Publications by authors named "Satya Dandekar"

82 Publications

Fenofibrate promotes PPARα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus.

Sci Rep 2021 Jun 29;11(1):13454. Epub 2021 Jun 29.

Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California Davis, Davis, CA, 95616, USA.

Diabetes mellitus (DM) is associated with a dysfunctional intestinal barrier and an increased risk for systemic infection and inflammation in people, though the pathogenic mechanisms leading to this are poorly understood. Using a canine model of DM, we showed that the peroxisomal proliferator-activated receptor-α agonist fenofibrate modulates plasma lipid profiles and markers of intestinal barrier function. A 3-week course of fenofibrate reduced fasting interstitial glucose and inflammatory cytokine IL-8 and TNF-α concentrations, which correlated with reduced triglyceride levels. The lipidomic profile exhibited significantly lower levels of triacylglycerols, phosphatidylethanolamines, diacylglycerols, and ceramides following fenofibrate administration. On histopathological analysis, we observed an aberrant amount of intraepithelial CD3 T lymphocytes (IEL) in the small intestine of dogs with spontaneous and induced-DM. Fenofibrate reduced IEL density in the duodenum of dogs with DM and enhanced markers of intestinal barrier function in vivo and in vitro. There were minimal changes in the intestinal microbial composition following fenofibrate administration, suggesting that repair of intestinal barriers can be achieved independently of the resident microbiota. Our findings indicate that lipid metabolism is critical to functionality of the intestinal epithelium, which can be rescued by PPARα activation in dogs with DM.
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http://dx.doi.org/10.1038/s41598-021-92966-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241862PMC
June 2021

SARS-CoV-2 detection and genomic sequencing from hospital surface samples collected at UC Davis.

PLoS One 2021 24;16(6):e0253578. Epub 2021 Jun 24.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, School of Medicine, University of California, Davis, California, United States of America.

Rationale: There is little doubt that aerosols play a major role in the transmission of SARS-CoV-2. The significance of the presence and infectivity of this virus on environmental surfaces, especially in a hospital setting, remains less clear.

Objectives: We aimed to analyze surface swabs for SARS-CoV-2 RNA and infectivity, and to determine their suitability for sequence analysis.

Methods: Samples were collected during two waves of COVID-19 at the University of California, Davis Medical Center, in COVID-19 patient serving and staff congregation areas. qRT-PCR positive samples were investigated in Vero cell cultures for cytopathic effects and phylogenetically assessed by whole genome sequencing.

Measurements And Main Results: Improved cleaning and patient management practices between April and August 2020 were associated with a substantial reduction of SARS-CoV-2 qRT-PCR positivity (from 11% to 2%) in hospital surface samples. Even though we recovered near-complete genome sequences in some, none of the positive samples (11 of 224 total) caused cytopathic effects in cultured cells suggesting this nucleic acid was either not associated with intact virions, or they were present in insufficient numbers for infectivity. Phylogenetic analysis suggested that the SARS-CoV-2 genomes of the positive samples were derived from hospitalized patients. Genomic sequences isolated from qRT-PCR negative samples indicate a superior sensitivity of viral detection by sequencing.

Conclusions: This study confirms the low likelihood that SARS-CoV-2 contamination on hospital surfaces contains infectious virus, disputing the importance of fomites in COVID-19 transmission. Ours is the first report on recovering near-complete SARS-CoV-2 genome sequences directly from environmental surface swabs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253578PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224861PMC
July 2021

Gut germinal center regeneration and enhanced antiviral immunity by mesenchymal stem/stromal cells in SIV infection.

JCI Insight 2021 Jun 22;6(12). Epub 2021 Jun 22.

Department of Medical Microbiology and Immunology and.

Although antiretroviral therapy suppresses HIV replication, it does not eliminate viral reservoirs or restore damaged lymphoid tissue, posing obstacles to HIV eradication. Using the SIV model of AIDS, we investigated the effect of mesenchymal stem/stromal cell (MSC) infusions on gut mucosal recovery, antiviral immunity, and viral suppression and determined associated molecular/metabolic signatures. MSC administration to SIV-infected macaques resulted in viral reduction and heightened virus-specific responses. Marked clearance of SIV-positive cells from gut mucosal effector sites was correlated with robust regeneration of germinal centers, restoration of follicular B cells and T follicular helper (Tfh) cells, and enhanced antigen presentation by viral trapping within the follicular DC network. Gut transcriptomic analyses showed increased antiviral response mediated by pathways of type I/II IFN signaling, viral restriction factors, innate immunity, and B cell proliferation and provided the molecular signature underlying enhanced host immunity. Metabolic analysis revealed strong correlations between B and Tfh cell activation, anti-SIV antibodies, and IL-7 expression with enriched retinol metabolism, which facilitates gut homing of antigen-activated lymphocytes. We identified potentially new MSC functions in modulating antiviral immunity for enhanced viral clearance predominantly through type I/II IFN signaling and B cell signature, providing a road map for multipronged HIV eradication strategies.
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http://dx.doi.org/10.1172/jci.insight.149033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262475PMC
June 2021

Short-Term Western Diet Intake Promotes IL-23‒Mediated Skin and Joint Inflammation Accompanied by Changes to the Gut Microbiota in Mice.

J Invest Dermatol 2021 Jul 22;141(7):1780-1791. Epub 2021 Jan 22.

