20 results on '"Xu, Cuiling"'
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2. CD8 + T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production.
- Author
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Policicchio BB, Cardozo-Ojeda EF, Xu C, Ma D, He T, Raehtz KD, Sivanandham R, Kleinman AJ, Perelson AS, Apetrei C, Pandrea I, and Ribeiro RM
- Subjects
- Humans, Animals, CD8-Positive T-Lymphocytes, Macaca mulatta, Integrase Inhibitors pharmacology, Viral Load, Virus Replication, Simian Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus
- Abstract
Whether CD8
+ T lymphocytes control human immunodeficiency virus infection by cytopathic or non-cytopathic mechanisms is not fully understood. Multiple studies highlighted non-cytopathic effects, but one hypothesis is that cytopathic effects of CD8+ T cells occur before viral production. Here, to examine the role of CD8+ T cells prior to virus production, we treated SIVmac251-infected macaques with an integrase inhibitor combined with a CD8-depleting antibody, or with either reagent alone. We analyzed the ensuing viral dynamics using a mathematical model that included infected cells pre- and post- viral DNA integration to compare different immune effector mechanisms. Macaques receiving the integrase inhibitor alone experienced greater viral load decays, reaching lower nadirs on treatment, than those treated also with the CD8- depleting antibody. Models including CD8+ cell-mediated reduction of viral production (non-cytolytic) were found to best explain the viral profiles across all macaques, in addition an effect in killing infected cells pre-integration (cytolytic) was supported in some of the best models. Our results suggest that CD8+ T cells have both a cytolytic effect on infected cells before viral integration, and a direct, non-cytolytic effect by suppressing viral production., (© 2023. Springer Nature Limited.)- Published
- 2023
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3. Prolonged experimental CD4 + T-cell depletion does not cause disease progression in SIV-infected African green monkeys.
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Le Hingrat Q, Sette P, Xu C, Rahmberg AR, Tarnus L, Annapureddy H, Kleinman A, Brocca-Cofano E, Sivanandham R, Sivanandham S, He T, Capreri DJ, Ma D, Estes JD, Brenchley JM, Apetrei C, and Pandrea I
- Subjects
- Animals, Chlorocebus aethiops, Disease Progression, CD4-Positive T-Lymphocytes, Simian Acquired Immunodeficiency Syndrome, HIV Infections, Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus
- Abstract
CD4
+ T-cell depletion is a hallmark of HIV infection, leading to impairment of cellular immunity and opportunistic infections, but its contribution to SIV/HIV-associated gut dysfunction is unknown. Chronically SIV-infected African Green Monkeys (AGMs) partially recover mucosal CD4+ T-cells, maintain gut integrity and do not progress to AIDS. Here we assess the impact of prolonged, antibody-mediated CD4 + T-cell depletion on gut integrity and natural history of SIV infection in AGMs. All circulating CD4+ T-cells and >90% of mucosal CD4+ T-cells are depleted. Plasma viral loads and cell-associated viral RNA in tissues are lower in CD4+ -cell-depleted animals. CD4+ -cell-depleted AGMs maintain gut integrity, control immune activation and do not progress to AIDS. We thus conclude that CD4+ T-cell depletion is not a determinant of SIV-related gut dysfunction, when gastrointestinal tract epithelial damage and inflammation are absent, suggesting that disease progression and resistance to AIDS are independent of CD4+ T-cell restoration in SIVagm-infected AGMs., (© 2023. The Author(s).)- Published
- 2023
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4. Changes to the Simian Immunodeficiency Virus (SIV) Reservoir and Enhanced SIV-Specific Responses in a Rhesus Macaque Model of Functional Cure after Serial Rounds of Romidepsin Administrations.
- Author
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Kleinman AJ, Sivanandham S, Sette P, Sivanandham R, Policicchio BB, Xu C, Penn E, Brocca-Cofano E, Le Hingrat Q, Ma D, Pandrea I, and Apetrei C
- Subjects
- Animals, CD4-Positive T-Lymphocytes virology, CD8-Positive T-Lymphocytes, HIV Infections, Leukocytes, Mononuclear virology, Macaca mulatta, Viral Load, Virus Activation drug effects, Virus Replication, Anti-Retroviral Agents pharmacology, Depsipeptides pharmacology, Simian Acquired Immunodeficiency Syndrome drug therapy, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus
- Abstract
HIV persistence requires lifelong antiretroviral therapy (ART), calling for a cure. The histone deacetylase inhibitor, romidepsin, is used in the "shock and kill" approach with the goal of reactivating virus and subsequently clearing infected cells through cell-mediated immune responses. We tested serial and double infusions of romidepsin in a rhesus macaque (RM) model of SIV functional cure, which controls virus without ART. Off ART, romidepsin reactivated SIV in all RMs. Subsequent infusions resulted in diminished reactivation, and two RMs did not reactivate the virus after the second or third infusions. Therefore, those two RMs received CD8-depleting antibody to assess the replication competence of the residual reservoir. The remaining RMs received double infusions, i.e., two doses separated by 48-h. Double infusions were well tolerated, induced immune activation, and effectively reactivated SIV. Although reactivation was gradually diminished, cell-associated viral DNA was minimally changed, and viral outgrowth occurred in 4/5 RMs. In the RM which did not reactivate after CD8 depletion, viral outgrowth was not detected in peripheral blood mononuclear cells (PBMC)-derived CD4
+ cells. The frequency of SIV-specific CD8+ T cells increased after romidepsin administration, and the increased SIV-specific immune responses were associated, although not statistically, with the diminished reactivation. Thus, our data showing sequential decreases in viral reactivation with repeated romidepsin administrations with all RMs and absence of viral reactivation after CD8+ T-cell depletion in one animal suggest that, in the context of healthy immune responses, romidepsin affected the inducible viral reservoir and gradually increased immune-mediated viral control. Given the disparities between the results of romidepsin administration to ART-suppressed SIVmac239-infected RMs and HIV-infected normal progressors compared to our immune-healthy model, our data suggest that improving immune function for greater SIV-specific responses should be the starting point of HIV cure strategies. IMPORTANCE HIV cure is sought after due to the prevalence of comorbidities that occur in persons with HIV. One of the most investigated HIV cure strategies is the "shock and kill" approach. Our study investigated the use of romidepsin, a histone deacetylase (HDAC) inhibitor, in our rhesus macaque model of functional cure, which allows for better resolution of viral reactivation due to the lack of antiretroviral therapy. We found that repeated rounds of romidepsin resulted in gradually diminished viral reactivation. One animal inevitably lacked replication-competent virus in the blood. With the accompanying enhancement of the SIV-specific immune response, our data suggest that there is a reduction of the viral reservoir in one animal by the cell-mediated immune response. With the differences observed between our model and persons living with HIV (PWH) treated with romidepsin, specifically in the context of a healthy immune system in our model, our data thereby indicate the importance of restoring the immune system for cure strategies.- Published
- 2022
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5. African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity.
