title: PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors.
abstract: 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.
authors.affiliation: Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Ji-Yuan
authors.initials: JY
authors.lastname: Zhang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xicheng
authors.initials: X
authors.lastname: Wang
authors.forename: Jun-Liang
authors.initials: JL
authors.lastname: Fu
authors.forename: Jinxia
authors.initials: J
authors.lastname: Yao
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Jiao
authors.forename: Liangen
authors.initials: L
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Jianan
authors.initials: J
authors.lastname: Wei
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.forename: George Fu
authors.initials: GF
authors.lastname: Gao
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Fu-Sheng
authors.initials: FS
authors.lastname: Wang
mesh_terms: 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
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D007371:Interferon-gamma