Department of Dermatology, University of California Davis School of Medicine, Sacramento, California, USA. Electronic address:

We previously showed that exposure to a high-sugar and moderate-fat diet (i.e., Western diet [WD]) in mice induces appreciable skin inflammation and enhances the susceptibility to imiquimod-induced psoriasiform dermatitis, suggesting that dietary components may render the skin susceptible to psoriatic inflammation. In this study, utilizing an IL-23 minicircle-based model with features of both psoriasiform dermatitis and psoriatic arthritis, we showed that intake of WD for 10 weeks predisposed mice not only to skin but also to joint inflammation. Both WD-induced skin and joint injuries were associated with an expansion of IL-17A‒producing γδ T cells and increased expression of T helper type 17 cytokines. After IL-23 minicircle delivery, WD-fed mice had reduced microbial diversity and pronounced dysbiosis. Treatment with broad-spectrum antibiotics suppressed IL-23‒mediated skin and joint inflammation in the WD-fed mice. Strikingly, reduced skin and joint inflammation with a partial reversion of the gut microbiota were noted when mice switched from a WD to a standard diet after IL-23 minicircle delivery. These findings reveal that a short-term WD intake‒induced dysbiosis is accompanied by enhanced psoriasis-like skin and joint inflammation. Modifications toward a healthier dietary pattern should be considered in patients with psoriatic skin and/or joint disease.
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http://dx.doi.org/10.1016/j.jid.2020.11.032DOI Listing
July 2021

Efficacy of silk fibroin biomaterial vehicle for in vivo mucosal delivery of Griffithsin and protection against HIV and SHIV infection ex vivo.

J Int AIDS Soc 2020 10;23(10):e25628

Department of Medical Microbiology & Immunology, School of Medicine, University of California Davis, Davis, CA, USA.

Introduction: The majority of new HIV infections occur through mucosal transmission. The availability of readily applicable and accessible platforms for anti-retroviral (ARV) delivery is critical for the prevention of HIV acquisition through sexual transmission in both women and men. There is a compelling need for developing new topical delivery systems that have advantages over the pills, gels and rings, which currently fail to guarantee protection against mucosal viral transmission in vulnerable populations due to lack of user compliance. The silk fibroin (SF) platform offers another option that may be better suited to individual circumstances and preferences to increase efficacy through user compliance. The objective of this study was to test safety and efficacy of SF for anti-HIV drug delivery to mucosal sites and for viral prevention.

Methods: We formulated a potent HIV inhibitor Griffithsin (Grft) in a mucoadhesive silk fibroin (SF) drug delivery platform and tested the application in a non-human primate model in vivo and a pre-clinical human cervical and colorectal tissue explant model. Both vaginal and rectal compartments were assessed in rhesus macaques (Mucaca mulatta) that received SF (n = 4), no SF (n = 7) and SF-Grft (n = 11). In this study, we evaluated the composition of local microbiota, inflammatory cytokine production, histopathological changes in the vaginal and rectal compartments and mucosal protection after ex vivo SHIV challenge.

Results: Effective Grft release and retention in mucosal tissues from the SF-Grft platform resulted in protection against HIV in human cervical and colorectal tissue as well as against SHIV challenge in both rhesus macaque vaginal and rectal tissues. Mucoadhesion of SF-Grft inserts did not cause any inflammatory responses or changes in local microbiota.

Conclusions: We demonstrated that in vivo delivery of SF-Grft in rhesus macaques fully protects against SHIV challenge ex vivo after two hours of application and is safe to use in both the vaginal and rectal compartments. Our study provides support for the development of silk fibroin as a highly promising, user-friendly HIV prevention modality to address the global disparity in HIV infection.
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http://dx.doi.org/10.1002/jia2.25628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569169PMC
October 2020

A Summary of the Fifth Annual Virology Education HIV Microbiome Workshop.

AIDS Res Hum Retroviruses 2020 11 7;36(11):886-895. Epub 2020 Sep 7.

Department of Epidemiology, The George Washington University, Washington, District of Columbia, USA.

In October of 2019, researchers and community members from around the world met at the NIH for the fifth annual International Workshop on Microbiome in HIV. New research was presented on the role of the microbiome on chronic inflammation and vaccine design, interactions of genetics, environment, sexual practice and HIV infection with the microbiome and the development and clinical trials of microbiome-based therapeutic approaches intended to decrease the probability of HIV acquisition/transmission or ameliorate sequelae of HIV. The keynote address by Dr. Jacques Ravel focused on his work on the vaginal microbiome and efforts to improve the analysis and resolution of microbiome data.
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http://dx.doi.org/10.1089/AID.2020.0121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869876PMC
November 2020

A Summary of the Fourth Annual Virology Education HIV Microbiome Workshop.

AIDS Res Hum Retroviruses 2020 05 9;36(5):349-356. Epub 2020 Mar 9.

Division of Gerontology, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.

Each year, a growing international collection of researchers meets at the NIH to share and discuss developments in the microbiome HIV story. This past year has seen continued progress toward a detailed understanding of host-microbe interactions both within and outside the field of HIV. Commensal microbes are being linked to an ever-growing list of maladies and physiologic states, including major depressive disorder, chronic kidney disease, and Parkinson disease. PubMed citations for "microbiome" are growing at an exponential rate with over 11,000 in 2018. Various microbial taxa have been associated with HIV infection, and some of these taxa associated with HIV infection have also been associated with systemic markers of inflammation in HIV infected individuals. Causality remains unclear however as environmental and behavioral factors may drive HIV risk, inflammation, and gut enterotype. Much of the work currently being done addresses potential mechanisms by which gut microbes influence immune and inflammatory pathways. No portion of the microbiome landscape has grown as rapidly as study of the interplay between gut microbes and response to cancer immunotherapy. As Dr. Wargo discussed in her keynote address, this area has opened the door to better understanding on how commensal microbes interact with the human immune system.
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http://dx.doi.org/10.1089/AID.2019.0197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360108PMC
May 2020

PPARα-targeted mitochondrial bioenergetics mediate repair of intestinal barriers at the host-microbe intersection during SIV infection.

Proc Natl Acad Sci U S A 2019 12 18;116(49):24819-24829. Epub 2019 Nov 18.