- Author
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Raehtz KD, Barrenäs F, Xu C, Busman-Sahay K, Valentine A, Law L, Ma D, Policicchio BB, Wijewardana V, Brocca-Cofano E, Trichel A, Gale M Jr, Keele BF, Estes JD, Apetrei C, and Pandrea I
- Subjects
- Animals, Bacterial Translocation, Chlorocebus aethiops, Disease Progression, Gastrointestinal Microbiome, HIV Infections immunology, HIV Infections microbiology, HIV Infections pathology, HIV Infections virology, HIV-1 physiology, Humans, Intestinal Mucosa microbiology, Male, Simian Acquired Immunodeficiency Syndrome microbiology, Simian Acquired Immunodeficiency Syndrome pathology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus physiology, Intestinal Mucosa immunology, Simian Acquired Immunodeficiency Syndrome immunology
- Abstract
Unlike HIV infection, SIV infection is generally nonpathogenic in natural hosts, such as African green monkeys (AGMs), despite life-long high viral replication. Lack of disease progression was reportedly based on the ability of SIV-infected AGMs to prevent gut dysfunction, avoiding microbial translocation and the associated systemic immune activation and chronic inflammation. Yet, the maintenance of gut integrity has never been documented, and the mechanism(s) by which gut integrity is preserved are unknown. We sought to investigate the early events of SIV infection in AGMs, specifically examining the impact of SIVsab infection on the gut mucosa. Twenty-nine adult male AGMs were intrarectally infected with SIVsab92018 and serially sacrificed at well-defined stages of SIV infection, preramp-up (1-3 days post-infection (dpi)), ramp-up (4-6 dpi), peak viremia (9-12 dpi), and early chronic SIV infection (46-55 dpi), to assess the levels of immune activation, apoptosis, epithelial damage and microbial translocation in the GI tract and peripheral lymph nodes. Tissue viral loads, plasma cytokines and plasma markers of gut dysfunction were also measured throughout the course of early infection. While a strong, but transient, interferon-based inflammatory response was observed, the levels of plasma markers linked to enteropathy did not increase. Accordingly, no significant increases in apoptosis of either mucosal enterocytes or lymphocytes, and no damage to the mucosal epithelium were documented during early SIVsab infection of AGMs. These findings were supported by RNAseq of the gut tissue, which found no significant alterations in gene expression that would indicate microbial translocation. Thus, for the first time, we confirmed that gut epithelial integrity is preserved, with no evidence of microbial translocation, in AGMs throughout early SIVsab infection. This might protect AGMs from developing intestinal dysfunction and the subsequent chronic inflammation that drives both HIV disease progression and HIV-associated comorbidities., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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6. High-fat diet exacerbates SIV pathogenesis and accelerates disease progression.
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He T, Xu C, Krampe N, Dillon SM, Sette P, Falwell E, Haret-Richter GS, Butterfield T, Dunsmore TL, McFadden WM Jr, Martin KJ, Policicchio BB, Raehtz KD, Penn EP, Tracy RP, Ribeiro RM, Frank DN, Wilson CC, Landay AL, Apetrei C, and Pandrea I
- Subjects
- Adipose Tissue pathology, Animals, Bacterial Translocation, Cardiovascular Diseases etiology, Chlorocebus aethiops, Disease Progression, Inflammation etiology, Liver pathology, Simian Acquired Immunodeficiency Syndrome mortality, Diet, High-Fat adverse effects, Simian Acquired Immunodeficiency Syndrome etiology
- Abstract
Consuming a high-fat diet (HFD) is a risk factor for obesity and diabetes; both of these diseases are also associated with systemic inflammation, similar to HIV infection. A HFD induces intestinal dysbiosis and impairs liver function and coagulation, with a potential negative impact on HIV/SIV pathogenesis. We administered a HFD rich in saturated fats and cholesterol to nonpathogenic (African green monkeys) and pathogenic (pigtailed macaques) SIV hosts. The HFD had a negative impact on SIV disease progression in both species. Thus, increased cell-associated SIV DNA and RNA occurred in the HFD-receiving nonhuman primates, indicating a potential reservoir expansion. The HFD induced prominent immune cell infiltration in the adipose tissue, an important SIV reservoir, and heightened systemic immune activation and inflammation, altering the intestinal immune environment and triggering gut damage and microbial translocation. Furthermore, HFD altered lipid metabolism and HDL oxidation and also induced liver steatosis and fibrosis. These metabolic disturbances triggered incipient atherosclerosis and heightened cardiovascular risk in the SIV-infected HFD-receiving nonhuman primates. Our study demonstrates that dietary intake has a discernable impact on the natural history of HIV/SIV infections and suggests that dietary changes can be used as adjuvant approaches for HIV-infected subjects, to reduce inflammation and the risk of non-AIDS comorbidities and possibly other infectious diseases.
