PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention

DE Kaufmann, BD Walker - The Journal of Immunology, 2009 - journals.aai.org
The Journal of Immunology, 2009journals.aai.org
The balance between proinflammatory mechanisms and the dampening of excessive
immune activation is critical for successful clearance of a pathogen without harm to the host.
In particular, molecules of the B7: CD28 family play a critical role in regulating T cell
activation and peripheral tolerance. Chronic pathogens like HIV, which is characterized by
ongoing viral replication despite detectable virus-specific T cell responses, and cancer cells
have exploited these pathways to attenuate Ag-specific T cell immunity. This review …
Abstract
The balance between proinflammatory mechanisms and the dampening of excessive immune activation is critical for successful clearance of a pathogen without harm to the host. In particular, molecules of the B7:CD28 family play a critical role in regulating T cell activation and peripheral tolerance. Chronic pathogens like HIV, which is characterized by ongoing viral replication despite detectable virus-specific T cell responses, and cancer cells have exploited these pathways to attenuate Ag-specific T cell immunity. This review summarizes evidence that molecules of the B7:CD28 family, PD-1, CTLA-4, and their ligands, play an active and reversible role in virus-specific T cell exhaustion associated with HIV infection in humans and in the SIV model in macaques. We discuss the potential for immunotherapeutic interventions based on manipulation of these inhibitory networks, the promising data obtained with blockade of the PD-1 pathway in animal models, and the challenges to such therapies.
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