This document discusses the relationship between the human microbiome and HIV. It presents findings from several studies that analyzed differences in microbiome composition between HIV-positive and HIV-negative individuals as well as between different HIV phenotypes. The document also discusses how HIV infection can damage the gastrointestinal tract and lead to microbial translocation, increased inflammation and immune activation. This chronic inflammation and immune activation may perpetuate HIV persistence and increase risk for other diseases. The document proposes that HIV may be associated with dysbiosis of the gut microbiome and that this dysbiosis could contribute to systemic inflammation.
Dr. Michael Murtaugh and Dr. Cheryl Dvorak - Natural Infection, Immunity & Pr...John Blue
PCV2 is highly prevalent in swine herds worldwide. The document summarizes research showing that:
1) Pigs are born already infected with PCV2, as the virus is present in pre-farrowing sows and transmitted to piglets in utero or during birth.
2) Piglets remain viremic for life even in the presence of antibodies, as PCV2 infection causes lifelong persistent infection.
3) The farrowing environment is thoroughly contaminated with PCV2, exposing growing piglets to constant viral challenge from the sow and environment.
PPT Bonora "Clinica e terapia dell'HIV"StopTb Italia
The document discusses the clinical management of HIV infection and lessons from anti-tuberculosis therapy. It notes that combination antiretroviral therapy is effective at suppressing HIV due to its ability to prevent the selection of drug-resistant strains, in contrast to less effective single-drug regimens. Over time, combination therapy has resulted in more HIV-infected individuals achieving sufficient immune recovery to approach the life expectancy of the general population. However, non-AIDS comorbidities have become more prevalent as the HIV-infected population ages.
Association of human leukocyte antigen class II allele and haplotypes Trans R...Subrat Thanapati
This study analyzed the association between human leukocyte antigen (HLA) class II alleles and haplotypes in patients with chikungunya viral infection in western India. The researchers found that the frequency of the DRB1*11 allele and the DRB1*11/DQB1*03 haplotype were significantly lower in patients compared to controls, suggesting these confer resistance to chikungunya infection. In contrast, the DRB1*04/DQB1*03 haplotype was significantly higher in patients, indicating it may contribute to susceptibility. Additionally, the DQB1*04 allele was only found in patients with detectable viral load, suggesting it could be involved in chikungun
The views expressed in the presentations are that of the author and do not necessarily reflect the views of the Government of Canada. Presentations are shared in the original format received from the presenter.
Presentations given at the Conference to Develop a Federal Framework on Lyme Disease are the property of the author, unless otherwise cited. If you reference the author's work, you must give the author credit by naming the author and their work as well as the place and date it was presented.
For more information, contact the Lyme Disease Conference Secretariat at maladie_lyme_disease@phac-aspc.gc.ca
This article summarizes a study of 785 Tanzanian children living in an area with intense malaria transmission. The study found that iron deficiency (ID), as measured by ferritin levels in blood samples taken at routine visits, significantly decreased the odds of subsequent malaria parasitemia, severe malaria, and all-cause mortality in children. When samples from sick visits were also included, ID was associated with significantly lower prevalence of parasitemia, hyperparasitemia (very high parasite levels), and severe malaria at the time of sample collection. The results suggest that naturally occurring ID protects against severe malaria and death in young children, and that iron supplementation may increase malaria risk even in children with ID. Future studies are needed to determine
Dr. Andrea Wilson - New PRRS disease phenotypes as vaccine and genetic improv...John Blue
New PRRS disease phenotypes as vaccine and genetic improvement targets - Dr. Andrea Wilson, Roslin Institute, from the 2017 North American PRRS/National Swine Improvement Federation Joint Meeting, December 1‐3, 2017, Chicago, Illinois, USA.
More presentations at http://www.swinecast.com/2017-north-american-prrs-nsif-joint-meeting
Dr. Michael Murtaugh and Dr. Cheryl Dvorak - Natural Infection, Immunity & Pr...John Blue
PCV2 is highly prevalent in swine herds worldwide. The document summarizes research showing that:
1) Pigs are born already infected with PCV2, as the virus is present in pre-farrowing sows and transmitted to piglets in utero or during birth.
2) Piglets remain viremic for life even in the presence of antibodies, as PCV2 infection causes lifelong persistent infection.
3) The farrowing environment is thoroughly contaminated with PCV2, exposing growing piglets to constant viral challenge from the sow and environment.
