Objective: CD4+ T-cell depletion is central to HIV pathogenesis. However, the relative impact of HIV on Th17 and regulatory T cell (Treg) subsets remains unclear. CD161+ CD4 cells are a recently identified, gut-homing Th17 precursor population. The balance between pro-inflammatory Th17 and immunoregulatory Tregs may be critical in HIV pathogenesis. This study addressed changes in CD161+, Th17 and Treg subsets during untreated HIV infection.
Methods: Peripheral blood mononuclear cells were isolated from HIV-infected and HIV-uninfected individuals and stained to characterize CD161+ CD4 cells, Th17 cells [by elaboration of interleukin (IL)-17A], Tregs (CD3+CD4+CD25hiFoxP3+ cells) and CD8 activation (CD38+/HLA-DR+ cells). In-vitro infectability of CD161+ and Th17 cells by HIV was assessed in healthy donor CD4 cells by intracellular p24 expression.
Results: Peripheral blood Th17 cells were depleted 10-fold in HIV-infected, compared to HIV-uninfected individuals (P < 0.0001) across a range of disease stages, accompanied by a significant reduction of CD161+ T cells (P = 0.024). Both Th17 cells and CD161+ CD4+ T cells were permissive to HIV replication in vitro. Profound loss of Th17 cells before the onset of advanced disease contrasted with a gradual decline in absolute Tregs during HIV disease progression in untreated individuals followed longitudinally (R = 0.71, P = 0.003). Loss of Tregs was associated with increased immune activation (R = −0.33, P = 0.03).
Conclusion: HIV-infected individuals showed profound loss of Th17 cells, which may impair mucosal immunity, and reduced CD161+ CD4 cells, which may limit Th17 reconstitution. A gradual decline in Tregs during disease progression was associated with increased immune activation.
aDepartment of Paediatrics, University of Oxford, UK
bBiomedical Research Centre, John Radcliffe Hospital, UK
cNuffield Department of Medicine, University of Oxford, Oxford, UK
dThe Florey Unit, Department of Genitourinary Medicine, Royal Berkshire NHS Foundation Trust, Reading, UK
eDepartment of Genitourinary Medicine, Northampton General Hospital, Northampton, UK
fDepartment of Genitourinary Medicine, Wycombe Hospital, High Wycombe, UK.
Received 1 June, 2009
Revised 11 September, 2009
Accepted 16 October, 2009
Correspondence to Dr Andrew Prendergast, Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, UK. Tel: +44 1865 271973; fax: +44 1865 281890; e-mail: firstname.lastname@example.org