Modulation of susceptibility to HIV-1 infection by the cytotoxic T lymphocyte antigen 4 costimulatory molecule.
CD4 T cells activated in vitro by anti-CD3/28-coated beads are resistant to infection by CC chemokine receptor 5 (CCR5)-dependent HIV-1 isolates. In vivo, antigen-presenting cells (APCs) activate CD4 T cells in part by signaling through the T cell receptor and CD28, yet cells stimulated in this manner are susceptible to HIV-1 infection. We show that cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement counteracts the CD28 antiviral effects, and that the ratio of CTLA-4 to CD28 engagement determines the susceptibility of HIV-1 infection. Furthermore, unopposed CTLA-4 signaling provided by CD28 blockade promotes vigorous HIV-1 replication, despite minimal T cell proliferation. Finally, CTLA-4 antibodies decrease the susceptibility of antigen-activated CD4 T cells to HIV, suggesting a potential approach to prevent or limit viral spread in HIV-1-infected individuals.
Riley
J L
JL
Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia 19104, USA.
Schlienger
K
K
Blair
P J
PJ
Carreno
B
B
Craighead
N
N
Kim
D
D
Carroll
R G
RG
June
C H
CH
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D006801:Humans; D018796:Immunoconjugates; D010835:Phytohemagglutinins / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000821:virology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019742:Chemokines, CC; D018796:Immunoconjugates; D010835:Phytohemagglutinins; D019713:Receptors, CCR5; D000069594:Abatacept