- Published
- 2019
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7. Macrophage-associated wound healing contributes to African green monkey SIV pathogenesis control.
- Author
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Barrenas F, Raehtz K, Xu C, Law L, Green RR, Silvestri G, Bosinger SE, Nishida A, Li Q, Lu W, Zhang J, Thomas MJ, Chang J, Smith E, Weiss JM, Dawoud RA, Richter GH, Trichel A, Ma D, Peng X, Komorowski J, Apetrei C, Pandrea I, and Gale M Jr
- Subjects
- Animals, Chlorocebus aethiops genetics, Chlorocebus aethiops immunology, Disease Progression, Fibronectins metabolism, Intestinal Mucosa metabolism, Macaca mulatta genetics, Macaca mulatta immunology, Macrophages metabolism, Rectum immunology, Rectum metabolism, Simian Immunodeficiency Virus, Systems Biology, Transcriptome, Transforming Growth Factor beta genetics, Wound Healing genetics, Fibronectins immunology, Intestinal Mucosa immunology, Macrophages immunology, Simian Acquired Immunodeficiency Syndrome immunology, Transforming Growth Factor beta immunology, Wound Healing immunology
- Abstract
Natural hosts of simian immunodeficiency virus (SIV) avoid AIDS despite lifelong infection. Here, we examined how this outcome is achieved by comparing a natural SIV host, African green monkey (AGM) to an AIDS susceptible species, rhesus macaque (RM). To asses gene expression profiles from acutely SIV infected AGMs and RMs, we developed a systems biology approach termed Conserved Gene Signature Analysis (CGSA), which compared RNA sequencing data from rectal AGM and RM tissues to various other species. We found that AGMs rapidly activate, and then maintain, evolutionarily conserved regenerative wound healing mechanisms in mucosal tissue. The wound healing protein fibronectin shows distinct tissue distribution and abundance kinetics in AGMs. Furthermore, AGM monocytes exhibit an embryonic development and repair/regeneration signature featuring TGF-β and concomitant reduced expression of inflammatory genes compared to RMs. This regenerative wound healing process likely preserves mucosal integrity and prevents inflammatory insults that underlie immune exhaustion in RMs.
- Published
- 2019
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8. Marginal Effects of Systemic CCR5 Blockade with Maraviroc on Oral Simian Immunodeficiency Virus Transmission to Infant Macaques.
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Brocca-Cofano E, Xu C, Wetzel KS, Cottrell ML, Policicchio BB, Raehtz KD, Ma D, Dunsmore T, Haret-Richter GS, Musaitif K, Keele BF, Kashuba AD, Collman RG, Pandrea I, and Apetrei C
- Subjects
- Animals, CCR5 Receptor Antagonists pharmacokinetics, Cyclohexanes pharmacokinetics, Humans, Infant, Maraviroc, Palatine Tonsil chemistry, Serum chemistry, Treatment Outcome, Triazoles pharmacokinetics, Viral Load, CCR5 Receptor Antagonists administration & dosage, Cyclohexanes administration & dosage, Infectious Disease Transmission, Vertical prevention & control, Macaca mulatta, Simian Acquired Immunodeficiency Syndrome drug therapy, Simian Acquired Immunodeficiency Syndrome transmission, Triazoles administration & dosage
- Abstract
Current approaches do not eliminate all human immunodeficiency virus type 1 (HIV-1) maternal-to-infant transmissions (MTIT); new prevention paradigms might help avert new infections. We administered maraviroc (MVC) to rhesus macaques (RMs) to block CCR5-mediated entry, followed by repeated oral exposure of a CCR5-dependent clone of simian immunodeficiency virus (SIV) mac251 (SIVmac766). MVC significantly blocked the CCR5 coreceptor in peripheral blood mononuclear cells and tissue cells. All control animals and 60% of MVC-treated infant RMs became infected by the 6th challenge, with no significant difference between the number of exposures ( P = 0.15). At the time of viral exposures, MVC plasma and tissue (including tonsil) concentrations were within the range seen in humans receiving MVC as a therapeutic. Both treated and control RMs were infected with only a single transmitted/founder variant, consistent with the dose of virus typical of HIV-1 infection. The uninfected RMs expressed the lowest levels of CCR5 on the CD4
+ T cells. Ramp-up viremia was significantly delayed ( P = 0.05) in the MVC-treated RMs, yet peak and postpeak viral loads were similar in treated and control RMs. In conclusion, in spite of apparent effective CCR5 blockade in infant RMs, MVC had a marginal impact on acquisition and only a minimal impact on the postinfection delay of viremia following oral SIV infection. Newly developed, more effective CCR5 blockers may have a more dramatic impact on oral SIV transmission than MVC. IMPORTANCE We have previously suggested that the very low levels of simian immunodeficiency virus (SIV) maternal-to-infant transmissions (MTIT) in African nonhuman primates that are natural hosts of SIVs are due to a low availability of target cells (CCR5+ CD4+ T cells) in the oral mucosa of the infants, rather than maternal and milk factors. To confirm this new MTIT paradigm, we performed a proof-of-concept study in which we therapeutically blocked CCR5 with maraviroc (MVC) and orally exposed MVC-treated and naive infant rhesus macaques to SIV. MVC had only a marginal effect on oral SIV transmission. However, the observation that the infant RMs that remained uninfected at the completion of the study, after 6 repeated viral challenges, had the lowest CCR5 expression on the CD4+ T cells prior to the MVC treatment appears to confirm our hypothesis, also suggesting that the partial effect of MVC is due to a limited efficacy of the drug. New, more effective CCR5 inhibitors may have a better effect in preventing SIV and HIV transmission., (Copyright © 2018 American Society for Microbiology.)- Published
- 2018
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9. Dynamics of Simian Immunodeficiency Virus Two-Long-Terminal-Repeat Circles in the Presence and Absence of CD8 + Cells.
