISSN: 0022-1899; 1537-6613; 1537-6591; 1537-6613
• DOI: 10.1086/588712

Background. The in vivo impact of mannose-binding lectin (MBL), a molecule involved in innate immunity, on the pathogenesis of human immunodeficiency virus (HIV)–1 infection and AIDS is unknown. Methods. A total of 1102 HIV-positive and 2213 HIV-negative adult subjects were screened for polymorphisms in the coding and promoter regions of MBL2, the gene that encodes MBL. Results. Variations in MBL2 did not influence the risk of acquiring HIV-1. Heterozygosity for coding mutations (O allele) and homozygosity for the −221 promoter polymorphism (X allele) in MBL2 were associated with a delay in and an accelerated rate of disease progression, respectively. MBL2 variations influenced the rate of progression to AIDS-defining illnesses. In a multivariate model, the effects of MBL2 variations were independent of several parameters known to influence disease progression, including steady-state viral load, baseline CD4+ T cell counts, and delayed-type hypersensitivity skin test responses, an in vivo marker of cell-mediated immunity. The effects of MBL2 variations were most evident in those who possessed protective genotypes of CCR5 and a high copy number of CCL3L1, the most potent HIV-suppressive CCR5 ligand. Conclusions. MBL2 genotypes are independent determinants of HIV disease progression and heterozygosity for MBL2 coding mutations confer disease-retarding effects. MBL-dependent immune responses may play a role in the pathogenesis of HIV infection.