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

Abstract

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.

Transcriptomic Analysis of Peripheral Blood Mononuclear Cells in Rapid Progressors in Early HIV Infection Identifies a Signature Closely Correlated with Disease Progression

“…Besides reshaping the expression of protein-coding genes, transcriptional reprogramming during HIV infection also alters microRNA (miRNA) expression profiles (10 ). Interferonstimulated genes, genes controlling T-cell differentiation, cell cycle, and apoptosis, as well as several miRNA signatures, have been shown to contribute to the distinct clinical outcomes of HIV infection (11)(12)(13)(14)(15)(16). However, the pattern of the transcriptomic profile associated with HIV disease progression remains largely elusive and the miRNA profiles of peripheral blood mononuclear cells (PBMCs) from RPs have yet to be examined (16 -18 ).…”

MicroRNA miR-126-5p Enhances the Inflammatory Responses of Monocytes to Lipopolysaccharide Stimulation by Suppressing Cylindromatosis in Chronic HIV-1 Infection

“…CYLD was recently deemed to be involved in hematopoietic stem cell quiescence and function via inhibition of the p38-MAPK pathway (68). Taking into consideration the observation that circulating monocytes in HIV-1-infected subjects exhibit a differential gene signature (69,70), CYLD may serve as an important regulator in monocytes, as it is significantly downregulated in monocytes from HIV-1-infected subjects who are naive to ART in comparison to monocytes from healthy donors.…”

Monocytes and their Role in Human Immunodeficiency Virus Pathogenesis

“…However, this study only tested 14,000 genes from the human genome. There have been no studies performed on monocytes in HIV-1+patients, 1 which encompass all 25,000 human genes, therefore the studies by Giri et al (2009) et al (2007) analyzed the secretome of HIV-1-infected human monocyte-derived macrophages. They identified 110 proteins in culture supernatants of control (uninfected) and virus-infected cells.…”

“…Of these 38 genes, 28 of them were stably modulated to suggest increased monocyte survival, i.e., pro-apoptotic genes were down regulated, or antiapoptotic genes were up regulated. Through functional analysis, Giri and her colleagues also showed that these genes are associated with four pathways, being p53 modulation, TNF signaling, CD40L signaling and MAPK signaling (Giri et al, 2009). Giri and her colleagues were the first to provide evidence of a stable anti-apoptosis gene expression in monocytes in chronic HIV-1 infection.…”