PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors.
The immunoreceptor PD-1 is significantly up-regulated on exhausted CD8+ T cells during chronic viral infections such as HIV-1. However, it remains unknown whether PD-1 expression on CD8+ T cells differs between typical progressors (TPs) and long-term nonprogressors (LTNPs). In this report, we examined PD-1 expression on HIV-specific CD8+ T cells from 63 adults with chronic HIV infection. We found that LTNPs exhibited functional HIV-specific memory CD8+ T cells with markedly lower PD-1 expression. TPs, in contrast, showed significantly up-regulated PD-1 expression that was closely correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load. Importantly, PD-1 up-regulation was also associated with reduced perforin and IFN-gamma production, as well as decreased HIV-specific effector memory CD8+ T-cell proliferation in TPs but not LTNPs. Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8+ T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 up-regulation mediates HIV-specific CD8+ T-cell exhaustion. Blocking the PD-1/PD-L1 pathway may represent a new therapeutic option for this disease and provide more insight into immune pathogenesis in LTNPs.
Zhang
Ji-Yuan
JY
Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Zhang
Zheng
Z
Wang
Xicheng
X
Fu
Jun-Liang
JL
Yao
Jinxia
J
Jiao
Yanmei
Y
Chen
Liangen
L
Zhang
Hui
H
Wei
Jianan
J
Jin
Lei
L
Shi
Ming
M
Gao
George Fu
GF
Wu
Hao
H
Wang
Fu-Sheng
FS
D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis* / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000097:blood*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic / Q000737:chemistry; D015854:Up-Regulation
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D007371:Interferon-gamma