title: Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir.
abstract: Raltegravir is a recently, Food and Drug Administration-approved, small-molecule drug that inhibits retroviral integrase, thereby preventing HIV DNA from inserting itself into the human genome. We report here that the activity profile of raltegravir on the replication of murine leukemia virus is similar to that for HIV, and that the drug specifically affects autoimmune disease in mice, in which endogenous retroelements are suspected to play a role. While NZW and BALB/c mice, which do not succumb to autoimmune disease, are not affected by raltegravir, lupus-prone (NZBxNZW) F(1) mice die of glomerulonephritis more than a month earlier than untreated mice. Raltegravir-treated NZB mice, which share the H-2 haplotype with BALB/c mice, but which are predisposed to autoimmune hemolytic anemia, develop auto-antibodies to their red blood cells >3 months earlier than untreated mice of the same strain. Because nonautoimmune mice are not affected by raltegravir, we consider off-target effects unlikely and attribute the exacerbation of autoimmunity to the inhibition of retroviral integrase.
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, CA 94143-0414, USA.
authors.forename: Gabriele B
authors.initials: GB
authors.lastname: Beck-Engeser
authors.forename: Dan
authors.initials: D
authors.lastname: Eilat
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrer
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Jäck
authors.forename: Matthias
authors.initials: M
authors.lastname: Wabl
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000150:complications; D001483:Base Sequence; D004270:DNA, Circular / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004198:Disease Susceptibility / Q000150:complications; D005090:Exodeoxyribonucleases / Q000378:metabolism; D005260:Female; D019428:HIV Integrase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced / Q000150:complications; D009052:Leukemia Virus, Murine / Q000187:drug effects / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000150:complications; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism; D011760:Pyrrolidinones / Q000009:adverse effects* / Q000494:pharmacology; D000068898:Raltegravir Potassium; D017384:Sequence Deletion; D020079:Terminal Repeat Sequences / Q000235:genetics; D013997:Time Factors; D014759:Viral Envelope Proteins / Q000737:chemistry; D016662:Virus Integration / Q000187:drug effects
chemical_list: D004270:DNA, Circular; D018076:DNA, Complementary; D019428:HIV Integrase Inhibitors; D010750:Phosphoproteins; D011760:Pyrrolidinones; D014759:Viral Envelope Proteins; D000068898:Raltegravir Potassium; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1