- Author
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Policicchio BB, Cardozo EF, Sette P, Xu C, Haret-Richter G, Dunsmore T, Apetrei C, Pandrea I, and Ribeiro RM
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- Animals, CD8-Positive T-Lymphocytes virology, Leukocytes, Mononuclear virology, Lymph Nodes virology, Macaca mulatta, Simian Acquired Immunodeficiency Syndrome genetics, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus genetics, Viral Load, Virus Replication, CD8-Positive T-Lymphocytes immunology, Leukocytes, Mononuclear immunology, Lymph Nodes immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology, Terminal Repeat Sequences
- Abstract
CD8
+ cells play a key role in human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, but their specific mechanism(s) of action in controlling the virus is unclear. Two-long-terminal-repeat (2-LTR) circles are extrachromosomal products generated upon failed integration of HIV/SIV. To understand the specific effects of CD8+ cells on infected cells, we analyzed the dynamics of 2-LTR circles in SIVmac251-infected rhesus macaques (RMs) treated with an integrase inhibitor (INT). Twenty RMs underwent CD8+ cell depletion and received raltegravir (RAL) monotherapy or a combination of both. Blood, lymph nodes (LNs), and gut biopsy specimens were routinely sampled. Plasma viral loads (pVLs) and 2-LTR circles from peripheral blood mononuclear cells (PBMCs) and LN lymphocytes were measured with quantitative reverse transcription-PCR (qRT-PCR). In the CD8 depletion group, an ∼1-log increase in pVLs and a slow increase in PBMC 2-LTRs occurred following depletion. In the INT group, a strong decline in pVLs upon treatment initiation and no change in 2-LTR levels were observed. In the INT and CD8+ cell depletion group, an increase in pVLs following CD8 depletion similar to that in the CD8 depletion group was observed, with a modest decline following INT initiation, and 2-LTR circles significantly increased in PBMCs and LNs. Analyzing the 2-LTR data across all treatment groups with a mathematical model indicates that the data best support an effect of CD8+ cells in killing cells prior to viral integration. Sensitivity analyses of these results confirm that effect but also allow for additional effects, which the data do not discriminate well. Overall, we show that INT does not significantly increase the levels of 2-LTR circles. However, CD8+ cell depletion increases the 2-LTR levels, which are enhanced in the presence of an INT. IMPORTANCE CD8+ T cells play an essential role in controlling HIV and SIV infection, but the specific mechanisms involved remain poorly understood. Due to failed viral infection, HIV and SIV can form 2-LTR extrachromosomal circles that can be quantified. We present novel data on the dynamics of these 2-LTR forms in a SIV-infected macaque model under three different treatment conditions: depletion of CD8+ cells, administration of the integrase inhibitor in a monotherapy, which favors the formation of 2-LTR circles, and a combination of the two treatments. We used a new mathematical model to help interpret the data, and the results suggest that CD8+ cells exert a killing effect on infected cells prior to virus integration. These results provide new insights into the mechanisms of action of CD8+ cells in SIV infection. Confirmation of our results would be an important step in understanding immune control of HIV., (Copyright © 2018 American Society for Microbiology.)- Published
- 2018
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10. Emergence of resistance mutations in simian immunodeficiency virus (SIV)-infected rhesus macaques receiving non-suppressive antiretroviral therapy (ART).
- Author
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Policicchio BB, Sette P, Xu C, Haret-Richter G, Dunsmore T, Pandrea I, Ribeiro RM, and Apetrei C
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- Animals, Anti-Retroviral Agents administration & dosage, Disease Models, Animal, Drug Resistance, Multiple, Viral genetics, Drug Therapy, Combination, Emtricitabine administration & dosage, Genes, Viral, Humans, Integrases genetics, Macaca mulatta, Mutation, RNA-Directed DNA Polymerase genetics, Raltegravir Potassium administration & dosage, Simian Immunodeficiency Virus drug effects, Simian Immunodeficiency Virus enzymology, Tenofovir administration & dosage, Viral Load drug effects, Simian Acquired Immunodeficiency Syndrome drug therapy, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus genetics
- Abstract
Two SIVmac251-infected rhesus macaques received tenofovir/emtricitabine with raltegravir intensification. Viral rebound occurred during treatment and sequencing of reverse transcriptase and integrase genes identified multiple resistance mutations. Similar to HIV infection, antiretroviral-resistance mutations may occur in SIV-infected nonhuman primates receiving nonsuppressive ART. As ART administration to nonhuman primates is currently dramatically expanding, fueled by both cure research and the study of HIV-related comorbidities, viral resistance should be factored in the study design and data interpretation.
- Published
- 2018
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11. Pathogenic Correlates of Simian Immunodeficiency Virus-Associated B Cell Dysfunction.