PPT Bonora "Clinica e terapia dell'HIV"StopTb Italia
The document discusses the clinical management of HIV infection and lessons from anti-tuberculosis therapy. It notes that combination antiretroviral therapy is effective at suppressing HIV due to its ability to prevent the selection of drug-resistant strains, in contrast to less effective single-drug regimens. Over time, combination therapy has resulted in more HIV-infected individuals achieving sufficient immune recovery to approach the life expectancy of the general population. However, non-AIDS comorbidities have become more prevalent as the HIV-infected population ages.
Association of human leukocyte antigen class II allele and haplotypes Trans R...Subrat Thanapati
This study analyzed the association between human leukocyte antigen (HLA) class II alleles and haplotypes in patients with chikungunya viral infection in western India. The researchers found that the frequency of the DRB1*11 allele and the DRB1*11/DQB1*03 haplotype were significantly lower in patients compared to controls, suggesting these confer resistance to chikungunya infection. In contrast, the DRB1*04/DQB1*03 haplotype was significantly higher in patients, indicating it may contribute to susceptibility. Additionally, the DQB1*04 allele was only found in patients with detectable viral load, suggesting it could be involved in chikungun
The views expressed in the presentations are that of the author and do not necessarily reflect the views of the Government of Canada. Presentations are shared in the original format received from the presenter.
Presentations given at the Conference to Develop a Federal Framework on Lyme Disease are the property of the author, unless otherwise cited. If you reference the author's work, you must give the author credit by naming the author and their work as well as the place and date it was presented.
For more information, contact the Lyme Disease Conference Secretariat at maladie_lyme_disease@phac-aspc.gc.ca
This article summarizes a study of 785 Tanzanian children living in an area with intense malaria transmission. The study found that iron deficiency (ID), as measured by ferritin levels in blood samples taken at routine visits, significantly decreased the odds of subsequent malaria parasitemia, severe malaria, and all-cause mortality in children. When samples from sick visits were also included, ID was associated with significantly lower prevalence of parasitemia, hyperparasitemia (very high parasite levels), and severe malaria at the time of sample collection. The results suggest that naturally occurring ID protects against severe malaria and death in young children, and that iron supplementation may increase malaria risk even in children with ID. Future studies are needed to determine
Dr. Andrea Wilson - New PRRS disease phenotypes as vaccine and genetic improv...John Blue
New PRRS disease phenotypes as vaccine and genetic improvement targets - Dr. Andrea Wilson, Roslin Institute, from the 2017 North American PRRS/National Swine Improvement Federation Joint Meeting, December 1‐3, 2017, Chicago, Illinois, USA.
More presentations at http://www.swinecast.com/2017-north-american-prrs-nsif-joint-meeting
Development of monoclonal antibodies WorkshopAngel Hernández
This document summarizes a two-day conference on developing monoclonal antibodies for HIV treatment and cure. Over 100 broadly neutralizing antibodies have been identified that work against most HIV strains. Clinical trials are exploring using these antibodies for prevention, treatment, and potentially curing HIV. Experts discussed the current state of the leading antibody candidates and engineering antibodies to enhance their potency and duration of action. Key challenges include choosing optimal antibody combinations, designing clinical trials, and large-scale manufacturing. Industry representatives expressed interest in antibody research but want more data to drive their involvement. Continued research priorities include advancing antibody candidates in clinical trials and identifying new strategies beyond existing vaccine approaches.
Hyper IgM Syndrome, also known as X-linked immunodeficiency with hyper–immunoglobulin M, is caused by mutations in the CD40 ligand gene which is required for immunoglobulin class switching. This leads to elevated IgM levels but reduced IgG, IgA, and IgE. Patients have recurrent infections, pneumonia being most common, and are at risk for autoimmune disorders. Physical exam may reveal oral ulcers, lymphadenopathy, or hepatosplenomegaly related to infection. Differential diagnoses include common variable immunodeficiency, severe combined immunodeficiency, and agammaglobulinemia.
Dr. Jack Dekkers and Dr. Bob Rowland - Introduction of the ProgramJohn Blue
Introduction of the Program - Dr. Jack Dekkers,Iowa State University, and Dr. Bob Rowland, Kansas State University, from the 2017 North American PRRS/National Swine Improvement Federation Joint Meeting, December 1‐3, 2017, Chicago, Illinois, USA.
