16alpha-Bromo-epiandrosterone therapy modulates experimental feline immunodeficiency virus viremia: initial enhancement leading to long-term suppression.
16alpha-Bromo-epiandrosterone (epiBr), a synthetic derivative of the natural hormone dehyroepiandrosterone (DHEA), was evaluated for its effects on feline immunodeficiency virus (FIV) infection in experimental cats. The rationale for this study was based on the ability of DHEA to significantly reduce the mortality to viral infections in mice. DHEA and epiBr also have demonstrable in vitro anti-viral activity for both HIV-1 and FIV. Preliminary pharmacokinetic studies in cats demonstrated that subcutaneously injected epiBr was rapidly absorbed, completely metabolized, and nontoxic. Metabolites were excreted in both urine and feces, with the latter having the most complex pattern of breakdown products. Cats were then divided into four groups; two groups were infected with FIV and two uninfected. Two groups, one infected and one uninfected were treated on 5 consecutive days of weeks 0, 4, 8, 12 and 16 with epiBr. The remaining two groups were mock treated with the drug vehicle alone. Treatment started 1 week prior to infection and extended for 4 weeks after infection. Cats were observed for 20 weeks post-FIV infection. Infected cats had identical decreases in blood neutrophil and lymphocyte counts following, regardless of whether they were treated with epiBr or vehicle alone. The CD4/CD8 T-cell ratio was decreased following FIV exposure, but was significantly more decreased for the epiBr treated animals from week 2 post-infection onward. CD4+ T cells were decreased in FIV-infected cats treated with epiBr compared to their untreated cohort, while CD8+ T cells tended to be higher in treated animals. FIV infected cats that were treated with epiBr had over one-log higher virus loads at week 2 post-infection than non-epiBr treated cohorts. In spite of this enhanced initial viremia, the subsequent levels of virus in the blood were significantly lower in epiBr treated versus untreated animals. EpiBr treated cats had significantly higher FIV-p24 antibody responses than control cats receiving vehicle alone, although primary and secondary antibody responses to a T-cell dependent non-FIV antigen, keyhole limpet hemocyanin (KLH), were unaffected. EpiBr treatment significantly decreased the expected FIV-induced suppression of IL-12 p40 mRNA levels in peripheral blood mononuclear cells (PBMCs) observed at weeks 4, 5, 8, 9 and 16 post-infection, but had no influence on FIV-induced changes in IL-4, IL-6, IL-10, IFN-gamma, MIP-1alpha and RANTES.
Pedersen
Niels C
NC
Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. ncpedersen@ucdavis.edu
North
Thomas W
TW
Rigg
Richard
R
Reading
Chris
C
Higgins
Joanne
J
Leutenegger
Christian
C
Henderson
Gary L
GL
D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000652:urine; D000738:Androsterone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000652:urine; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000097:blood; D016516:CD4-CD8 Ratio / Q000662:veterinary; D002415:Cats; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay / Q000662:veterinary; D005243:Feces / Q000737:chemistry; D016181:Feline Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016089:Immunodeficiency Virus, Feline / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008297:Male; D016133:Polymerase Chain Reaction / Q000662:veterinary; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014766:Viremia / Q000188:drug therapy / Q000276:immunology / Q000662:veterinary
D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D016207:Cytokines; D012333:RNA, Messenger; C032020:16-bromoepiandrosterone; D007371:Interferon-gamma; D000738:Androsterone