Activated dendritic cells and monocytes in HIV immunological nonresponders: HIV-induced interferon-inducible protein-10 correlates with low future CD4+ recovery

Abstract

Objective: To explore monocyte and dendritic cell immune responses, and their association with future CD4+ gain in treated HIV patients with suboptimal CD4+ recovery. Design: A cross-sectional study of HIV-infected, virally suppressed individuals on antiretroviral therapy for at least 24 months; 41 immunological nonresponders (INRs) (CD4+ cell count <400 cells/μl) and 26 immunological responders (CD4+ cell count >600 cells/μl). Ten HIV-infected antiretroviral therapy-naive and 10 HIV-negative healthy persons served as controls. CD4+ cell counts were registered after median 2.4 and 4.7 years. Methods: Monocyte, dendritic-cell and T-cell activation and regulatory T cells (Tregs) were analyzed by flow cytometry. In INR and immunological responder subgroups matched on age and nadir CD4+ cell count, upregulation of interferon-inducible protein-10 (IP-10) and indoleamine 2,3-dioxygenase in monocytes and dendritic cells and cytokines in cell supernatants were measured in vitro in peripheral blood mononuclear cells stimulated with aldrithiol-2-inactivated HIV-1. Results: The INR group displayed higher spontaneous activation of both monocytes (HLA-DR+) and myeloid and plasmacytoid dendritic cells (HLA-DR+, CD83+ and CD86+) compared with immunological responders, and this was associated with increased T-cell activation (CD38+HLA-DR+), an effector memory T-cell phenotype and activated Tregs. The IP-10 response in monocytes after in-vitro HIV stimulation was negatively associated with prospective CD4+ gain. IP-10, indoleamine 2,3-dioxygenase and cytokines levels were comparable between the groups, but inversely correlated with activated Tregs in INRs. Conclusion: HIV-infected individuals with suboptimal immune recovery demonstrated more activated monocytes and in particular dendritic cells, compared with patients with acceptable CD4+ gain. A high level of HIV-specific IP-10 expression in monocytes may be predictive of future CD4+ recovery.