Department of Medical Microbiology & Immunology, University of California Davis School of Medicine, Davis, CA 95616;

Chronic gut inflammatory diseases are associated with disruption of intestinal epithelial barriers and impaired mucosal immunity. HIV-1 (HIV) causes depletion of mucosal CD4 T cells early in infection and disruption of gut epithelium, resulting in chronic inflammation and immunodeficiency. Although antiretroviral therapy (ART) is effective in suppressing viral replication, it is incapable of restoring the "leaky gut," which poses an impediment for HIV cure efforts. Strategies are needed for rapid repair of the epithelium to protect intestinal microenvironments and immunity in inflamed gut. Using an in vivo nonhuman primate intestinal loop model of HIV/AIDS, we identified the pathogenic mechanism underlying sustained disruption of gut epithelium and explored rapid repair of gut epithelium at the intersection of microbial metabolism. Molecular, immunological, and metabolomic analyses revealed marked loss of peroxisomal proliferator-activated receptor-α (PPARα) signaling, predominant impairment of mitochondrial function, and epithelial disruption both in vivo and in vitro. To elucidate pathways regulating intestinal epithelial integrity, we introduced probiotic into Simian immunodeficiency virus (SIV)-inflamed intestinal lumen. Rapid recovery of the epithelium occurred within 5 h of administration, independent of mucosal CD4 T cell recovery, and in the absence of ART. This intestinal barrier repair was driven by -induced PPARα activation and restoration of mitochondrial structure and fatty acid β-oxidation. Our data highlight the critical role of PPARα at the intersection between microbial metabolism and epithelial repair in virally inflamed gut and as a potential mitochondrial target for restoring gut barriers in other infectious or gut inflammatory diseases.
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http://dx.doi.org/10.1073/pnas.1908977116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900595PMC
December 2019

Disruption of latent HIV in vivo during the clearance of actinic keratosis by ingenol mebutate.

JCI Insight 2019 04 4;4(7). Epub 2019 Apr 4.

Department of Medical Microbiology and Immunology and.

Actinic keratosis (AK) is a precancerous skin lesion that is common in HIV-positive patients. Without effective treatment, AKs can progress to squamous cell carcinoma. Ingenol mebutate, a PKC agonist, is a US Food and Drug Administration-approved (FDA-approved) topical treatment for AKs. It can induce reactivation of latent HIV transcription in CD4+ T cells both in vitro and ex vivo. Although PKC agonists are known to be potent inducers of HIV expression from latency, their effects in vivo are not known because of the concerns of toxicity. Therefore, we sought to determine the effects of topical ingenol mebutate gel on the HIV transcription profile in HIV-infected individuals with AKs, specifically in the setting of suppressive antiretroviral therapy (ART). We found that AKs cleared following topical application of ingenol mebutate and detected marginal changes in immune activation in the peripheral blood and in skin biopsies. An overall increase in the level of HIV transcription initiation, elongation, and complete transcription was detected only in skin biopsies after the treatment. Our data demonstrate that application of ingenol mebutate to AKs in ART-suppressed HIV-positive patients can effectively cure AKs as well as disrupt HIV latency in the skin tissue microenvironment in vivo without causing massive immune activation.
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http://dx.doi.org/10.1172/jci.insight.126027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483647PMC
April 2019

Pharmaceutical Approaches to HIV Treatment and Prevention.

Adv Ther (Weinh) 2018 Oct 29;1(6). Epub 2018 Jul 29.

Department of Biomedical Engineering Tufts University 4 Colby Street, Medford, MA 02155, USA.

Human immunodeficiency virus (HIV) infection continues to pose a major infectious disease threat worldwide. It is characterized by the depletion of CD4 T cells, persistent immune activation, and increased susceptibility to secondary infections. Advances in the development of antiretroviral drugs and combination antiretroviral therapy have resulted in a remarkable reduction in HIV-associated morbidity and mortality. Antiretroviral therapy (ART) leads to effective suppression of HIV replication with partial recovery of host immune system and has successfully transformed HIV infection from a fatal disease to a chronic condition. Additionally, antiretroviral drugs have shown promise for prevention in HIV pre-exposure prophylaxis and treatment as prevention. However, ART is unable to cure HIV. Other limitations include drug-drug interactions, drug resistance, cytotoxic side effects, cost, and adherence. Alternative treatment options are being investigated to overcome these challenges including discovery of new molecules with increased anti-viral activity and development of easily administrable drug formulations. In light of the difficulties associated with current HIV treatment measures, and in the continuing absence of a cure, the prevention of new infections has also arisen as a prominent goal among efforts to curtail the worldwide HIV pandemic. In this review, the authors summarize currently available anti-HIV drugs and their combinations for treatment, new molecules under clinical development and prevention methods, and discuss drug delivery formats as well as associated challenges and alternative approaches for the future.
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http://dx.doi.org/10.1002/adtp.201800054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413291PMC
October 2018

A Summary of the Third Annual HIV Microbiome Workshop.

AIDS Res Hum Retroviruses 2018 10 9;34(10):828-834. Epub 2018 Oct 9.

13 Department of Immunology/Microbiology, Rush University Medical Center , Chicago, Illinois.

Our microbial cotravelers have increasingly apparent roles in both maintaining health and causing disease in several organ systems. Investigators gather annually at the National Institutes of Health to present new discoveries regarding the role of the microbiome in human health and a special focus on persons living with HIV. Here, we summarize the discussions from the third annual Virology Education workshop on the microbiome in HIV, which took place in October of 2017.
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http://dx.doi.org/10.1089/AID.2018.0103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422011PMC
October 2018

Subclinical Cytomegalovirus Infection Is Associated with Altered Host Immunity, Gut Microbiota, and Vaccine Responses.

J Virol 2018 07 13;92(13). Epub 2018 Jun 13.

Department of Medical Microbiology and Immunology, University of California, Davis, California, USA

Subclinical viral infections (SVI), including cytomegalovirus (CMV), are highly prevalent in humans, resulting in lifelong persistence. However, the impact of SVI on the interplay between the host immunity and gut microbiota in the context of environmental exposures is not well defined. We utilized the preclinical nonhuman primate (NHP) model consisting of SVI-free (specific-pathogen-free [SPF]) rhesus macaques and compared them to the animals with SVI (non-SPF) acquired through natural exposure and investigated the impact of SVI on immune cell distribution and function, as well as on gut microbiota. These changes were examined in animals housed in the outdoor environment compared to the controlled indoor environment. We report that SVI are associated with altered immune cell subsets and gut microbiota composition in animals housed in the outdoor environment. Non-SPF animals harbored a higher proportion of potential butyrate-producing and higher numbers of lymphocytes, effector T cells, and cytokine-producing T cells. Surprisingly, these differences diminished following their transfer to the controlled indoor environment, suggesting that non-SPFs had increased responsiveness to environmental exposures. An experimental infection of indoor SPF animals with CMV resulted in an increased abundance of butyrate-producing bacteria, validating that CMV enhanced colonization of butyrate-producing commensals. Finally, non-SPF animals displayed lower antibody responses to influenza vaccination compared to SPF animals. Our data show that subclinical CMV infection heightens host immunity and gut microbiota changes in response to environmental exposures. This may contribute to the heterogeneity in host immune response to vaccines and environmental stimuli at the population level. Humans harbor several latent viruses that modulate host immunity and commensal microbiota, thus introducing heterogeneity in their responses to pathogens, vaccines, and environmental exposures. Most of our understanding of the effect of CMV on the immune system is based on studies of children acquiring CMV or of immunocompromised humans with acute or reactivated CMV infection or in ageing individuals. The experimental mouse models are genetically inbred and are completely adapted to the indoor laboratory environment. In contrast, nonhuman primates are genetically outbred and are raised in the outdoor environment. Our study is the first to report the impact of long-term subclinical CMV infection on host immunity and gut microbiota, which is evident only in the outdoor environment but not in the indoor environment. The significance of this study is in highlighting the impact of SVI on enhancing host immune susceptibility to environmental exposures and immune heterogeneity.
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http://dx.doi.org/10.1128/JVI.00167-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002712PMC
July 2018

HIV latency is reversed by ACSS2-driven histone crotonylation.

J Clin Invest 2018 03 19;128(3):1190-1198. Epub 2018 Feb 19.

Department of Medical Microbiology and Immunology, UCD, Davis, California, USA.

Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat (LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA-producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2). This reprogrammed the local chromatin at the HIV LTR through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminished histone crotonylation-induced HIV replication and reactivation. ACSS2 induction was highly synergistic in combination with either a protein kinase C agonist (PEP005) or a histone deacetylase inhibitor (vorinostat) in reactivating latent HIV. In the SIV-infected nonhuman primate model of AIDS, the expression of ACSS2 was significantly induced in intestinal mucosa in vivo, which correlated with altered fatty acid metabolism. Our study links the HIV/SIV infection-induced fatty acid enzyme ACSS2 to HIV latency and identifies histone lysine crotonylation as a novel epigenetic regulator for HIV transcription that can be targeted for HIV eradication.
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http://dx.doi.org/10.1172/JCI98071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824862PMC
March 2018

A Summary of the Second Annual HIV Microbiome Workshop.

AIDS Res Hum Retroviruses 2017 12 26;33(12):1258-1264. Epub 2017 Oct 26.

14 Department of Immunology/Microbiology, Rush University Medical Center , Chicago, Illinois.

Commensal organisms appear to play significant roles in normal homeostasis as well as in the pathogenesis of HIV infection in a number of different organ systems. On November 17th and 18th, 2016, leading researchers from around the world met to discuss their insights on advances in our understanding of HIV and the microbiome at the National Institutes of Health (NIH) in Bethesda. Dr. Elhanan Borenstein of the University of Washington gave a keynote address where he discussed new developments in systems biology which hold the promise of illuminating the pathways by which these organisms interact with human physiology. He suggested that we need to get past correlations in microbiome research by using models and informatics which incorporate metagenomics to predict functional changes in the microbiome.
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http://dx.doi.org/10.1089/aid.2017.0137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770117PMC
December 2017

Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma.

Mol Cancer Ther 2017 11 28;16(11):2627-2638. Epub 2017 Aug 28.

Department of Dermatology, University of California Davis (UC Davis) School of Medicine, Sacramento, California.

Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Currently, treatment options for patients with PEL are limited. Oncolytic viruses have been engineered as anticancer agents and have recently shown increased therapeutic promise. Similarly, lytic activation of endogenous viruses from latently infected tumor cells can also be applied as a cancer therapy. In theory, such a therapeutic strategy would induce oncolysis by viral replication, while simultaneously stimulating an immune response to viral lytic cycle antigens. We examined the combination of the FDA-approved drug ingenol-3-angelate (PEP005) with epigenetic drugs as a rational therapeutic approach for KSHV-mediated malignancies. JQ1, a bromodomain and extra terminal (BET) protein inhibitor, in combination with PEP005, not only robustly induced KSHV lytic replication, but also inhibited IL6 production from PEL cells. Using the dosages of these agents that were found to be effective in reactivating HIV (as a means to clear latent virus with highly active antiretroviral therapy), we were able to inhibit PEL growth and delay tumor growth in a PEL xenograft tumor model. KSHV reactivation was mediated by activation of the NF-κB pathway by PEP005, which led to increased occupancy of RNA polymerase II onto the KSHV genome. RNA-sequencing analysis further revealed cellular targets of PEP005, JQ1, and the synergistic effects of both. Thus, combination of PEP005 with a BET inhibitor may be considered as a rational therapeutic approach for the treatment of PEL. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914504PMC
November 2017

HIV Exploits Antiviral Host Innate GCN2-ATF4 Signaling for Establishing Viral Replication Early in Infection.

mBio 2017 05 2;8(3). Epub 2017 May 2.

Department of Medical Microbiology and Immunology, University of California, Davis, California, USA

Antiviral innate host defenses against acute viral infections include suppression of host protein synthesis to restrict viral protein production. Less is known about mechanisms by which viral pathogens subvert host antiviral innate responses for establishing their replication and dissemination. We investigated early innate defense against human immunodeficiency virus (HIV) infection and viral evasion by utilizing human CD4 T cell cultures and a simian immunodeficiency virus (SIV) model of AIDS Our data showed that early host innate defense against the viral infection involves GCN2-ATF4 signaling-mediated suppression of global protein synthesis, which is exploited by the virus for supporting its own replication during early viral infection and dissemination in the gut mucosa. Suppression of protein synthesis and induction of protein kinase GCN2-ATF4 signaling were detected in the gut during acute SIV infection. These changes diminished during chronic viral infection. HIV replication induced by serum deprivation in CD4 T cells was linked to the induction of ATF4 that was recruited to the HIV long terminal repeat (LTR) to promote viral transcription. Experimental inhibition of GCN2-ATF4 signaling either by a specific inhibitor or by amino acid supplementation suppressed the induction of HIV expression. Enhancing ATF4 expression through selenium administration resulted in reactivation of latent HIV as well as in the primary CD4 T cells isolated from patients receiving suppressive antiretroviral therapy (ART). In summary, HIV/SIV exploits the early host antiviral response through GCN2-ATF4 signaling by utilizing ATF4 for activating the viral LTR transcription to establish initial viral replication and is a potential target for HIV prevention and therapy. Understanding how HIV overcomes host antiviral innate defense response in order to establish infection and dissemination is critical for developing prevention and treatment strategies. Most investigations focused on the viral pathogenic mechanisms leading to immune dysfunction following robust viral infection and dissemination. Less is known about mechanisms that enable HIV to establish its presence despite rapid onset of host antiviral innate response. Our novel findings provide insights into the viral strategy that hijacks the host innate response of the suppression of protein biosynthesis to restrict the virus production. The virus leverages transcription factor ATF4 expression during the GCN2-ATF4 signaling response and utilizes it to activate viral transcription through the LTR to support viral transcription and production in both HIV and SIV infections. This unique viral strategy is exploiting the innate response and is distinct from the mechanisms of immune dysfunction after the critical mass of viral loads is generated.
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http://dx.doi.org/10.1128/mBio.01518-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414007PMC
May 2017

Divergent Annexin A1 expression in periphery and gut is associated with systemic immune activation and impaired gut immune response during SIV infection.

Sci Rep 2016 08 3;6:31157. Epub 2016 Aug 3.

Institute of Genetics and Biochemistry, Federal University of Uberlandia, Uberlandia, MG, Brazil.

HIV-1 disease progression is paradoxically characterized by systemic chronic immune activation and gut mucosal immune dysfunction, which is not fully defined. Annexin A1 (ANXA1), an inflammation modulator, is a potential link between systemic inflammation and gut immune dysfunction during the simian immunodeficiency virus (SIV) infection. Gene expression of ANXA1 and cytokines were assessed in therapy-naïve rhesus macaques during early and chronic stages of SIV infection and compared with SIV-negative controls. ANXA1 expression was suppressed in the gut but systemically increased during early infection. Conversely, ANXA1 expression increased in both compartments during chronic infection. ANXA1 expression in peripheral blood was positively correlated with HLA-DR+CD4+ and CD8+ T-cell frequencies, and negatively associated with the expression of pro-inflammatory cytokines and CCR5. In contrast, the gut mucosa presented an anergic cytokine profile in relation to ANXA1 expression. In vitro stimulations with ANXA1 peptide resulted in decreased inflammatory response in PBMC but increased activation of gut lymphocytes. Our findings suggest that ANXA1 signaling is dysfunctional in SIV infection, and may contribute to chronic inflammation in periphery and with immune dysfunction in the gut mucosa. Thus, ANXA1 signaling may be a novel therapeutic target for the resolution of immune dysfunction in HIV infection.
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http://dx.doi.org/10.1038/srep31157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971494PMC
August 2016

A Summary of the First HIV Microbiome Workshop 2015.

AIDS Res Hum Retroviruses 2016 Oct/Nov;32(10-11):935-941. Epub 2016 Jul 14.

2 Department of Immunology/Microbiology, Rush University Medical Center , Chicago, Illinois.

The role of microbiota in the pathogenesis of HIV infection has become the subject of intense research in recent years. A rapidly growing amount of data suggest that microbial dysbiosis-in the gut or the genital tract-can influence HIV transmission and/or disease progression; however, a deeper understanding of the mechanisms involved is lacking. To better understand the relationship between the microbiome and HIV infection, investigators from a wide variety of disciplines, including those working in basic and clinical HIV studies, cardiovascular disease, reproductive health, and bioinformatics, gathered at the first International Workshop on Microbiome in HIV Pathogenesis, Prevention and Treatment, at NIH on 7 and 8 April, 2015.
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http://dx.doi.org/10.1089/AID.2016.0034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445214PMC
December 2017

Gene expression of Lactobacillus plantarum and the commensal microbiota in the ileum of healthy and early SIV-infected rhesus macaques.

Sci Rep 2016 04 22;6:24723. Epub 2016 Apr 22.

Department of Food Science and Technology, University of California, Davis, CA, USA.

Chronic HIV infection results in impairment of gut-associated lymphoid tissue leading to systemic immune activation. We previously showed that in early SIV-infected rhesus macaques intestinal dysfunction is initiated with the induction of the IL-1β pathway in the small intestine and reversed by treatment with an exogenous Lactobacillus plantarum strain. Here, we provide evidence that the transcriptomes of L. plantarum and ileal microbiota are not altered shortly after SIV infection. L. plantarum adapts to the small intestine by expressing genes required for tolerating oxidative stress, modifying cell surface composition, and consumption of host glycans. The ileal microbiota of L. plantarum-containing healthy and SIV+ rhesus macaques also transcribed genes for host glycan metabolism as well as for cobalamin biosynthesis. Expression of these pathways by bacteria were proposed but not previously demonstrated in the mammalian small intestine.
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http://dx.doi.org/10.1038/srep24723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840379PMC
April 2016

Loss of Multicellular Behavior in Epidemic African Nontyphoidal Salmonella enterica Serovar Typhimurium ST313 Strain D23580.

mBio 2016 Mar 1;7(2):e02265. Epub 2016 Mar 1.

Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington, USA

Unlabelled: Nontyphoidal Salmonella enterica serovar Typhimurium is a frequent cause of bloodstream infections in children and HIV-infected adults in sub-Saharan Africa. Most isolates from African patients with bacteremia belong to a single sequence type, ST313, which is genetically distinct from gastroenteritis-associated ST19 strains, such as 14028s and SL1344. Some studies suggest that the rapid spread of ST313 across sub-Saharan Africa has been facilitated by anthroponotic (person-to-person) transmission, eliminating the need for Salmonella survival outside the host. While these studies have not ruled out zoonotic or other means of transmission, the anthroponotic hypothesis is supported by evidence of extensive genomic decay, a hallmark of host adaptation, in the sequenced ST313 strain D23580. We have identified and demonstrated 2 loss-of-function mutations in D23580, not present in the ST19 strain 14028s, that impair multicellular stress resistance associated with survival outside the host. These mutations result in inactivation of the KatE stationary-phase catalase that protects high-density bacterial communities from oxidative stress and the BcsG cellulose biosynthetic enzyme required for the RDAR (red, dry, and rough) colonial phenotype. However, we found that like 14028s, D23580 is able to elicit an acute inflammatory response and cause enteritis in mice and rhesus macaque monkeys. Collectively, these observations suggest that African S. Typhimurium ST313 strain D23580 is becoming adapted to an anthroponotic mode of transmission while retaining the ability to infect and cause enteritis in multiple host species.

Importance: The last 3 decades have witnessed an epidemic of invasive nontyphoidal Salmonella infections in sub-Saharan Africa. Genomic analysis and clinical observations suggest that the Salmonella strains responsible for these infections are evolving to become more typhoid-like with regard to patterns of transmission and virulence. This study shows that a prototypical African nontyphoidal Salmonella strain has lost traits required for environmental stress resistance, consistent with an adaptation to a human-to-human mode of transmission. However, in contrast to predictions, the strain remains capable of causing acute inflammation in the mammalian intestine. This suggests that the systemic clinical presentation of invasive nontyphoidal Salmonella infections in Africa reflects the immune status of infected hosts rather than intrinsic differences in the virulence of African Salmonella strains. Our study provides important new insights into the evolution of host adaptation in bacterial pathogens.
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http://dx.doi.org/10.1128/mBio.02265-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810497PMC
March 2016

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition.

Antimicrob Agents Chemother 2016 05 22;60(5):2771-81. Epub 2016 Apr 22.

Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

This study investigated the effects of HIV-1 infection and antiretroviral therapy (ART) on the expression of intestinal drug efflux transporters, i.e., P-glycoprotein (Pgp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP), and metabolic enzymes, such as cytochrome P450s (CYPs), in the human upper intestinal tract. Intestinal biopsy specimens were obtained from HIV-negative healthy volunteers, ART-naive HIV-positive (HIV(+)) subjects, and HIV(+) subjects receiving ART (10 in each group). Intestinal tissue expression of drug transporters and metabolic enzymes was examined by microarray, real-time quantitative reverse transcription-PCR (qPCR), and immunohistochemistry analyses. Microarray analysis demonstrated significantly lower expression of CYP3A4 and ABCC2/MRP2 in the HIV(+) ART-naive group than in uninfected subjects. qPCR analysis confirmed significantly lower expression of ABCC2/MRP2 in ART-naive subjects than in the control group, while CYP3A4 and ABCG2/BCRP showed a trend toward decreased expression. Protein expression of MRP2 and BCRP was also significantly lower in the HIV(+) naive group than in the control group and was partially restored to baseline levels in HIV(+) subjects receiving ART. In contrast, gene and protein expression of ABCB1/Pgp was significantly increased in HIV(+) subjects on ART relative to HIV(+) ART-naive subjects. These data demonstrate that the expression of drug-metabolizing enzymes and efflux transporters is significantly altered in therapy-naive HIV(+) subjects and in those receiving ART. Since CYP3A4, Pgp, MRPs, and BCRP metabolize or transport many antiretroviral drugs, their altered expression with HIV infection may negatively impact drug pharmacokinetics in HIV(+) subjects. This has clinical implications when using data from healthy volunteers to guide ART.
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http://dx.doi.org/10.1128/AAC.02278-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862509PMC
May 2016

Gene expression and TB pathogenesis in rhesus macaques: TR4, CD40, CD40L, FAS (CD95), and TNF are host genetic markers in peripheral blood mononuclear cells that are associated with severity of TB lesions.

Infect Genet Evol 2015 Dec 19;36:396-409. Epub 2015 Oct 19.

Graduate Group of Comparative Pathology, University of California, Davis, United States; Department of Anthropology, University of California, Davis, United States; California National Primate Research Center (CNPRC), University of California Davis, Davis, CA 95616, United States.