More presentations at http://www.swinecast.com/2017-north-american-prrs-nsif-joint-meeting
La disponibilidad de un sistema de multiplicación del virus de la hepatitis C (VHC) infeccioso en cultivos celulares está permitiendo investigar nuevos factores de respuesta a tratamientos antivíricos en condiciones controladas. Se presentará evidencia de que el fitness vírico puede ser un factor de multiresistencia a inhibidores y quese pueden obtener eficientes reducciones de carga viral empleando diseños secuenciales de administración de inhibidores que incluyan ribavirina. Se discutirán posibilidades de aplicación clínica.
This study aimed to determine the epidemiological characteristics and outcomes of lymphomas in HIV-positive patients in Russia. The study analyzed data from 73 patients treated between 2006-2016 at several medical centers. It found that diffuse large B-cell lymphoma was most common, comprising 34% of cases. The 2-year overall survival was 64% and was improved with chemotherapy combined with antiretroviral therapy. Poor prognostic factors included elevated LDH levels and B symptoms. Rituximab improved outcomes for CD20-positive lymphomas. Autologous stem cell transplantation was found to be a safe treatment for relapsed/refractory cases. Genome editing of stem cells may provide a cure for HIV by generating HIV-resistant immune
The document summarizes information about human granulocytic anaplasmosis (HGA), a tick-borne disease caused by the bacterium Anaplasma phagocytophilum. It was first reported in the United States in 1990. HGA symptoms include fever, headache, muscle aches, and fatigue. It can cause severe complications in some patients, such as respiratory failure and death. The disease is transmitted through tick bites and patients may experience symptoms 1-2 weeks after being bitten by an infected tick.
This patient is a 40 year-old African American female who was diagnosed with asymptomatic HIV in 2003. She presents with well-controlled hypertension and a history of cocaine dependence. Her current CD4 count is 876 and viral load is undetectable. She has been coinfected with hepatitis B.
Management of Hepatitis C with Natural and Synthetic Medicine icsp
This document summarizes a study comparing the management of Hepatitis C with natural and synthetic medicines. The study compared two Unani (Eastern medicine) formulations, Hepotin tablets and Vironil syrup, to the conventional allopathic drugs interferon alfa-2b and ribavirin. Sixty patients with Hepatitis C were randomly assigned to receive either the Unani medicines or allopathic drugs for six months. Clinical signs and symptoms, biochemical markers, and viral load were measured and statistically compared between the two groups. The results showed the Unani medicines were as effective as the allopathic drugs in improving clinical symptoms, liver enzymes, and reducing viral load, with fewer side effects. The study provides evidence that Unani
C1_2 Michael Saag Chronic Disease in Longer-Term HIV PatientsDSHS
Strategies for Antiretroviral Therapy discusses when to start and how to finish HIV treatment. It notes that unchecked viral replication can lead to harm through inflammation, and that earlier treatment may be beneficial due to improved drug tolerability and reduced transmission risk. Studies show treating HIV can lower rates of illness and death, even at higher CD4 counts. Overall, current guidelines recommend considering treatment for asymptomatic patients with CD4 counts below 500, though some experts argue the benefits of starting at any CD4 count.
PWP Recommendations: Treatment As PreventionCDC NPIN
This document discusses recommendations for using antiretroviral therapy (ART) as prevention of HIV transmission. [1] It reviews data showing ART reduces HIV transmission risk and existing US treatment guidelines. [2] The recommendations are that HIV-infected persons with ongoing risk behavior should be offered ART regardless of CD4 count to reduce transmission risk, and that ART should be initiated for those willing and able to commit to long-term therapy, guided by optimal treatment of the individual. [3] The benefits of ART for prevention must be balanced with continuing other prevention measures and prioritizing treatment of infected individuals.
The presentation discusses strategies for functionally curing HIV infection. It describes examples like the Berlin Patient who was cured through stem cell transplantation from a CCR5-delta32 donor, and the Mississippi Baby who experienced remission after early ART but rebounded. Strategies discussed include "kick and kill" using latency reversing agents plus immune-based killing, enhancing HIV-specific immunity through vaccines or PD-1 blockade, and making cells resistant to HIV through gene therapy approaches. Biomarkers to monitor progress on the path to a cure are needed.
In this downloadable slideset, expert faculty members Andrew Carr, MBBS, MD, FRACP, FRCPA; Daniel R. Kuritzkes, MD; and Ian M. Sanne, MBBCH, FCP(SA), review key studies presented at the 2016 International AIDS Conference.
