HIV-1 infection is characterized by profound depletion of CD161+ Th17 cells and gradual decline in regulatory T cells.
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 (CD3CD4CD25FoxP3 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).


CONCLUSIONS
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.
Prendergast
Andrew
A
Department of Paediatrics, University of Oxford, South Parks Road, Oxford, UK. andrew.prendergast@paediatrics.ox.ac.uk
Prado
Julia G
JG
Kang
Yu-Hoi
YH
Chen
Fabian
F
Riddell
Lynn A
LA
Luzzi
Graz
G
Goulder
Philip
P
Klenerman
Paul
P
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018450:Disease Progression; D005753:Gastric Mucosa / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism