Variation in blood microbial lipopolysaccharide (LPS) contributes to immune reconstitution in response to suppressive antiretroviral therapy in HIV
Summary: Background: In HIV infection, even under long-term antiretroviral therapy (ART), up to 20% of HIV-infected individuals fail to restore CD4+ T cell counts to the levels similar to those of healthy controls. The mechanisms of poor CD4+ T cell reconstitution on suppressive ART are not fully u...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396422002183 |
| _version_ | 1828335404538920960 |
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| author | Zhenwu Luo Sonya L. Health Min Li Hyojik Yang Yongxia Wu Michael Collins Steven G. Deeks Jeffrey N. Martin Alison Scott Wei Jiang |
| author_facet | Zhenwu Luo Sonya L. Health Min Li Hyojik Yang Yongxia Wu Michael Collins Steven G. Deeks Jeffrey N. Martin Alison Scott Wei Jiang |
| author_sort | Zhenwu Luo |
| collection | DOAJ |
| description | Summary: Background: In HIV infection, even under long-term antiretroviral therapy (ART), up to 20% of HIV-infected individuals fail to restore CD4+ T cell counts to the levels similar to those of healthy controls. The mechanisms of poor CD4+ T cell reconstitution on suppressive ART are not fully understood. Methods: Here, we tested the hypothesis that lipopolysaccharide (LPS) from bacteria enriched in the plasma from immune non-responders (INRs) contributes to blunted CD4+ T cell recovery on suppressive ART in HIV. We characterized plasma microbiome in HIV INRs (aviremic, CD4+ T cell counts < 350 cells/μl), immune responders (IRs, CD4+ T cell counts > 500 cells/μl), and healthy controls. Next, we analyzed the structure of the lipid A domain of three bacterial species identified by mass spectrometry (MS) and evaluated the LPS function through LPS induced proinflammatory responses and CD4+ T cell apoptosis in PBMCs. In comparison, we also evaluated plasma levels of proinflammatory cytokine and chemokine patterns in these three groups. At last, to study the causality of microbiome-blunted CD4+ T cell recovery in HIV, B6 mice were intraperitoneally (i.p.) injected with heat-killed Burkholderia fungorum, Serratia marcescens, or Phyllobacterium myrsinacearum, twice per week for total of eight weeks. Findings: INRs exhibited elevated plasma levels of total microbial translocation compared to the IRs and healthy controls. The most enriched bacteria were Burkholderia and Serratia in INRs and were Phyllobacterium in IRs. Further, unlike P. myrsinacearum LPS, B. fungorum and S. marcescens LPS induced proinflammatory responses and CD4+ T cell apoptosis in PBMCs, and gene profiles of bacteria-mediated cell activation pathways in THP-1 cells in vitro. Notably, LPS structural analysis by mass spectrometry revealed that lipid A from P. myrsinacearum exhibited a divergent structure consistent with weak toll-like receptor (TLR) 4 agonism, similar to the biological profile of probiotic bacteria. In contrast, lipid A from B. fungorum and S. marcescens showed structures more consistent with canonical TLR4 agonists stemming from proinflammatory bacterial strains. Finally, intraperitoneal (i.p.) injection of inactivated B. fungorum and S. marcescens but not P. myrsinacearum resulted in cell apoptosis in mesenteric lymph nodes of C57BL/6 mice in vivo. Interpretation: These results suggest that the microbial products are causally associated with INR phenotype. In summary, variation in blood microbial LPS immunogenicity may contribute to immune reconstitution in response to suppressive ART. Collectively, this work is consistent with immunologically silencing microbiome being causal and targetable with therapy in HIV. Funding: This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID; R01 AI128864, Jiang) (NIAID; P30 AI027767, Saag/Health), the Medical Research Service at the Ralph H. Johnson VA Medical Center (merit grant VA CSRD MERIT I01 CX-002422, Jiang), and the National Institute of Aging (R21 AG074331, Scott). The SCOPE cohort was supported by the UCSF/Gladstone Institute of Virology & Immunology CFAR (P30 AI027763, Gandhi) and the CFAR Network of Integrated Clinical Systems (R24 AI067039, Saag). The National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001450 (the pilot grant, Jiang). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. |
| first_indexed | 2024-04-13T21:45:57Z |
| format | Article |
| id | doaj.art-0d7ae50991c14a8ca41749dde00904fa |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-13T21:45:57Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-0d7ae50991c14a8ca41749dde00904fa2022-12-22T02:28:34ZengElsevierEBioMedicine2352-39642022-06-0180104037Variation in blood microbial lipopolysaccharide (LPS) contributes to immune reconstitution in response to suppressive antiretroviral therapy in HIVZhenwu Luo0Sonya L. Health1Min Li2Hyojik Yang3Yongxia Wu4Michael Collins5Steven G. Deeks6Jeffrey N. Martin7Alison Scott8Wei Jiang9Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave. Charleston, Charleston, SC 29425, USADivision of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave. Charleston, Charleston, SC 29425, USADepartment of Microbial Pathogenesis, School of Dentistry, University of Maryland, 650 W. Baltimore St. Office 9209, Baltimore, MD 21201, USADepartment of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave. Charleston, Charleston, SC 29425, USACollege of Medicine, Medical University of South Carolina, Charleston, SC 29425, USAUniversity of California, San FranciscoDepartment of Epidemiology and BiostatisticsUniversity of California, San FranciscoDepartment of Epidemiology and BiostatisticsDepartment of Microbial Pathogenesis, School of Dentistry, University of Maryland, 650 W. Baltimore St. Office 9209, Baltimore, MD 21201, USA; Corresponding author: Alison Scott, 650 W. Baltimore St. Office 9209, Baltimore, MD, 21201.Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave. Charleston, Charleston, SC 29425, USA; Department of Medicine, Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29425, USA; Ralph H. Johnson VA Medical Center, Charleston, SC, USA; Corresponding author at: Wei Jiang, 173 Ashley Ave. Charleston, SC, 29425.Summary: Background: In HIV infection, even under long-term antiretroviral therapy (ART), up to 20% of HIV-infected individuals fail to restore CD4+ T cell counts to the levels similar to those of healthy controls. The mechanisms of poor CD4+ T cell reconstitution on suppressive ART are not fully understood. Methods: Here, we tested the hypothesis that lipopolysaccharide (LPS) from bacteria enriched in the plasma from immune non-responders (INRs) contributes to blunted CD4+ T cell recovery on suppressive ART in HIV. We characterized plasma microbiome in HIV INRs (aviremic, CD4+ T cell counts < 350 cells/μl), immune responders (IRs, CD4+ T cell counts > 500 cells/μl), and healthy controls. Next, we analyzed the structure of the lipid A domain of three bacterial species identified by mass spectrometry (MS) and evaluated the LPS function through LPS induced proinflammatory responses and CD4+ T cell apoptosis in PBMCs. In comparison, we also evaluated plasma levels of proinflammatory cytokine and chemokine patterns in these three groups. At last, to study the causality of microbiome-blunted CD4+ T cell recovery in HIV, B6 mice were intraperitoneally (i.p.) injected with heat-killed Burkholderia fungorum, Serratia marcescens, or Phyllobacterium myrsinacearum, twice per week for total of eight weeks. Findings: INRs exhibited elevated plasma levels of total microbial translocation compared to the IRs and healthy controls. The most enriched bacteria were Burkholderia and Serratia in INRs and were Phyllobacterium in IRs. Further, unlike P. myrsinacearum LPS, B. fungorum and S. marcescens LPS induced proinflammatory responses and CD4+ T cell apoptosis in PBMCs, and gene profiles of bacteria-mediated cell activation pathways in THP-1 cells in vitro. Notably, LPS structural analysis by mass spectrometry revealed that lipid A from P. myrsinacearum exhibited a divergent structure consistent with weak toll-like receptor (TLR) 4 agonism, similar to the biological profile of probiotic bacteria. In contrast, lipid A from B. fungorum and S. marcescens showed structures more consistent with canonical TLR4 agonists stemming from proinflammatory bacterial strains. Finally, intraperitoneal (i.p.) injection of inactivated B. fungorum and S. marcescens but not P. myrsinacearum resulted in cell apoptosis in mesenteric lymph nodes of C57BL/6 mice in vivo. Interpretation: These results suggest that the microbial products are causally associated with INR phenotype. In summary, variation in blood microbial LPS immunogenicity may contribute to immune reconstitution in response to suppressive ART. Collectively, this work is consistent with immunologically silencing microbiome being causal and targetable with therapy in HIV. Funding: This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID; R01 AI128864, Jiang) (NIAID; P30 AI027767, Saag/Health), the Medical Research Service at the Ralph H. Johnson VA Medical Center (merit grant VA CSRD MERIT I01 CX-002422, Jiang), and the National Institute of Aging (R21 AG074331, Scott). The SCOPE cohort was supported by the UCSF/Gladstone Institute of Virology & Immunology CFAR (P30 AI027763, Gandhi) and the CFAR Network of Integrated Clinical Systems (R24 AI067039, Saag). The National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001450 (the pilot grant, Jiang). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.http://www.sciencedirect.com/science/article/pii/S2352396422002183HIVImmune non-respondersImmune respondersLipopolysaccharideLipid A |
| spellingShingle | Zhenwu Luo Sonya L. Health Min Li Hyojik Yang Yongxia Wu Michael Collins Steven G. Deeks Jeffrey N. Martin Alison Scott Wei Jiang Variation in blood microbial lipopolysaccharide (LPS) contributes to immune reconstitution in response to suppressive antiretroviral therapy in HIV EBioMedicine HIV Immune non-responders Immune responders Lipopolysaccharide Lipid A |
| title | Variation in blood microbial lipopolysaccharide (LPS) contributes to immune reconstitution in response to suppressive antiretroviral therapy in HIV |
| title_full | Variation in blood microbial lipopolysaccharide (LPS) contributes to immune reconstitution in response to suppressive antiretroviral therapy in HIV |
| title_fullStr | Variation in blood microbial lipopolysaccharide (LPS) contributes to immune reconstitution in response to suppressive antiretroviral therapy in HIV |
| title_full_unstemmed | Variation in blood microbial lipopolysaccharide (LPS) contributes to immune reconstitution in response to suppressive antiretroviral therapy in HIV |
| title_short | Variation in blood microbial lipopolysaccharide (LPS) contributes to immune reconstitution in response to suppressive antiretroviral therapy in HIV |
| title_sort | variation in blood microbial lipopolysaccharide lps contributes to immune reconstitution in response to suppressive antiretroviral therapy in hiv |
| topic | HIV Immune non-responders Immune responders Lipopolysaccharide Lipid A |
| url | http://www.sciencedirect.com/science/article/pii/S2352396422002183 |
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