title: Expansion of monocytic myeloid-derived suppressor cells dampens T cell function in HIV-1-seropositive individuals.
abstract: T lymphocyte dysfunction contributes to human immunodeficiency virus type 1 (HIV-1) disease progression by impairing antivirus cellular immunity. However, the mechanisms of HIV-1 infection-mediated T cell dysfunction are not completely understood. Here, we provide evidence that expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) suppressed T cell function in HIV-1-infected individuals. We observed a dramatic elevation of M-MDSCs (HLA-DR(-/low) CD11b(+) CD33(+/high) CD14(+) CD15(-) cells) in the peripheral blood of HIV-1-seropositive subjects (n = 61) compared with healthy controls (n = 51), despite efficacious antiretroviral therapy for nearly 2 years. The elevated M-MDSC frequency in HIV-1(+) subjects correlated with prognostic HIV-1 disease markers, including the HIV-1 load (r = 0.5957; P < 0.0001), CD4(+) T cell loss (r = -0.5312; P < 0.0001), and activated T cells (r = 0.4421; P = 0.0004). Functional studies showed that M-MDSCs from HIV-1(+) subjects suppressed T cell responses in both HIV-1-specific and antigen-nonspecific manners; this effect was dependent on the induction of arginase 1 and required direct cell-cell contact. Further investigations revealed that direct HIV-1 infection or culture with HIV-1-derived Tat protein significantly enhanced human MDSC generation in vitro, and MDSCs from healthy donors could be directly infected by HIV-1 to facilitate HIV-1 replication and transmission, indicating that a positive-feedback loop between HIV-1 infection and MDSC expansion existed. In summary, our studies revealed a novel mechanism of T cell dysfunction in HIV-1-infected individuals and suggested that targeting MDSCs may be a promising strategy for HIV-1 immunotherapy.
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Qin
authors.forename: Weiping
authors.initials: W
authors.lastname: Cai
authors.forename: Ting
authors.initials: T
authors.lastname: Pan
authors.forename: Kang
authors.initials: K
authors.lastname: Wu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.forename: Nina
authors.initials: N
authors.lastname: Wang
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Liu
authors.forename: Dehong
authors.initials: D
authors.lastname: Yan
authors.forename: Fengyu
authors.initials: F
authors.lastname: Hu
authors.forename: Pengle
authors.initials: P
authors.lastname: Guo
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Tang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D001119:Arginase / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006680:HLA Antigens / Q000032:analysis; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D006680:HLA Antigens; C574619:ARG1 protein, human; D001119:Arginase