Format: Microsoft PowerPoint (.ppt)
File size: 1.28 MB
Date posted: 8/5/2016
This webinar discusses immunometabolism and its relationship to COVID-19. It explores how elevated glucose levels can favor SARS-CoV-2 infection by inducing viral replication and cytokine expression through a HIF-1α/glycolysis pathway. Insulin treatment is also discussed and its association with increased mortality in COVID-19 patients with diabetes. The role of mitochondria in producing reactive oxygen species during infection is covered, as is the potential for antioxidants and dietary changes like ketogenic diets to impact the immune response. Biomarkers of immunometabolism are proposed for monitoring clinical outcomes.
The document discusses rationales for pursuing a cure for HIV, including that lifelong antiretroviral therapy does not restore full life expectancy and carries risks of toxicity and side effects. It outlines two potential strategies for a cure: sterilizing cure, which eliminates all HIV-infected cells, and functional cure, which controls HIV in the absence of therapy. It reviews examples of each from bone marrow transplantation and elite controllers. Measuring and targeting the latent HIV reservoir in resting immune cells is key to a cure.
The document discusses how PET-guided treatment based on early PET scans after 2 cycles of chemotherapy can help escalate or de-escalate treatment for early and advanced stage Hodgkin lymphoma patients. Studies have shown that escalating treatment to BEACOPP for early stage patients who are PET-positive after 2 cycles significantly improves outcomes, while de-escalating treatment by omitting radiation for early stage PET-negative patients is also effective. Randomized trials are still needed but results so far suggest PET-guided escalation of treatment to BEACOPP for advanced stage PET-positive patients and de-escalation to AB
HIV persists within the body despite successful suppression of virus replication with antiretroviral therapy (ART). HIV lurks in latent and active reservoirs, leading to rebound of virus spread if ART is interrupted. The latent HIV reservoir is a natural consequence of the lifecycle of HIV, with integration of HIV into the genomes of cells that are or later enter the resting state, resulting in transcriptionally quiescent provirus. Resting CD4 T cells comprise the majority of the latent reservoir. Multiple factors such as the degree of virus exposure, timing of ART, and host factors can influence the size and characteristics of the HIV reservoir. Constructing and testing effective strategies for HIV eradication and measuring their impact will require a sophisticated knowledge of the HIV reservoir, detailed understanding of the antiviral immune response, and of the diversity and kinetics of the latent viral reservoir.
This document provides information on adenosine deaminase (ADA) deficiency and gene therapy as a treatment. ADA is an enzyme involved in purine metabolism and immune system development. ADA deficiency causes severe combined immunodeficiency (SCID) due to immune defects and other issues. Current treatments include bone marrow transplantation, enzyme replacement therapy with PEG-ADA, and gene therapy. Gene therapy for ADA-SCID aims to transfer the ADA gene to hematopoietic stem cells or T lymphocytes using retroviral vectors to restore ADA expression and immune function. Preclinical studies explored these cell-based gene therapy approaches as a potential cure for ADA-SCID.
BRN Symposium 03/06/16 The gut microbiome in HIV infectionbrnmomentum
This document summarizes a study examining the relationship between the gut microbiome and HIV. It describes:
1) How HIV infection damages the gut-associated lymphoid tissue and leads to microbial translocation, inflammation, and immune activation.
2) The study's aims to characterize the gut microbiome in HIV patients with different phenotypes and risk groups, and to evaluate associations with diet, genetics, and HIV markers.
3) The study's methodology which involved collecting fecal samples from 156 HIV patients in Barcelona and analyzing them using 16S rRNA sequencing and shotgun metagenomics to characterize the microbiome composition and gene content.
1) Manuel L. Gonzalez-Garay presented research projects at UTHealth from 2009-2015 investigating rare genetic disorders using next-generation sequencing and metabolomics.
2) An experimental design involved whole exome sequencing of 81 healthy volunteers from the Young Presidents' Organization to explore the practical value and challenges of genomic information for healthy individuals.
3) Analysis of the sequencing data and metabolomics profiles identified several disease-causing variants and metabolic deficiencies, demonstrating the potential for precision medicine approaches in volunteers of normal health.