Tuberculosis (TB) pathologic lesions in rhesus macaques resemble those in humans. The expression levels of several host TB candidate genes in the peripheral blood mononuclear cells (PBMCs) of six rhesus macaques experimentally infected with Mycobacterium tuberculosis were quantified pre-infection and at several dates post-infection. Quantitative measures of TB histopathology in the lungs including: granuloma count, granuloma size, volume of granulomatous and non-granulomatous lesions, and direct bacterial load, were used as the outcomes of a multi-level Bayesian regression model in which expression levels of host genes at various dates were used as predictors. The results indicate that the expression levels of TR4, CD40, CD40L, FAS (CD95) and TNF in PBMC were associated with quantitative measures of the severity of TB histopathologic lesions in the lungs of the study animals. Moreover, no reliable association between the expression levels of IFNE in PBMCs and the severity of TB lesions in the lungs of the study animals was found. In conclusion, PBMC expression profiles derived from the above-listed host genes might be appropriate biomarkers for probabilistic diagnosis and/or prognosis of TB severity in rhesus macaques.
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http://dx.doi.org/10.1016/j.meegid.2015.10.010DOI Listing
December 2015

Functional analysis of the relationship between intestinal microbiota and the expression of hepatic genes and pathways during the course of liver regeneration.

J Hepatol 2016 Mar 12;64(3):641-50. Epub 2016 Jan 12.

Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA. Electronic address:

Background & Aims: The pathways regulating liver regeneration have been extensively studied within the liver. However, the signaling contribution derived from the gut microbiota to liver regeneration is poorly understood.

Methods: Microbiota and expression of hepatic genes in regenerating livers obtained from mice at 0h to 9days post 2/3 partial hepatectomy were temporally profiled to establish their interactive relationships.

Results: Partial hepatectomy led to rapid changes in gut microbiota that was reflected in an increased abundance of Bacteroidetes S24-7 and Rikenellaceae and decreased abundance of Firmicutes Clostridiales, Lachnospiraceae, and Ruminococcaceae. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to infer biological functional changes of the shifted microbiota. RNA-sequencing data revealed 6125 genes with more than a 2-fold difference in their expression levels during regeneration. By analyzing their expression pattern, six uniquely expressed patterns were observed. In addition, there were significant correlations between hepatic gene expression profiles and shifted bacterial populations during regeneration. Moreover, hepatic metabolism and immune function were closely associated with the abundance of Ruminococcacea, Lachnospiraceae, and S24-7. Bile acid profile was analyzed because bacterial enzymes produce bile acids that significantly impact hepatocyte proliferation. The data revealed that specific bacteria were closely associated with the concentration of certain bile acids and expression of hepatic genes.

Conclusions: The presented data established, for the first time, an intimate relationship between intestinal microbiota and the expression of hepatic genes in regenerating livers.
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http://dx.doi.org/10.1016/j.jhep.2015.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761311PMC
March 2016

SIV-infection-driven changes of pattern recognition receptor expression in mesenteric lymph nodes and gut microbiota dysbiosis.

J Med Primatol 2015 Oct 14;44(5):241-52. Epub 2015 Aug 14.

Department of Medical Microbiology & Immunology, University of California, Davis, CA, USA.

Background: The impact of HIV infection on pattern recognition receptor (PRR) expression in gut-associated lymphoid tissue and its association with dysbiosis is not well understood.

Methods: PRR and cytokine gene expression were examined in mesenteric lymph nodes (mLN) of rhesus macaques during acute and chronic (untreated and early antiretroviral (ART) treated) infections. Gene expression was correlated with microbial abundance in the gut and immune activation.

Results: PRR expression rapidly increases during acute infection and is significantly decreased in chronic infection. Early ART maintains elevated PRR expression. Correlation analysis revealed three distinct groups of bacterial taxa that were associated with gene expression changes in infection.

Conclusions: PRR and cytokine gene expression in the gut-draining mLN are rapidly modulated in response to viral infection and are correlated with gut dysbiosis. These data suggest that the dysregulation of PRR and related cytokine expression may contribute to chronic immune activation in SIV infection.
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http://dx.doi.org/10.1111/jmp.12187DOI Listing
October 2015

Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation.

PLoS Pathog 2015 Jul 30;11(7):e1005066. Epub 2015 Jul 30.

Department of Medical Microbiology and Immunology, University of California, Davis, Davis, California, United States of America; Department of Internal Medicine, Division of Infectious Diseases, University of California Davis Medical Center, Sacramento, California, United States of America.

Although anti-retroviral therapy (ART) is highly effective in suppressing HIV replication, it fails to eradicate the virus from HIV-infected individuals. Stable latent HIV reservoirs are rapidly established early after HIV infection. Therefore, effective strategies for eradication of the HIV reservoirs are urgently needed. We report that ingenol-3-angelate (PEP005), the only active component in a previously FDA approved drug (PICATO) for the topical treatment of precancerous actinic keratosis, can effectively reactivate latent HIV in vitro and ex vivo with relatively low cellular toxicity. Biochemical analysis showed that PEP005 reactivated latent HIV through the induction of the pS643/S676-PKCδ/θ-IκBα/ε-NF-κB signaling pathway. Importantly, PEP005 alone was sufficient to induce expression of fully elongated and processed HIV RNAs in primary CD4+ T cells from HIV infected individuals receiving suppressive ART. Furthermore, PEP005 and the P-TEFb agonist, JQ1, exhibited synergism in reactivation of latent HIV with a combined effect that is 7.5-fold higher than the effect of PEP005 alone. Conversely, PEP005 suppressed HIV infection of primary CD4+ T cells through down-modulation of cell surface expression of HIV co-receptors. This anti-cancer compound is a potential candidate for advancing HIV eradication strategies.
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http://dx.doi.org/10.1371/journal.ppat.1005066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520526PMC
July 2015

Cytomegalovirus enhances macrophage TLR expression and MyD88-mediated signal transduction to potentiate inducible inflammatory responses.

J Immunol 2014 Dec 29;193(11):5604-12. Epub 2014 Oct 29.

