The central challenge in AIDS research is that virus infection persists and disease progresses, despite often vigorous host immune responses. Despite the acute phase of the infection, virus replication is countered by the onset of MHC-restricted CTL and virus-specific antibody responses. Several recent publications (on herpes-, flavi-, and retroviruses) suggest that Fas ligand positive (FasL+), CD4+ T cells are elicited during infection and suppress virus-specific immune responses. Our studies in the SIV/rhesus macaque model for AIDS implicate FasL-mediated cell death as a possible accelerator of disease progression in AIDS. We showed: i) uninfected animals contain FasL+. CD4+ cells capable of lysing targets expressing SIVenv in an MHC-unrestricted manner, lytic activity are stable in individual macaques, and iv) high levels of baseline MHC-unrestricted lytic activity are correlated with rapid disease progression after SIV infection (Yin et al, J Virol. 1999). Here we propose to test the hypothesis that FasL+, CD4+ effectors counteract virus-specific host immunity and promote disease progression. Disease progression is well-defined in the SIV/macaque model in terms of virus loads, antibody levels and the rate of CD4+ cell loss. We will perform a direct test of the role of FasL in disease progression by treating macaques with an antibody that binds FasL and has been shown to block MHC-unrestricted lysis in vitro. Based on preliminary data, treatment with anti-FasL reduces viral burden during acute SIV infection, raises serum antibody to SIV antigens, and gives a degree of protection that is comparable or better than reductions in virus burden observed after vaccination. We are exploring the efficacy and mechanism of action for anti-FasL as a contribution of virus-induced FasL-mediated apoptosis to the destruction of host immune responses and to the progression of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046244-03
Application #
6349916
Study Section
Special Emphasis Panel (ZRG1-AARR-2 (01))
Program Officer
Wassef, Nabila M
Project Start
2000-02-01
Project End
2003-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
3
Fiscal Year
2001
Total Cost
$294,942
Indirect Cost
Name
University of MD Biotechnology Institute
Department
Type
Organized Research Units
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21202
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