In:
Journal of Virology, American Society for Microbiology, Vol. 87, No. 3 ( 2013-02), p. 1477-1490
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.
Type of Medium:
Online Resource
ISSN:
0022-538X
,
1098-5514
DOI:
10.1128/JVI.01759-12
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2013
detail.hit.zdb_id:
1495529-5
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