Division of Gastroenterology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294; and

Circulating monocytes carrying human CMV (HCMV) migrate into tissues, where they differentiate into HCMV-infected resident macrophages that upon interaction with bacterial products may potentiate tissue inflammation. In this study, we investigated the mechanism by which HCMV promotes macrophage-orchestrated inflammation using a clinical isolate of HCMV (TR) and macrophages derived from primary human monocytes. HCMV infection of the macrophages, which was associated with viral DNA replication, significantly enhanced TNF-α, IL-6, and IL-8 gene expression and protein production in response to TLR4 ligand (LPS) stimulation compared with mock-infected LPS-stimulated macrophages during a 6-d in vitro infection. HCMV infection also potentiated TLR5 ligand-stimulated cytokine production. To elucidate the mechanism by which HCMV infection potentiated inducible macrophage responses, we show that infection by HCMV promoted the maintenance of surface CD14 and TLR4 and TLR5, which declined over time in mock-infected macrophages, and enhanced both the intracellular expression of adaptor protein MyD88 and the inducible phosphorylation of IκBα and NF-κB. These findings provide additional information toward elucidating the mechanism by which HCMV potentiates bacteria-induced NF-κB-mediated macrophage inflammatory responses, thereby enhancing organ inflammation in HCMV-infected tissues.
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http://dx.doi.org/10.4049/jimmunol.1302608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239158PMC
December 2014

Targeting NF-κB signaling with protein kinase C agonists as an emerging strategy for combating HIV latency.

AIDS Res Hum Retroviruses 2015 Jan;31(1):4-12

Department of Medical Microbiology and Immunology, University of California , Davis, California.

Highly active antiretroviral therapy (HAART) is very effective in suppressing HIV-1 replication and restoring immune functions in HIV-infected individuals. However, it fails to eradicate the latent viral reservoirs and fully resolve chronic inflammation in HIV infection. The "shock-and-kill" strategy was recently proposed to induce latent HIV expression in the presence of HAART. Recent studies have shown that the protein kinase C (PKC) agonists are highly potent in inducing latent HIV expression from the viral reservoirs in vitro and ex vivo and in protecting primary CD4(+) T cells from HIV infection through down-modulation of their HIV coreceptor expression. The PKC agonists are excellent candidates for advancing to clinical HIV eradication strategies. This article will present a critical review of the structure and function of known PKC agonists, their mechanisms for the reactivation of latent HIV expression, and the potential of these compounds for advancing clinical HIV eradication strategies.
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http://dx.doi.org/10.1089/AID.2014.0199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287114PMC
January 2015

Transcriptional profiling of peripheral CD8+T cell responses to SIVΔnef and SIVmac251 challenge reveals a link between protective immunity and induction of systemic immunoregulatory mechanisms.

Virology 2014 Nov 1;468-470:581-591. Epub 2014 Oct 1.

Department of Medical Microbiology and Immunology, University of California, Davis, Davis, CA, United States. Electronic address:

Immunization of macaques with attenuated simian immunodeficiency virus (SIV) with deletions in nef (SIVΔnef) is shown to elicit protective immunity to infection by pathogenic SIV, yet the mechanisms that orchestrate protection and prevent pathogenesis remains unknown. We utilized whole-genome transcriptional profiling to reveal molecular signatures of protective immunity in circulating CD8+ T cells of rhesus macaques vaccinated with SIVmac239Δnef and challenged with pathogenic SIVmac251. Our findings suggest that protective immunity to pathogenic SIV infection induced by SIVmac239∆nef is associated with balanced induction of T cell activation and immunoregulatory mechanisms and dampened activation of interferon-induced signaling pathways and cytolytic enzyme production as compared with pathogenic SIVmac251 infection of unvaccinated controls. We provide evidence that protective immunity to SIVmac251 correlates with induction of biomarkers of T cell activation, differentiation, signaling, and adhesion that were down regulated in unvaccinated controls. The study highlights potential immunomodulatory networks associated with protective immunity against the virus.
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http://dx.doi.org/10.1016/j.virol.2014.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252368PMC
November 2014

Early mucosal sensing of SIV infection by paneth cells induces IL-1β production and initiates gut epithelial disruption.

PLoS Pathog 2014 Aug 28;10(8):e1004311. Epub 2014 Aug 28.

Department of Medical Microbiology & Immunology, University of California, Davis, Davis, California, United States of America.

HIV causes rapid CD4+ T cell depletion in the gut mucosa, resulting in immune deficiency and defects in the intestinal epithelial barrier. Breakdown in gut barrier integrity is linked to chronic inflammation and disease progression. However, the early effects of HIV on the gut epithelium, prior to the CD4+ T cell depletion, are not known. Further, the impact of early viral infection on mucosal responses to pathogenic and commensal microbes has not been investigated. We utilized the SIV model of AIDS to assess the earliest host-virus interactions and mechanisms of inflammation and dysfunction in the gut, prior to CD4+ T cell depletion. An intestinal loop model was used to interrogate the effects of SIV infection on gut mucosal immune sensing and response to pathogens and commensal bacteria in vivo. At 2.5 days post-SIV infection, low viral loads were detected in peripheral blood and gut mucosa without CD4+ T cell loss. However, immunohistological analysis revealed the disruption of the gut epithelium manifested by decreased expression and mislocalization of tight junction proteins. Correlating with epithelial disruption was a significant induction of IL-1β expression by Paneth cells, which were in close proximity to SIV-infected cells in the intestinal crypts. The IL-1β response preceded the induction of the antiviral interferon response. Despite the disruption of the gut epithelium, no aberrant responses to pathogenic or commensal bacteria were observed. In fact, inoculation of commensal Lactobacillus plantarum in intestinal loops led to rapid anti-inflammatory response and epithelial tight junction repair in SIV infected macaques. Thus, intestinal Paneth cells are the earliest responders to viral infection and induce gut inflammation through IL-1β signaling. Reversal of the IL-1β induced gut epithelial damage by Lactobacillus plantarum suggests synergistic host-commensal interactions during early viral infection and identify these mechanisms as potential targets for therapeutic intervention.
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http://dx.doi.org/10.1371/journal.ppat.1004311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148401PMC
August 2014
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