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Brocca-Cofano E, Kuhrt D, Siewe B, Xu C, Haret-Richter GS, Craigo J, Labranche C, Montefiori DC, Landay A, Apetrei C, and Pandrea I
- Subjects
- Animals, Antibodies, Neutralizing blood, Antibodies, Viral biosynthesis, Antibodies, Viral blood, B-Lymphocyte Subsets physiology, B-Lymphocytes, Regulatory immunology, B-Lymphocytes, Regulatory physiology, Chlorocebus aethiops, Disease Progression, Epitopes chemistry, Epitopes immunology, HIV Infections virology, Humans, Immunity, Humoral, Immunologic Memory, Interleukin-10 blood, Lymphocyte Count, Macaca nemestrina, Simian Immunodeficiency Virus metabolism, T-Lymphocytes, Helper-Inducer immunology, B-Lymphocyte Subsets immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus immunology, Simian Immunodeficiency Virus pathogenicity
- Abstract
We compared and contrasted pathogenic (in pig-tailed macaques [PTMs]) and nonpathogenic (in African green monkeys [AGMs]) SIVsab infections to assess the significance of the B cell dysfunction observed in simian (SIV) and human immunodeficiency virus (HIV) infections. We report that the loss of B cells is specifically associated with the pathogenic SIV infection, while in the natural hosts, in which SIV is nonpathogenic, B cells rapidly increase in both lymph nodes (LNs) and intestine. SIV-associated B cell dysfunction associated with the pathogenic SIV infection is characterized by loss of naive B cells, loss of resting memory B cells due to their redistribution to the gut, increases of the activated B cells and circulating tissue-like memory B cells, and expansion of the B regulatory cells (Bregs). While circulating B cells are virtually restored to preinfection levels during the chronic pathogenic SIV infection, restoration is mainly due to an expansion of the "exhausted," virus-specific B cells, i.e., activated memory cells and tissue-like memory B cells. Despite of the B cell dysfunction, SIV-specific antibody (Ab) production was higher in the PTMs than in AGMs, with the caveat that rapid disease progression in PTMs was strongly associated with lack of anti-SIV Ab. Neutralization titers and the avidity and maturation of immune responses did not differ between pathogenic and nonpathogenic infections, with the exception of the conformational epitope recognition, which evolved from low to high conformations in the natural host. The patterns of humoral immune responses in the natural host are therefore more similar to those observed in HIV-infected subjects, suggesting that natural hosts may be more appropriate for modeling the immunization strategies aimed at preventing HIV disease progression. The numerous differences between the pathogenic and nonpathogenic infections with regard to dynamics of the memory B cell subsets point to their role in the pathogenesis of HIV/SIV infections and suggest that monitoring B cells may be a reliable approach for assessing disease progression. IMPORTANCE We report here that the HIV/SIV-associated B cell dysfunction (defined by loss of total and memory B cells, increased B regulatory cell [Breg] counts, and B cell activation and apoptosis) is specifically associated with pathogenic SIV infection and absent during the course of nonpathogenic SIV infection in natural nonhuman primate hosts. Alterations of the B cell population are not correlated with production of neutralizing antibodies, the levels of which are similar in the two species. Rapid progressive infections are associated with a severe impairment in SIV-specific antibody production. While we did not find major differences in avidity and maturation between the pathogenic and nonpathogenic SIV infections, we identified a major difference in conformational epitope recognition, with the nonpathogenic infection being characterized by an evolution from low to high conformations. B cell dysfunction should be considered in designing immunization strategies aimed at preventing HIV disease progression., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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12. Cutting Edge: T Regulatory Cell Depletion Reactivates Latent Simian Immunodeficiency Virus (SIV) in Controller Macaques While Boosting SIV-Specific T Lymphocytes.
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He T, Brocca-Cofano E, Policicchio BB, Sivanandham R, Gautam R, Raehtz KD, Xu C, Pandrea I, and Apetrei C
- Subjects
- Animals, Antibodies, Viral blood, Antigens, Viral immunology, Cells, Cultured, Diphtheria Toxin administration & dosage, Humans, Immunity, Cellular, Interleukin-2 administration & dosage, Lymphocyte Activation, Lymphocyte Depletion, Macaca mulatta, RNA, Viral genetics, Recombinant Fusion Proteins administration & dosage, Viral Load drug effects, Virus Activation drug effects, Virus Replication drug effects, CD8-Positive T-Lymphocytes immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus physiology, T-Lymphocytes, Regulatory immunology, Virus Latency drug effects
- Abstract
T regulatory cells (Tregs) are critical in shaping the latent HIV/SIV reservoir, as they are preferentially infected, reverse CD4
+ T cell activation status, and suppress CTL responses. To reactivate latent virus and boost cell-mediated immune responses, we performed in vivo Treg depletion with Ontak (denileukin diftitox) in two SIVsab-infected controller macaques. Ontak induced significant (>75%) Treg depletion and major CD4+ T cell activation, and only minimally depleted CD8+ T cells. The overall ability of Tregs to control immune responses was significantly impaired despite their incomplete depletion, resulting in both reactivation of latent virus (virus rebound to 103 viral RNA copies/ml plasma in the absence of antiretroviral therapy) and a significant boost of SIV-specific CD8+ T cell frequency, with rapid clearance of reactivated virus. As none of the latency-reversing agents in development have such dual activity, our strategy holds great promise for cure research., (Copyright © 2016 by The American Association of Immunologists, Inc.)- Published
- 2016
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13. Multi-dose Romidepsin Reactivates Replication Competent SIV in Post-antiretroviral Rhesus Macaque Controllers.