Development of monoclonal antibodies WorkshopAngel Hernández
This document summarizes a two-day conference on developing monoclonal antibodies for HIV treatment and cure. Over 100 broadly neutralizing antibodies have been identified that work against most HIV strains. Clinical trials are exploring using these antibodies for prevention, treatment, and potentially curing HIV. Experts discussed the current state of the leading antibody candidates and engineering antibodies to enhance their potency and duration of action. Key challenges include choosing optimal antibody combinations, designing clinical trials, and large-scale manufacturing. Industry representatives expressed interest in antibody research but want more data to drive their involvement. Continued research priorities include advancing antibody candidates in clinical trials and identifying new strategies beyond existing vaccine approaches.
Hyper IgM Syndrome, also known as X-linked immunodeficiency with hyper–immunoglobulin M, is caused by mutations in the CD40 ligand gene which is required for immunoglobulin class switching. This leads to elevated IgM levels but reduced IgG, IgA, and IgE. Patients have recurrent infections, pneumonia being most common, and are at risk for autoimmune disorders. Physical exam may reveal oral ulcers, lymphadenopathy, or hepatosplenomegaly related to infection. Differential diagnoses include common variable immunodeficiency, severe combined immunodeficiency, and agammaglobulinemia.
Dr. Jack Dekkers and Dr. Bob Rowland - Introduction of the ProgramJohn Blue
Introduction of the Program - Dr. Jack Dekkers,Iowa State University, and Dr. Bob Rowland, Kansas State University, from the 2017 North American PRRS/National Swine Improvement Federation Joint Meeting, December 1‐3, 2017, Chicago, Illinois, USA.
More presentations at http://www.swinecast.com/2017-north-american-prrs-nsif-joint-meeting
La disponibilidad de un sistema de multiplicación del virus de la hepatitis C (VHC) infeccioso en cultivos celulares está permitiendo investigar nuevos factores de respuesta a tratamientos antivíricos en condiciones controladas. Se presentará evidencia de que el fitness vírico puede ser un factor de multiresistencia a inhibidores y quese pueden obtener eficientes reducciones de carga viral empleando diseños secuenciales de administración de inhibidores que incluyan ribavirina. Se discutirán posibilidades de aplicación clínica.
This study aimed to determine the epidemiological characteristics and outcomes of lymphomas in HIV-positive patients in Russia. The study analyzed data from 73 patients treated between 2006-2016 at several medical centers. It found that diffuse large B-cell lymphoma was most common, comprising 34% of cases. The 2-year overall survival was 64% and was improved with chemotherapy combined with antiretroviral therapy. Poor prognostic factors included elevated LDH levels and B symptoms. Rituximab improved outcomes for CD20-positive lymphomas. Autologous stem cell transplantation was found to be a safe treatment for relapsed/refractory cases. Genome editing of stem cells may provide a cure for HIV by generating HIV-resistant immune
The document summarizes information about human granulocytic anaplasmosis (HGA), a tick-borne disease caused by the bacterium Anaplasma phagocytophilum. It was first reported in the United States in 1990. HGA symptoms include fever, headache, muscle aches, and fatigue. It can cause severe complications in some patients, such as respiratory failure and death. The disease is transmitted through tick bites and patients may experience symptoms 1-2 weeks after being bitten by an infected tick.
This patient is a 40 year-old African American female who was diagnosed with asymptomatic HIV in 2003. She presents with well-controlled hypertension and a history of cocaine dependence. Her current CD4 count is 876 and viral load is undetectable. She has been coinfected with hepatitis B.
Management of Hepatitis C with Natural and Synthetic Medicine icsp
This document summarizes a study comparing the management of Hepatitis C with natural and synthetic medicines. The study compared two Unani (Eastern medicine) formulations, Hepotin tablets and Vironil syrup, to the conventional allopathic drugs interferon alfa-2b and ribavirin. Sixty patients with Hepatitis C were randomly assigned to receive either the Unani medicines or allopathic drugs for six months. Clinical signs and symptoms, biochemical markers, and viral load were measured and statistically compared between the two groups. The results showed the Unani medicines were as effective as the allopathic drugs in improving clinical symptoms, liver enzymes, and reducing viral load, with fewer side effects. The study provides evidence that Unani
C1_2 Michael Saag Chronic Disease in Longer-Term HIV PatientsDSHS
Strategies for Antiretroviral Therapy discusses when to start and how to finish HIV treatment. It notes that unchecked viral replication can lead to harm through inflammation, and that earlier treatment may be beneficial due to improved drug tolerability and reduced transmission risk. Studies show treating HIV can lower rates of illness and death, even at higher CD4 counts. Overall, current guidelines recommend considering treatment for asymptomatic patients with CD4 counts below 500, though some experts argue the benefits of starting at any CD4 count.
