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Circulating Monocytes in HIV-1-Infected Viremic Subjects Exhibit an Antiapoptosis Gene Signature and Virus- and Host-Mediated Apoptosis Resistance¹

Malavika S. Giri^*, Michael Nebozyhn^*, Andrea Raymond^*, Bethsebah Gekonge^*, Aidan Hancock^*, Shenoa Creer^*, Calen Nicols^*, Malik Yousef^*, Andrea S. Foulkes, Karam Mounzer, Jane Shull, Guido Silvestri, Jay Kostman, Ronald G. Collman^¶, Louise Showe^* and Luis J. Montaner^2,*

^* The Wistar Institute, Philadelphia, PA 19104; School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003; Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, PA 19104; Hospital of the University of Pennsylvania, Philadelphia, PA 19104; and ^¶ Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grant AI047760, the Philadelphia Foundation, and Wistar funds from the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health.

² Address correspondence and reprint requests to Dr. Luis J. Montaner, HIV-1 Immunopathogenesis Laboratory, Room 480, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104-4268. E-mail address: montaner{at}wistar.org

³ Abbreviations used in this paper: M/M, monocyte/macrophage; AFC, absolute fold change; C, control subject sample; MDM, monocyte-derived macrophages; P, HIV-1 patient subject sample; 7-AAD, 7-aminoactinomycin D.

⁴ The online version of this article contains supplemental material.