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Policicchio BB, Xu C, Brocca-Cofano E, Raehtz KD, He T, Ma D, Li H, Sivanandham R, Haret-Richter GS, Dunsmore T, Trichel A, Mellors JW, Hahn BH, Shaw GM, Ribeiro RM, Pandrea I, and Apetrei C
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, Macaca mulatta, RNA, Viral blood, Simian Acquired Immunodeficiency Syndrome blood, Time Factors, Anti-Retroviral Agents pharmacology, Depsipeptides pharmacology, Simian Acquired Immunodeficiency Syndrome drug therapy, Simian Immunodeficiency Virus physiology, Virus Replication drug effects
- Abstract
Viruses that persist despite seemingly effective antiretroviral treatment (ART) and can reinitiate infection if treatment is stopped preclude definitive treatment of HIV-1 infected individuals, requiring lifelong ART. Among strategies proposed for targeting these viral reservoirs, the premise of the "shock and kill" strategy is to induce expression of latent proviruses [for example with histone deacetylase inhibitors (HDACis)] resulting in elimination of the affected cells through viral cytolysis or immune clearance mechanisms. Yet, ex vivo studies reported that HDACis have variable efficacy for reactivating latent proviruses, and hinder immune functions. We developed a nonhuman primate model of post-treatment control of SIV through early and prolonged administration of ART and performed in vivo reactivation experiments in controller RMs, evaluating the ability of the HDACi romidepsin (RMD) to reactivate SIV and the impact of RMD treatment on SIV-specific T cell responses. Ten RMs were IV-infected with a SIVsmmFTq transmitted-founder infectious molecular clone. Four RMs received conventional ART for >9 months, starting from 65 days post-infection. SIVsmmFTq plasma viremia was robustly controlled to <10 SIV RNA copies/mL with ART, without viral blips. At ART cessation, initial rebound viremia to ~106 copies/mL was followed by a decline to < 10 copies/mL, suggesting effective immune control. Three post-treatment controller RMs received three doses of RMD every 35-50 days, followed by in vivo experimental depletion of CD8+ cells using monoclonal antibody M-T807R1. RMD was well-tolerated and resulted in a rapid and massive surge in T cell activation, as well as significant virus rebounds (~104 copies/ml) peaking at 5-12 days post-treatment. CD8+ cell depletion resulted in a more robust viral rebound (107 copies/ml) that was controlled upon CD8+ T cell recovery. Our results show that RMD can reactivate SIV in vivo in the setting of post-ART viral control. Comparison of the patterns of virus rebound after RMD administration and CD8+ cell depletion suggested that RMD impact on T cells is only transient and does not irreversibly alter the ability of SIV-specific T cells to control the reactivated virus., Competing Interests: The authors have declared no competing interests exist.
- Published
- 2016
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14. Antibiotic and Antiinflammatory Therapy Transiently Reduces Inflammation and Hypercoagulation in Acutely SIV-Infected Pigtailed Macaques.
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Pandrea I, Xu C, Stock JL, Frank DN, Ma D, Policicchio BB, He T, Kristoff J, Cornell E, Haret-Richter GS, Trichel A, Ribeiro RM, Tracy R, Wilson C, Landay AL, and Apetrei C
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Flow Cytometry, Immunohistochemistry, Inflammation etiology, Intestines drug effects, Intestines microbiology, Macaca nemestrina, Male, Rifamycins pharmacology, Rifaximin, Simian Acquired Immunodeficiency Syndrome complications, Simian Immunodeficiency Virus, Sulfasalazine pharmacology, Thrombophilia etiology, Anti-Inflammatory Agents pharmacology, Inflammation drug therapy, Simian Acquired Immunodeficiency Syndrome drug therapy, Thrombophilia drug therapy
- Abstract
Increased chronic immune activation and inflammation are hallmarks of HIV/SIV infection and are highly correlated with progression to AIDS and development of non-AIDS comorbidities, such as hypercoagulability and cardiovascular disease. Intestinal dysfunction resulting in microbial translocation has been proposed as a lead cause of systemic immune activation and hypercoagulability in HIV/SIV infection. Our goal was to assess the biological and clinical impact of a therapeutic strategy designed to reduce microbial translocation through reduction of the microbial content of the intestine (Rifaximin-RFX) and of gut inflammation (Sulfasalazine-SFZ). RFX is an intraluminal antibiotic that was successfully used in patients with hepatic encephalopathy. SFZ is an antiinflammatory drug successfully used in patients with mild to moderate inflammatory bowel disease. Both these clinical conditions are associated with increased microbial translocation, similar to HIV-infected patients. Treatment was administered for 90 days to five acutely SIV-infected pigtailed macaques (PTMs) starting at the time of infection; seven untreated SIVsab-infected PTMs were used as controls. RFX+SFZ were also administered for 90 days to three chronically SIVsab-infected PTMs. RFX+SFZ administration during acute SIVsab infection of PTMs resulted in: significantly lower microbial translocation, lower systemic immune activation, lower viral replication, better preservation of mucosal CD4+ T cells and significantly lower levels of hypercoagulation biomarkers. This effect was clear during the first 40 days of treatment and was lost during the last stages of treatment. Administration of RFX+SFZ to chronically SIVsab-infected PTMs had no discernible effect on infection. Our data thus indicate that early RFX+SFZ administration transiently improves the natural history of acute and postacute SIV infection, but has no effect during chronic infection.
- Published
- 2016
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15. Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues.
