TY - JOUR
T1 - Independent effects of genetic variations in mannose-binding lectin influence the course of HIV disease
T2 - The advantage of heterozygosity for coding mutations
AU - Catano, Gabriel
AU - Agan, Brian K.
AU - Kulkarni, Hemant
AU - Telles, Vanessa
AU - Marconi, Vincent C.
AU - Dolan, Matthew J.
AU - Ahuja, Sunil K.
N1 - Funding Information:
Financial support: Veterans Administration Center on AIDS and HIV Infection, South Texas Veterans Health Care System (to S.K.A.); National Institutes of Health (MERIT award R37046326 and awards AI043279 and MH069270 to S.K.A); Infectious Disease Clinical Research Program, Tri-Service AIDS Clinical Consortium, Uniformed Services University of the Health Sciences in collaboration with HHS/ NIH/NIAID/DCR (Interagency Agreement HU0001-05-2-0011). S.K.A. is a recipient of the Elizabeth Glaser Scientist Award and the Burroughs Wellcome Clinical Scientist Award in Translational Research.
PY - 2008/7/1
Y1 - 2008/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=46349101377&partnerID=8YFLogxK
U2 - 10.1086/588712
DO - 10.1086/588712
M3 - Article
C2 - 18498240
AN - SCOPUS:46349101377
SN - 0022-1899
VL - 198
SP - 72
EP - 80
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 1
ER -