PWP Recommendations: Treatment As PreventionCDC NPIN
This document discusses recommendations for using antiretroviral therapy (ART) as prevention of HIV transmission. [1] It reviews data showing ART reduces HIV transmission risk and existing US treatment guidelines. [2] The recommendations are that HIV-infected persons with ongoing risk behavior should be offered ART regardless of CD4 count to reduce transmission risk, and that ART should be initiated for those willing and able to commit to long-term therapy, guided by optimal treatment of the individual. [3] The benefits of ART for prevention must be balanced with continuing other prevention measures and prioritizing treatment of infected individuals.
The presentation discusses strategies for functionally curing HIV infection. It describes examples like the Berlin Patient who was cured through stem cell transplantation from a CCR5-delta32 donor, and the Mississippi Baby who experienced remission after early ART but rebounded. Strategies discussed include "kick and kill" using latency reversing agents plus immune-based killing, enhancing HIV-specific immunity through vaccines or PD-1 blockade, and making cells resistant to HIV through gene therapy approaches. Biomarkers to monitor progress on the path to a cure are needed.
In this downloadable slideset, expert faculty members Andrew Carr, MBBS, MD, FRACP, FRCPA; Daniel R. Kuritzkes, MD; and Ian M. Sanne, MBBCH, FCP(SA), review key studies presented at the 2016 International AIDS Conference.
Format: Microsoft PowerPoint (.ppt)
File size: 1.28 MB
Date posted: 8/5/2016
This webinar discusses immunometabolism and its relationship to COVID-19. It explores how elevated glucose levels can favor SARS-CoV-2 infection by inducing viral replication and cytokine expression through a HIF-1α/glycolysis pathway. Insulin treatment is also discussed and its association with increased mortality in COVID-19 patients with diabetes. The role of mitochondria in producing reactive oxygen species during infection is covered, as is the potential for antioxidants and dietary changes like ketogenic diets to impact the immune response. Biomarkers of immunometabolism are proposed for monitoring clinical outcomes.
The document discusses rationales for pursuing a cure for HIV, including that lifelong antiretroviral therapy does not restore full life expectancy and carries risks of toxicity and side effects. It outlines two potential strategies for a cure: sterilizing cure, which eliminates all HIV-infected cells, and functional cure, which controls HIV in the absence of therapy. It reviews examples of each from bone marrow transplantation and elite controllers. Measuring and targeting the latent HIV reservoir in resting immune cells is key to a cure.
The document discusses how PET-guided treatment based on early PET scans after 2 cycles of chemotherapy can help escalate or de-escalate treatment for early and advanced stage Hodgkin lymphoma patients. Studies have shown that escalating treatment to BEACOPP for early stage patients who are PET-positive after 2 cycles significantly improves outcomes, while de-escalating treatment by omitting radiation for early stage PET-negative patients is also effective. Randomized trials are still needed but results so far suggest PET-guided escalation of treatment to BEACOPP for advanced stage PET-positive patients and de-escalation to AB
HIV persists within the body despite successful suppression of virus replication with antiretroviral therapy (ART). HIV lurks in latent and active reservoirs, leading to rebound of virus spread if ART is interrupted. The latent HIV reservoir is a natural consequence of the lifecycle of HIV, with integration of HIV into the genomes of cells that are or later enter the resting state, resulting in transcriptionally quiescent provirus. Resting CD4 T cells comprise the majority of the latent reservoir. Multiple factors such as the degree of virus exposure, timing of ART, and host factors can influence the size and characteristics of the HIV reservoir. Constructing and testing effective strategies for HIV eradication and measuring their impact will require a sophisticated knowledge of the HIV reservoir, detailed understanding of the antiviral immune response, and of the diversity and kinetics of the latent viral reservoir.
This document provides information on adenosine deaminase (ADA) deficiency and gene therapy as a treatment. ADA is an enzyme involved in purine metabolism and immune system development. ADA deficiency causes severe combined immunodeficiency (SCID) due to immune defects and other issues. Current treatments include bone marrow transplantation, enzyme replacement therapy with PEG-ADA, and gene therapy. Gene therapy for ADA-SCID aims to transfer the ADA gene to hematopoietic stem cells or T lymphocytes using retroviral vectors to restore ADA expression and immune function. Preclinical studies explored these cell-based gene therapy approaches as a potential cure for ADA-SCID.