- Author
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He T, Brocca-Cofano E, Gillespie DG, Xu C, Stock JL, Ma D, Policicchio BB, Raehtz KD, Rinaldo CR, Apetrei C, Jackson EK, Macatangay BJ, and Pandrea I
- Subjects
- Animals, Chlorocebus aethiops, Chronic Disease, Cytokines immunology, Humans, Macaca nemestrina, Male, Receptors, Antigen, T-Cell immunology, Simian Acquired Immunodeficiency Syndrome pathology, T-Lymphocytes pathology, 5'-Nucleotidase immunology, Adenosine immunology, Antigens, CD immunology, Apyrase immunology, Dipeptidyl Peptidase 4 immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology, T-Lymphocytes immunology
- Abstract
Unlabelled: The role of the adenosine (ADO) pathway in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/SIV) infection remains unclear. We compared SIVsab-induced changes of markers related to ADO production (CD39 and CD73) and breakdown (CD26 and adenosine deaminase) on T cells from blood, lymph nodes, and intestine collected from pigtailed macaques (PTMs) and African green monkeys (AGMs) that experience different SIVsab infection outcomes. We also measured ADO and inosine (INO) levels in tissues by mass spectrometry. Finally, we assessed the suppressive effect of ADO on proinflammatory cytokine production after T cell receptor stimulation. The baseline level of both CD39 and CD73 coexpression on regulatory T cells and ADO levels were higher in AGMs than in PTMs. Conversely, high INO levels associated with dramatic increases in CD26 expression and adenosine deaminase activity were observed in PTMs during chronic SIV infection. Immune activation and inflammation markers in the gut and periphery inversely correlated with ADO and directly correlated with INO. Ex vivo administration of ADO significantly suppressed proinflammatory cytokine production by T cells in both species. In conclusion, the opposite dynamics of ADO pathway-related markers and contrasting ADO/INO levels in species with divergent proinflammatory responses to SIV infection support a key role of ADO in controlling immune activation/inflammation in nonprogressive SIV infections. Changes in ADO levels predominately occurred in the gut, suggesting that the ADO pathway may be involved in sparing natural hosts of SIVs from developing SIV-related gut dysfunction. Focusing studies of the ADO pathway on mucosal sites of viral replication is warranted., Importance: The mechanisms responsible for the severe gut dysfunction characteristic of progressive HIV and SIV infection in humans and macaques are not completely elucidated. We report that ADO may play a key role in controlling immune activation/inflammation in nonprogressive SIV infections by limiting SIV-related gut inflammation. Conversely, in progressive SIV infection, significant degradation of ADO occurs, possibly due to an early increase of ADO deaminase complexing protein 2 (CD26) and adenosine deaminase. Our study supports therapeutic interventions to offset alterations of this pathway during progressive HIV/SIV infections. These potential approaches to control chronic immune activation and inflammation during pathogenic SIV infection may prevent HIV disease progression., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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16. 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.
- Author
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Ma D, Xu C, Cillo AR, Policicchio B, Kristoff J, Haret-Richter G, Mellors JW, Pandrea I, and Apetrei C
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, Macaca mulatta, Male, Simian Immunodeficiency Virus genetics, Immune Tolerance, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus immunology, Simian Immunodeficiency Virus physiology, Virus Replication
- Abstract
Simian immunodeficiency virus SIVsab infection is completely controlled in rhesus macaques (RMs) through functional immune responses. We report that in SIVsab-infected RMs, (i) viral replication is controlled to <0 to 3 copies/ml, (ii) about one-third of the virus strains in reservoirs are replication incompetent, and (iii) rebounding virus after CD8(+) cell depletion is replication competent and genetically similar to the original virus stock, suggesting early reservoir seeding. This model permits assessment of strategies aimed at depleting the reservoir without multidrug antiretroviral therapy., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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17. Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication.
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Kristoff J, Haret-Richter G, Ma D, Ribeiro RM, Xu C, Cornell E, Stock JL, He T, Mobley AD, Ross S, Trichel A, Wilson C, Tracy R, Landay A, Apetrei C, and Pandrea I
- Subjects
- Animals, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, HIV Infections microbiology, HIV Infections therapy, Humans, Intestinal Mucosa immunology, Intestinal Mucosa pathology, Intestinal Mucosa virology, Macaca nemestrina, Sevelamer, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus physiology, Viral Load drug effects, Virus Replication, Bacterial Translocation drug effects, Polyamines pharmacology, Simian Acquired Immunodeficiency Syndrome drug therapy, Simian Acquired Immunodeficiency Syndrome microbiology
- Abstract
Damage to the intestinal mucosa results in the translocation of microbes from the intestinal lumen into the circulation. Microbial translocation has been proposed to trigger immune activation, inflammation, and coagulopathy, all of which are key factors that drive HIV disease progression and non-HIV comorbidities; however, direct proof of a causal link is still lacking. Here, we have demonstrated that treatment of acutely SIV-infected pigtailed macaques with the drug sevelamer, which binds microbial lipopolysaccharide in the gut, dramatically reduces immune activation and inflammation and slightly reduces viral replication. Furthermore, sevelamer administration reduced coagulation biomarkers, confirming the contribution of microbial translocation in the development of cardiovascular comorbidities in SIV-infected nonhuman primates. Together, our data suggest that early control of microbial translocation may improve the outcome of HIV infection and limit noninfectious comorbidities associated with AIDS.
- Published
- 2014
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18. Pathogenic features associated with increased virulence upon Simian immunodeficiency virus cross-species transmission from natural hosts.
