Attenuated disease in SIV-infected macaques treated with a monoclonal antibody against FasL.
Acute SIVmac infection in macaques is accompanied by high levels of plasma viremia that decline with the appearance of viral immunity and is a model for acute HIV disease in man. Despite specific immune responses, the virus establishes a chronic, persistent infection. The destruction of CD4+ and CD4- lymphocyte subsets in macaques contributes to viral persistence and suggests the importance of mechanisms for depleting both infected and uninfected (bystander) cells. Bystander cell killing can occur when FasL binds the Fas receptor on activated lymphocytes, which include T and B cell subpopulations that are responding to the infection. Destruction of specific immune cells could be an important mechanism for blunting viral immunity and establishing persistent infection with chronic disease. We inhibited the Fas pathway in vivo with a monoclonal antibody against FasL (RNOK203). Here we show that treatment with anti-FasL reduced cell death in circulating T and B cells, increased CTL and antibody responses to viral proteins, and lowered the setpoint viremia. By blocking FasL during only the first few weeks after infection, we attenuated SIVmac disease and increased the life span for infected and treated macaques.
Salvato
Maria S
MS
Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, MD 21201, USA.
Yin
C Cameron
CC
Yagita
Hideo
H
Maeda
Toshihiro
T
Okumura
Ko
K
Tikhonov
Ilia
I
Pauza
C David
CD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000821:virology; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D053222:Fas Ligand Protein / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D006801:Humans; D008251:Macaca; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D014764:Viral Proteins / Q000276:immunology; D014766:Viremia / Q000188:drug therapy
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D053222:Fas Ligand Protein; D014764:Viral Proteins