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: Aiping Qin, Weiping Cai, Ting Pan, Kang Wu, Qiong Yang, Nina Wang, Yufeng Liu, Dehong Yan, Fengyu Hu, Pengle Guo, Xiaoping Chen, Ling Chen, Hui Zhang, Xiaoping Tang, Jie Zhou
• Journal: Journal of virology (J Virol) Vol. 87 Issue 3 Pg. 1477-90 (Feb 2013) ISSN: 1098-5514 [Electronic] United States
• PMID: 23152536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• HLA Antigens
• ARG1 protein, human
• Arginase

Topics

• Adolescent
• Adult
• Antigens, CD (analysis)
• Arginase (metabolism)
• Cells, Cultured
• Female
• HIV Infections (immunology, pathology, virology)
• HIV-1 (immunology)
• HLA Antigens (analysis)
• Humans
• Immune Tolerance
• Immunophenotyping
• Male
• Middle Aged
• Monocytes (immunology)
• T-Lymphocytes (immunology)
• Young Adult