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Mandell DT, Kristoff J, Gaufin T, Gautam R, Ma D, Sandler N, Haret-Richter G, Xu C, Aamer H, Dufour J, Trichel A, Douek DC, Keele BF, Apetrei C, and Pandrea I
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes virology, Chlorocebus aethiops, HIV genetics, HIV pathogenicity, HIV physiology, HIV Infections immunology, HIV Infections transmission, HIV Infections virology, Humans, Macaca nemestrina, Serial Passage, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus genetics, Simian Immunodeficiency Virus physiology, Virulence, Virus Replication, Host Specificity, Simian Acquired Immunodeficiency Syndrome transmission, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus pathogenicity
- Abstract
Unlabelled: While simian immunodeficiency viruses (SIVs) are generally nonpathogenic in their natural hosts, dramatic increases in pathogenicity may occur upon cross-species transmission to new hosts. Deciphering the drivers of these increases in virulence is of major interest for understanding the emergence of new human immunodeficiency viruses (HIVs). We transmitted SIVsab from the sabaeus species of African green monkeys (AGMs) to pigtailed macaques (PTMs). High acute viral replication occurred in all SIVsab-infected PTMs, yet the outcome of chronic infection was highly variable, ranging from rapid progression to controlled infection, which was independent of the dynamics of acute viral replication, CD4(+) T cell depletion, or preinfection levels of microbial translocation. Infection of seven PTMs with plasma collected at necropsy from a rapid-progressor PTM was consistently highly pathogenic, with high acute and chronic viral replication, massive depletion of memory CD4(+) T cells, and disease progression in all PTMs. The plasma inoculum used for the serial passage did not contain adventitious bacterial or viral contaminants. Single-genome amplification showed that this inoculum was significantly more homogenous than the inoculum directly derived from AGMs, pointing to a strain selection in PTMs. In spite of similar peak plasma viral loads between the monkeys in the two passages, immune activation/inflammation levels dramatically increased in PTMs infected with the passaged virus. These results suggest that strain selection and a massive cytokine storm are major factors behind increased pathogenicity of SIV upon serial passage and adaptation of SIVs to new hosts following cross-species transmission., Importance: We report here that upon cross-species transmission and serial passage of SIVsab from its natural host, the sabaeus African green monkey (AGM), to a new host, the pigtailed macaque (PTM), viral adaptation and increased pathogenicity involve strain selection and a massive cytokine storm. These results permit the design of strategies aimed at preventing cross-species transmission from natural hosts of SIVs to humans in areas of endemicity. Furthermore, our study describes a new animal model for SIV infection. As the outcomes of SIVsab infection in PTMs, African green monkeys, and rhesus macaques are different, the use of these systems enables comparative studies between pathogenic, nonpathogenic, and elite-controlled infections, to gain insight into the mechanisms of SIV immunodeficiency and comorbidities., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
- Published
- 2014
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19. Kinetics of myeloid dendritic cell trafficking and activation: impact on progressive, nonprogressive and controlled SIV infections.
- Author
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Wijewardana V, Kristoff J, Xu C, Ma D, Haret-Richter G, Stock JL, Policicchio BB, Mobley AD, Nusbaum R, Aamer H, Trichel A, Ribeiro RM, Apetrei C, and Pandrea I
- Subjects
- Animals, Apoptosis immunology, Bone Marrow immunology, Bone Marrow pathology, Bystander Effect immunology, Chlorocebus aethiops, Dendritic Cells pathology, Myeloid Cells pathology, Simian Acquired Immunodeficiency Syndrome pathology, Toll-Like Receptor 7 immunology, Toll-Like Receptor 8 immunology, Cell Movement immunology, Dendritic Cells immunology, Myeloid Cells immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology
- 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.
- Published
- 2013
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20. Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates.
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Pandrea I, Cornell E, Wilson C, Ribeiro RM, Ma D, Kristoff J, Xu C, Haret-Richter GS, Trichel A, Apetrei C, Landay A, and Tracy R
- Subjects
- Animals, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Antithrombins metabolism, Biomarkers blood, Cardiovascular Diseases pathology, Cercocebus blood, Cercocebus virology, Chlorocebus aethiops, Chronic Disease, Fibrin Fibrinogen Degradation Products metabolism, Lipopolysaccharides administration & dosage, Lipopolysaccharides pharmacology, Macaca blood, Macaca virology, Receptors, Cell Surface metabolism, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus drug effects, Solubility drug effects, Thrombin metabolism, Time Factors, Blood Coagulation drug effects, Disease Progression, Primates blood, Primates virology, Simian Acquired Immunodeficiency Syndrome blood, Simian Acquired Immunodeficiency Syndrome pathology, Simian Immunodeficiency Virus physiology
- Abstract
HIV infection is associated with increased risk of cardiovascular complications, the underlying mechanism of which remains unclear. Plasma levels of the coagulation biomarker D-dimer (DD) correlate with increased mortality and cardiovascular events in HIV-infected patients. We compared the incidence of cardiovascular lesions and the levels of the coagulation markers DD and thrombin antithrombin in pathogenic SIV infections of rhesus and pigtailed macaques (PTMs) and in nonpathogenic SIV infection of African green monkeys (AGMs) and sooty mangabeys. Hypercoagulability and cardiovascular pathology were only observed in pathogenic SIV infections. In PTMs infected with SIV from AGMs (SIVagm), DD levels were highly indicative of AIDS progression and increased mortality and were associated with cardiovascular lesions, pointing to SIVagm-infected PTMs as an ideal animal model for the study of HIV-associated cardiovascular disease. In pathogenic SIV infection, DD increased early after infection, was strongly correlated with markers of immune activation/inflammation and microbial translocation (MT), and was only peripherally associated with viral loads. Endotoxin administration to SIVagm-infected AGMs (which lack chronic SIV-induced MT and immune activation) resulted in significant increases of DD. Our results demonstrate that hypercoagulation and cardiovascular pathology are at least in part a consequence of excessive immune activation and MT in SIV infection.
- Published
- 2012
- Full Text
- View/download PDF
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