Inhibitory TCR coreceptor PD-1 is a sensitive indicator of low-level replication of SIV and HIV-1.
Ongoing antigenic stimulation appears to be an important prerequisite for the persistent expression of programmed death 1 (PD-1), an inhibitory TCR coreceptor of the CD28 family. Although recent publications have emphasized the utility of PD-1 as a marker for dysfunctional T cells in chronic viral infections, its dependence on antigenic stimulation potentially renders it a sensitive indicator of low-level viral replication. To explore the antigenic threshold for the maintenance of PD-1 expression on virus-specific T cells, we compared PD-1 expression on virus-specific and memory T cell populations in controlled and uncontrolled SIV and HIV-1 infection. In both controlled live attenuated SIV infection in rhesus macaques and HIV-1 infection in elite controllers, elevated levels of PD-1 expression were observed on SIV- and HIV-1-specific CD8(+) T cells. However, in contrast to chronic wild-type SIV infection and uncontrolled HIV-1 infection, controlled SIV/HIV-1 infection did not result in increased expression of PD-1 on total memory T cells. PD-1 expression on SIV-specific CD8(+) T cells rapidly decreased after the emergence of CTL escape in cognate epitopes, but was maintained in the setting of low or undetectable levels of plasma viremia in live attenuated SIV-infected macaques. After inoculation of naive macaques with a single-cycle SIV, PD-1 expression on SIV-specific CD8(+) T cells initially increased, but was rapidly downregulated. These results demonstrate that PD-1 can serve as a sensitive indicator of persistent, low-level virus replication and that generalized PD-1 expression on T lymphocytes is a distinguishing characteristic of uncontrolled lentiviral infections.
Salisch
Nadine C
NC
Division of Immunology, Harvard Medical School, New England Primate Research Center, Southborough, MA 01772, USA.
Kaufmann
Daniel E
DE
Awad
Amany S
AS
Reeves
R Keith
RK
Tighe
Daniel P
DP
Li
Yuan
Y
Piatak
Michael
M
Lifson
Jeffrey D
JD
Evans
David T
DT
Pereyra
Florencia
F
Freeman
Gordon J
GJ
Johnson
R Paul
RP
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000276:immunology; D015415:Biomarkers / Q000032:analysis*; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008253:Macaca mulatta; D061026:Programmed Cell Death 1 Receptor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000378:metabolism; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014766:Viremia; D014779:Virus Replication / Q000276:immunology*
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor