Plasma factors during chronic HIV-1 infection impair IL-12 secretion by myeloid dendritic cells via a virus-independent pathway.
OBJECTIVE
Myeloid dendritic cell (mDC) dysfunction during HIV infection may hinder the formation of both innate and adaptive immune responses and contribute to pathogenesis. Our objective was to determine whether circulating factors during chronic HIV infection impair mDC function with respect to secretion of IL-12, a pro-Th1 cytokine, and T-cell stimulatory capacity. Particular focus was placed on the effect of combination antiretroviral therapy (cART) and the role of HIV itself on mDC function.


METHODS
Monocyte-derived DC (moDC) from uninfected donors were exposed to plasma from HIV-infected individuals before Toll-like receptor (TLR) stimulation. Cytokine secretion was measured via cytokine bead arrays, and T-cell proliferation and IFNγ secretion was evaluated after coculture with naive CD4 T cells. Expression of genes central to TLR-mediated signal transduction was analyzed via quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) arrays and western blot.


RESULTS
Exposure of monocyte-derived DC to plasma from untreated HIV-infected donors suppressed secretion of IL-12, and impaired Th1-skewing of CD4 T cells. The suppressive effect was less by plasma donors receiving cART. Removal of virus from plasma did not relieve suppression nor was IL-12 secretion decreased on addition of HIV to control plasma. On a transcriptional level, decreased expression of IKKβ, a key regulator in the TLR/NF-kappaB signaling pathway, corresponded to suppressed cytokine secretion.


CONCLUSIONS
Plasma factors during chronic HIV infection impair mDC function in a manner that likely impacts the formation of immune responses to HIV, opportunistic pathogens, and vaccines. Despite partial alleviation by cART, this suppression was not directly mediated by HIV.
Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
Elizabeth A
EA
Miller
Meredith R
MR
Spadaccia
Meagan P
MP
OʼBrien
Linda
L
Rolnitzky
Rachel
R
Sabado
Olivier
O
Manches
Davor
D
Frleta
Nina
N
Bhardwaj
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018920:Coculture Techniques; D003430:Cross-Sectional Studies; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics; D007108:Immune Tolerance; D018664:Interleukin-12 / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology; D019562:Viral Load / Q000276:immunology; D055815:Young Adult
D018664:Interleukin-12; D051550:I-kappa B Kinase