Independent effects of genetic variations in mannose-binding lectin influence the course of HIV disease: the advantage of heterozygosity for coding mutations.

Abstract

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. 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. 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. 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.