BRN Symposium 03/06/16 The gut microbiome in HIV infectionbrnmomentum
This document summarizes a study examining the relationship between the gut microbiome and HIV. It describes:
1) How HIV infection damages the gut-associated lymphoid tissue and leads to microbial translocation, inflammation, and immune activation.
2) The study's aims to characterize the gut microbiome in HIV patients with different phenotypes and risk groups, and to evaluate associations with diet, genetics, and HIV markers.
3) The study's methodology which involved collecting fecal samples from 156 HIV patients in Barcelona and analyzing them using 16S rRNA sequencing and shotgun metagenomics to characterize the microbiome composition and gene content.
1) Manuel L. Gonzalez-Garay presented research projects at UTHealth from 2009-2015 investigating rare genetic disorders using next-generation sequencing and metabolomics.
2) An experimental design involved whole exome sequencing of 81 healthy volunteers from the Young Presidents' Organization to explore the practical value and challenges of genomic information for healthy individuals.
3) Analysis of the sequencing data and metabolomics profiles identified several disease-causing variants and metabolic deficiencies, demonstrating the potential for precision medicine approaches in volunteers of normal health.
Joseph Eron, M.D., of University of North Carolina at Chapel Hill, presents "The State of the Art in HIV Cure Research – Hope or Hype: What Does It Mean for Patients" at AIDS Clinical Rounds
Assessment of Renal Function and Serum Levels of Alpha Tocopherol in HIV Sero...paperpublications3
Abstract: Increased Oxidative Stress markers in HIV/AIDS Patients may be as a result of free radicals generation and evidence is accumulating that Highly Active Antiretroviral Therapy (HAART) mimics AIDS progression but may be costly due to its Nephrotoxicity. In this research serum levels of Alpha tocopherol ( α- tocopherol), Urea, Creatinine as well as CD4 Counts were measured in 70 HIV Seropositive Patients (40 on HAART and 30 HAART-Naïve) and Thirty (30) apparently healthy individuals as controls in Federal Medical Centre Katsina, Nigeria.CD4 Counts, Serum Levels of Alpha tocopherol, Urea and Creatinine of HIV-HAART and HAART Naïve were 0.72±0.27mg/dl, 16.8±5.6 mmol/l, 237±123 µmol/l and 646±254cell/µl and 0.3±0.1mg/dl, 10.4±2.9 mmol/l, 91±26 µmol/l and 364±17 cell/ µl respectively. There were significantly (p<0.05) increased CD4 counts, serum levels of Alpha tocopherol, Urea and Creatinine in HIV/AIDS Patients on HAART compared to HAART- Naive. This is an indication that HIV/AIDS are predisposed to oxidative stress and that also HAART has debilitating effects on kidneys.
HCM - Egreso - Diarrea en Paciente con VIHguest40ed2d
The document discusses diarrhea in HIV/AIDS patients. It notes that diarrhea is more common in developing countries (90% vs 30-50% in developed nations) and is often the initial symptom (51-72% of cases). Common causes of diarrhea include protozoa like Cryptosporidium, bacteria such as Salmonella and Mycobacterium avium, and viruses like cytomegalovirus. Diagnosis involves stool exams, biopsies, and tests like PCR. Treatments include antiretrovirals, antibiotics, antidiarrheals, and nutrition/hydration support.
The document summarizes a randomized trial comparing a public health approach to a standard clinical approach for delivering antiretroviral therapy in Cameroon. The trial aims to compare the increase in CD4 cell count and other outcomes between the two approaches. It describes the standard clinical approach as relying on biological exams and physicians, while the public health approach uses simplified criteria and involves other personnel like nurses. The trial design involves randomizing patients across 9 rural hospitals to receive antiretrovirals through either approach and following outcomes over 24 months. Baseline characteristics of the 459 enrolled patients are provided. Survival and treatment change outcomes over time are shown graphically. The discussion covers feasibility challenges and capacity building efforts, as well as relevance for
This document summarizes results from a study of 148 patients initiating quadruple antiretroviral therapy during primary HIV-1 infection. By week 48 of treatment, 36% of patients had stopped treatment or were lost to follow-up. Among the 115 patients still in follow-up, viral loads decreased by a median of 5.4 log copies/mL and CD4 counts increased by a median of 147 cells/mm3. 84.2% of patients had viral loads ≤50 copies/mL and lower baseline CD8+/CD38++ T cell counts and cell-associated DNA levels predicted achieving viral loads ≤3 copies/mL. 83 patients experienced serious adverse events. The study demonstrates significant antiviral activity and immune reconstit
- HIVAN (HIV-associated nephropathy) is a type of kidney disease seen in some individuals with HIV. It was first described in 1984 and by 1999 it became the third leading cause of end-stage kidney disease.
