Natural host genetic resistance to lentiviral CNS disease: a neuroprotective MHC class I allele in SIV-infected macaques.
Human immunodeficiency virus (HIV) infection frequently causes neurologic disease even with anti-retroviral treatment. Although associations between MHC class I alleles and acquired immunodeficiency syndrome (AIDS) have been reported, the role MHC class I alleles play in restricting development of HIV-induced organ-specific diseases, including neurologic disease, has not been characterized. This study examined the relationship between expression of the MHC class I allele Mane-A*10 and development of lentiviral-induced central nervous system (CNS) disease using a well-characterized simian immunodeficiency (SIV)/pigtailed macaque model. The risk of developing CNS disease (SIV encephalitis) was 2.5 times higher for animals that did not express the MHC class I allele Mane-A*10 (P = 0.002; RR = 2.5). Animals expressing the Mane-A*10 allele had significantly lower amounts of activated macrophages, SIV RNA, and neuronal dysfunction in the CNS than Mane-A*10 negative animals (P<0.001). Mane-A*10 positive animals with the highest CNS viral burdens contained SIV gag escape mutants at the Mane-A*10-restricted KP9 epitope in the CNS whereas wild type KP9 sequences dominated in the brain of Mane-A*10 negative animals with comparable CNS viral burdens. These concordant findings demonstrate that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease.
Mankowski
Joseph L
JL
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. jmankows@jhmi.edu
Queen
Suzanne E
SE
Fernandez
Caroline S
CS
Tarwater
Patrick M
PM
Karper
Jami M
JM
Adams
Robert J
RJ
Kent
Stephen J
SJ
D000483:Alleles; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002494:Central Nervous System Infections / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000662:veterinary; D015331:Cohort Studies; D019610:Cytoprotection / Q000235:genetics; D005805:Genes, MHC Class I; D007113:Immunity, Innate / Q000235:genetics*; D016180:Lentivirus Infections / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology*; D008254:Macaca nemestrina / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length / Q000502:physiology; D012189:Retrospective Studies; D016097:Simian Acquired Immunodeficiency Syndrome / Q000134:cerebrospinal fluid / Q000150:complications / Q000235:genetics* / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D019562:Viral Load
D016564:Amyloid beta-Protein Precursor