Editors' ChoiceAIDS/HIV

Unveiling Neutrophil—T Cell Interactions in HIV Infection

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Science Translational Medicine  02 Apr 2014:
Vol. 6, Issue 230, pp. 230ec60
DOI: 10.1126/scitranslmed.3009042

HIV-infected patients with high viral titers tend to get opportunistic infections—a result of progressive loss of immune T cell function. Exactly how HIV infection disables T cell responses and innate immune cells is poorly understood. A key event associated with decrease of T cell effector function is the contact between the cell surface protein program death 1 (PD-1) on T cells and its ligand PD-L1 on phagocytes. PD-1 and its ligands have been shown to negatively regulate immune responses during viral and bacterial infection and in mouse models of lupus and arthritis. Their contributions to HIV infection are not clear, however.

Bowers et al. sought to elucidate the role of neutrophils in immune suppression to help explain HIV-1 pathogenesis. By using a variety of approaches, the authors zeroed in on molecular interactions responsible for the patients’ decreasing immune competence. They found that PD-L1 was more abundant on neutrophils from viremic patients, but that it decreased after the initiation of antiretroviral therapy. Also, neutrophil PD-L1 levels correlated with those of PD-1 on CD8+ and CD4+ T cells and of CD57 on CD4+ T cells, all of which also decrease with therapy. One cause of the high levels of PD-L1 seemed to be that inactivated HIV-1 virions and a TLR-7/8 ligand directly up-regulated neutrophil PD-L1. A particular population of CD15+ neutrophils was found to be instrumental in the immune suppression and a cause of decreased cytokine production by T cells; their removal reversed the suppression and increased cytokines.

The mechanism of immune suppression mediated by neutrophils and the PD-L1/PD-1 pathway presented in this study greatly enhances our understanding of T cell exhaustion in HIV-1 infection. These results highlight the possibility of targeting immunosuppressive pathways such as PD-L1/PD-1 in future therapeutic approaches to HIV-1–infected patients to improve immune competence.

N. L. Bowers et al., Immune suppression by neutrophils in HIV-1 infection: Role of PD-L1/PD-1 pathway. PLOS Pathog. 10, e1003993 (2014). [Full Text]

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