Kinetics of Myeloid Dendritic Cell Trafficking and Activation: Impact on Progressive, Nonprogressive and Controlled SIV Infections

Abstract

We assessed the role of myeloid dendritic cells (mDCs) in the outcome of SIV infection by comparing and contrasting their frequency, mobilization, phenotype, cytokine production and apoptosis in pathogenic (pigtailed macaques, PTMs), nonpathogenic (African green monkeys, AGMs) and controlled (rhesus macaques, RMs) SIVagmSab infection. Through the identification of recently replicating cells, we demonstrated that mDC mobilization from the bone marrow occurred in all species postinfection, being most prominent in RMs. Circulating mDCs were depleted with disease progression in PTMs, recovered to baseline values after the viral peak in AGMs, and significantly increased at the time of virus control in RMs. Rapid disease progression in PTMs was associated with low baseline levels and incomplete recovery of circulating mDCs during chronic infection. mDC recruitment to the intestine occurred in all pathogenic scenarios, but loss of mucosal mDCs was associated only with progressive infection. Sustained mDC immune activation occurred throughout infection in PTMs and was associated with increased bystander apoptosis in blood and intestine. Conversely, mDC activation occurred only during acute infection in nonprogressive and controlled infections. Postinfection, circulating mDCs rapidly became unresponsive to TLR7/8 stimulation in all species. Yet, stimulation with LPS, a bacterial product translocated in circulation only in SIV-infected PTMs, induced mDC hyperactivation, apoptosis and excessive production of proinflammatory cytokines. After infection, spontaneous production of proinflammatory cytokines by mucosal mDCs increased only in progressor PTMs. We thus propose that mDCs promote tolerance to SIV in the biological systems that lack intestinal dysfunction. In progressive infections, mDC loss and excessive activation of residual mDCs by SIV and additional stimuli, such as translocated microbial products, enhance generalized immune activation and inflammation. Our results thus provide a mechanistic basis for the role of mDCs in the pathogenesis of AIDS and elucidate the causes of mDC loss during progressive HIV/SIV infections.

Pathogenic Features Associated with Increased Virulence upon Simian Immunodeficiency Virus Cross-Species Transmission from Natural Hosts

“…Our new model also enables similar comparisons between the pathogenic infection of PTMs and natural host (AGM) infection by employing a single SIVsab strain (36), with several major advantages over the conventional RM/sooty mangabey/SIVmac/smm system: AGMs are not endangered and can thus accommodate invasive studies, which are prohibited in sooty mangabeys. Furthermore, since SIVsab infection of RMs is functionally cured (19), this system expands to comparative studies between pathogenic, nonpathogenic, and elite-controlled infections (10,35), to gain insight into the mechanisms of immunodeficiency associated with lentiviral infection. As such, this new system is unique and can be used to assess essential aspects of AIDS pathogenesis; among these are identifying the discrete immunopathogenic mechanisms of SIV infection and comparing the genetic evolution of SIV in different host species (76), both of which are needed to develop effective strategies for prevention of AIDS disease progression.…”

“…All MAbs were from BD Bioscience Pharmingen, San Diego, CA, unless otherwise indicated. All antibodies were previously tested and calibrated for use in PTMs (25,35,36). Cells were stained (10,31,33) and analyzed with a FACSCalibur flow cytometer (BD Immunocytometry Systems) using CellQuest software (BD).…”

Simian Immunodeficiency Virus SIVsab Infection of Rhesus Macaques as a Model of Complete Immunological Suppression with Persistent Reservoirs of Replication-Competent Virus: Implications for Cure Research

“…Eleven RMs were inoculated intravenously with plasma samples equivalent to 300 tissue culture infectious doses at 50% (TCID 50 ) of SIVsab92018. The same virus strain induces a persistent nonprogressive infection in the natural African green monkey (AGM) host (13,15) and a pathogenic progressive infection in pigtailed macaques (16)(17)(18). The remaining two RMs were inoculated with plasma samples collected from SIVsab92018 controllers collected at 4 years postinfection (p.i.…”

Prolyl oligopeptidase-like deficient Trypanosoma evansi parasites are associated with reduced interleukin-10 concentrations in vivo and in vitro

“…Paired experiments were carried out for each vial of spleen cells to differentiate between different sources of mouse cells. Spleen cells were harvested 24 h after incubation and prepared for flow cytometry as previously described (Wijewardana et al 2013). Briefly, cells were washed in PBS (pH 7·2) and resuspended in cell surface staining mix [fluorescence-activated cell sorting (FACS) buffer: PBS pH 7·2, Parasitology Open2% (v/v) foetal calf serum, anti-CD3 antibody-clone 145-2C11 and anti-CD8 antibody-clone 53-6·7; BD Biosciences, New Jersey, USA] and incubated for 30 min at 4°C.…”