Circulating monocytes in HIV-1-infected viremic subjects exhibit an antiapoptosis gene signature and virus- and host-mediated apoptosis resistance.
Mechanisms that may allow circulating monocytes to persist as CD4 T cells diminish in HIV-1 infection have not been investigated. We have characterized steady-state gene expression signatures in circulating monocytes from HIV-infected subjects and have identified a stable antiapoptosis gene signature comprised of 38 genes associated with p53, CD40L, TNF, and MAPK signaling networks. The significance of this gene signature is indicated by our demonstration of cadmium chloride- or Fas ligand-induced apoptosis resistance in circulating monocytes in contrast to increasing apoptosis in CD4 T cells from the same infected subjects. As potential mechanisms in vivo, we show that monocyte CCR5 binding by HIV-1 virus or agonist chemokines serves as independent viral and host modulators resulting in increased monocyte apoptosis resistance in vitro. We also show evidence for concordance between circulating monocyte apoptosis-related gene expression in HIV-1 infection in vivo and available datasets following viral infection or envelope exposure in monocyte-derived macrophages in vitro. The identification of in vivo gene expression associated with monocyte resistance to apoptosis is of relevance to AIDS pathogenesis since it would contribute to: 1) maintaining viability of infection targets and long-term reservoirs of HIV-1 infection in the monocyte/macrophage populations, and 2) protecting a cell subset critical to host survival despite sustained high viral replication.
Giri
Malavika S
MS
The Wistar Institute, Philadelphia, PA 19104, USA.
Nebozyhn
Michael
M
Raymond
Andrea
A
Gekonge
Bethsebah
B
Hancock
Aidan
A
Creer
Shenoa
S
Nicols
Calen
C
Yousef
Malik
M
Foulkes
Andrea S
AS
Mounzer
Karam
K
Shull
Jane
J
Silvestri
Guido
G
Kostman
Jay
J
Collman
Ronald G
RG
Showe
Louise
L
Montaner
Luis J
LJ
D000328:Adult; D017209:Apoptosis / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D023201:CD40 Ligand / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D016000:Cluster Analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D020411:Oligonucleotide Array Sequence Analysis; D019713:Receptors, CCR5 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014766:Viremia / Q000235:genetics / Q000276:immunology
D019713:Receptors, CCR5; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D023201:CD40 Ligand; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3