HIV-1 infection inhibits cytokine production in human thymic macrophages.
OBJECTIVE
The thymus serves as a critical site of T-lymphocyte ontogeny and selection. Thymic infection by HIV-1 is known to disrupt thymocyte maturation by both direct and indirect means; however, the mechanism behind these effects remains poorly defined. Macrophages represent one of the most important peripheral targets of HIV-1 infection, are resident in the thymic stroma, and play a central role in thymocyte maturation.


METHODS
Studies presented here define three primary features and outcomes of thymic macrophages (TM) and HIV-1 infection: (1) The distinctive TM phenotype (surface markers and cytokine production measured by immunofluorescence, fluorescence-activated cell sorting, and reverse transcriptase polymerase chain reaction) relative to macrophages from other sources (blood [monocyte-derived macrophages] and bone marrow); (2) infection of TM by different HIV-1 subtypes (X4, R5, and X4/R5) measured by enzyme-linked immunosorbent assay and polymerase chain reaction; and (3) consequences of HIV-1 infection on cytokine production by TM measured by reverse transcriptase polymerase chain reaction.


RESULTS
The results demonstrate that TM display a distinctive phenotype of HIV-1 receptors (CD4(lo), CXCR4(lo), CCR5(med), CCR3(hi)), chemokine production (macrophage inflammatory protein-1α(+); regulated on activation, normal T expressed and secreted(+); macrophage inflammatory protein-1b(-); stromal cell-derived factor -1(-)); and cytokine production (tumor necrosis factor-α(+), interleukin-8(+), macrophage colony-stimulating factor(+), interleukin-6(-)) relative to either monocyte-derived macrophages or bone marrow. TM were infected in vitro with R5 and X4/R5-tropic HIV-1 subtypes, and developed syncytia formation during long-term X4/R5 culture. In contrast, TM supported only transient replication of X4-tropic HIV-1. Lastly, infection of TM with HIV-1 abolished the production of all cytokines tested in long-term in vitro cultures.


CONCLUSIONS
Taken together, these results indicate that TM are a potential direct target of in situ HIV-1 infection, and that this infection may result in the disruption of macrophage functions that govern normal thymocyte maturation.
Rozmyslowicz
Tomasz
T
Department of Pathology and Laboratory Medicine, University of Pennsylvania, School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA. rozmyslo@mail.med.upenn.edu
Murphy
Samuel L
SL
Conover
Dareus O
DO
Gaulton
Glen N
GN
D016207:Cytokines / Q000096:biosynthesis*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D013950:Thymus Gland / Q000276:immunology*
D016207:Cytokines
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