Posted by: Indonesian Children | August 15, 2009

Signaling through Toll-Like Receptors Triggers HIV-1 Replication in Latently Infected Mast Cells

The Journal of Immunology, 2004, 172: 4391-4401.
Copyright © 2004 by The American Association of Immunologists

J. Bruce Sundstrom2,*, Dawn M. Little*, Francois Villinger*, Jane E. Ellis and Aftab A. Ansari*

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Departments of * Pathology and Laboratory Medicine and Obstetrics and Gynecology, Emory University School of Medicine, Atlanta, GA 30322

Evidence that human progenitor mast cells are susceptible to infection with CCR5-tropic strains of HIV-1 and that circulating HIV-1-infected FcRI+ cells with a similar progenitor phenotype have been isolated from AIDS patients has led to speculation that mast cells may serve as a potential reservoir for infectious HIV-1. In this study, progenitor mast cells, developed in vitro from CD34+ cord blood stem cells, were experimentally infected with the CCR5-tropic strain HIV-1Bal after 28 days in culture as they reached their HIV-1-susceptible progenitor stage. HIV-1 p24 Ag levels were readily detectable by day 7 postinfection (PI), peaked at 2–3 wk PI as mature (tryptase/chymase-positive) HIV-1 infection-resistant mast cells emerged, and then steadily declined to below detectable limits by 10 wk PI, at which point integrated HIV-1 proviral DNA was confirmed by PCR quantitation in (34% of) latently infected mast cells. Stimulation by ligands for Toll-like receptor (TLR) 2, TLR4, or TLR9 significantly enhanced viral replication in a dose- and time-dependent manner in both HIV-1-infected progenitor and latently infected mature mast cells, without promoting degranulation, apoptosis, cellular proliferation, or dysregulation of TLR agonist-induced cytokine production in infected mast cells. Limiting dilution analysis of TLR activated, latently infected mature mast cells indicated that one in four was capable of establishing productive infections in A301 sentinel cells. Taken together, these results indicate that mast cells may serve both as a viral reservoir and as a model for studying mechanisms of postintegration latency in HIV infection.

The advent and administration of highly active antiretroviral therapy (HAART)3 for AIDS patients has revealed that HIV-1 infection can persist even when plasma levels of viral RNA have dropped below detectable limits (1). Viral persistence is maintained either in specific anatomical compartments, where limited drug penetration allows viral replication to continue even in the presence of HAART, or in viral reservoirs composed of latently infected long-lived nonreplicating cells in which integrated proviral DNA is transcriptionally silent (2). The several cell lineages that are susceptible to infection with HIV-1 include T cells, macrophages, dendritic cells (3), astrocytes, endothelial cells (4), and microglial cells (5). Of these lineages, the CD4 memory T cells have to date been considered to have the greatest potential for fulfilling the essential requirements for serving as a viral reservoir for HIV-1 (6). According to the prevailing model (2, 7, 8), latency is established during the waning phase of an inflammatory response when HIV-1-susceptible proliferating effector T cells become infected because they are in the process of differentiating into long-lived resting memory T cells. Within the stable cellular environment of nondividing memory T cells, latent infection persists as long as integrated proviral DNA remains transcriptionally silent. However, as latently infected memory T cells encounter their recall Ags, ensuing proliferative responses trigger the replication and release of HIV-1 archival forms of viral sequences that have been stably preserved within the reservoir. Strategies such as drug holidays from HAART, sometimes in combination with the use of proinflammatory cytokines, have been developed in efforts to exploit this model of latency to expose reservoirs of infected memory T cells and to flush out and deplete ephemeral (t1/2 = 1 day) infected proliferating lymphoblasts in AIDS patients (9). Nevertheless, the effectiveness of these strategies is limited to viral reservoirs in anatomical sites that are exposed to HAART and to when viral replication occurs in productively infected cells that are actively proliferating. Recent reports that human progenitor mast cells (MCs) are susceptible to infection with HIV-1 and remain productively infected into maturity with a life span of months to years suggest that this new and unique reservoir HIV latency should also be considered.

Mast cells and monocytes appear to evolve from a common CD34+CD13+c-kit+ progenitor (10); however, unlike monocyte MCs, they are able to mature into effector cells with a very long life span. Mast cells develop along diverse ontological pathways in vivo, influenced by environmental signals that dictate homing patterns of precursor progenitor MCs and their ultimate mature functional phenotype. Furthermore, MCs recruit and interact with both T cells and dendritic cells in tissue sites of MC activation (11). Thus, in vivo, mature MCs are positioned in a variety of tissue spaces near blood vessels and in mucosal sites where they are exposed to environmental stimuli and function at the interface between innate and adaptive immunity (12, 13). Human cord blood-derived progenitor MCs (CBMCs) cultured in vitro become susceptible to CCR5-tropic strains of HIV-1 as they transiently express CD4 and CCR5 HIV coreceptors (14, 15). As virally infected progenitors mature, they remain productively infected even after they lose their expression of CD4 and CCR5 along with their susceptibility to infection with HIV. Thus, these findings led us to speculate that MCs may serve as a potential reservoir for persistent HIV infection, and we present three important questions to address this issue: 1) can a latent (nonproductive) infection be established in mature MCs; 2) if so, can postintegration latency be reversed, leading to productive infections and is this associated with MC apoptosis or necrosis; and 3) what are the biologically relevant signals that trigger reinitiation of viral replication in latently infected MCs.

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    Responses

    1. Cryo-Cell, a private cord blood bank in business since 1992, has been very active in stem cell research and development. In 2007 C’elle was introduced, a service that enables women to collect and preserve stem cells from their menstrual blood. Stem cells found in menstrual blood may potentially be useful in future therapies to treat a number of debilitating conditions such as heart disease, stroke and diabetes. They also have the potential to be used in regenerative medicine and even cosmeceutical applications such as anti-aging and sports medicine.

      Stem cell research and development is growing rapidly, and within the past few weeks, Cryo-Cell announced several new initiatives for C’elle. These include research and development initiatives in China and also in Brazil, where scientists will study diagnostic and therapeutic uses for endometriosis and stress urinary incontinence in women. Here in the U.S., they’re collaborating with a renowned expert in wound healing. Read more about the latest news and advancements from C’elle here in this recent interview with Cryo-Cell CEO Mercedes Walton: http://bit.ly/4hwTZ .

      — Ryan Smith, Cryo-Cell Associate
      http://www.celle.com , http://www.cryo-cell.com


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