- Pathologically it is characterized by collapsing focal segmental glomerulosclerosis, tubular microcystic dilation, and tubulointerstitial inflammation. On immunofluorescence there are deposits of IgM, C3 and less commonly C1 in collapsed segments.
- The incidence of HIVAN ranges from 3.9 to 11.2 cases per 1,000 person-years. Risk factors include older age, female sex, diabetes, hypertension, intravenous drug use,
This study aimed to develop a protocol for isolating monocyte populations from other immune cells to study monocytes as potential reservoirs for HIV. Researchers used flow cytometry cell sorting to isolate monocytes based on cell surface marker expression into four populations: CD14+16-, CD16+, CD3+CD19/20/56+, and CD19/20/56+. They then used quantitative PCR to analyze the expression of T cell receptor and CD3 genes in the isolated populations. The results showed low expression of CD3 genes in monocyte populations compared to the T cell population. While some expression of TCR genes was detected in monocytes, this could be due to a small subset known to express a TCR-like receptor or
Epstein-Barr virus genetic variants are associated with multiple sclerosis.Mutiple Sclerosis
Rosella Mechelli, Caterina Manzari, Claudia Policano, Anita Annese, Ernesto Picardi, Renato Umeton, Arianna Fornasiero, Anna Maria D’Erchia, Maria Chiara Buscarinu, Cristina Agliardi, Viviana Annibali, Barbara Serafini, Barbara Rosicarelli, Silvia Romano, Daniela F. Angelini, Vito A.G. Ricigliano, Fabio Buttari, Luca Battistini, Diego Centonze, Franca R. Guerini, Sandra D’Alfonso, Graziano Pesole, Marco Salvetti, Giovanni Ristori
OBJECTIVE:
We analyzed the Epstein-Barr nuclear antigen 2 (EBNA2) gene, which contains the most variable region of the viral genome, in persons with multiple sclerosis (MS) and control subjects to verify whether virus genetic variants are involved in disease development.
METHODS:
A seminested PCR approach and Sanger sequencing were used to analyze EBNA2 in 53 patients and 38 matched healthy donors (HDs). High-throughput sequencing by Illumina MiSeq was also applied in a subgroup of donors (17 patients and 17 HDs). Patients underwent gadolinium-enhanced MRI and human leucocyte antigen typing.
RESULTS:
MS risk significantly correlated with an excess of 1.2 allele (odds ratio [OR] = 5.13; 95% confidence interval [CI] 1.84-14.32; p = 0.016) and underrepresentation of 1.3B allele (OR = 0.23; 95% CI 0.08-0.51; p = 0.0006). We identified new genetic variants, mostly 1.2 allele- and MS-associated (especially amino acid variation at position 245; OR = 9.4; 95% CI 1.19-78.72; p = 0.0123). In all cases, the consensus sequence from deep sequencing confirmed Sanger sequencing (including the cosegregation of newly identified variants with known EBNA2 alleles) and showed that the extent of genotype intraindividual variability was higher than expected: rare EBNA2 variants were detected in all HDs and patients with MS (range 1-17 and 3-19, respectively). EBNA2 variants did not seem to correlate with human leucocyte antigen typing or clinical/MRI features.
CONCLUSIONS:
Our study unveils a strong association between Epstein-Barr virus genomic variants and MS, reinforcing the idea that Epstein-Barr virus contributes to disease development.
1) The patient presented with symptoms consistent with primary HIV infection including fever, rash, oral ulcers and lymphadenopathy. Testing confirmed HIV infection during the acute phase.
2) Treating primary HIV infection may lower viral setpoint and preserve immune function, reducing disease progression rates. However, the benefits are not proven and treatment can cause toxicities or resistance.
3) The patient was referred to a study evaluating immediate treatment versus deferred treatment during acute infection to help address unresolved issues around managing primary HIV.
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Format: Microsoft PowerPoint (.ppt)
File size: 720 KB
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BRN Symposium 03/06/16 The gut microbiome in HIV infection
1. MICROBIOME & HIV
Roger Paredes
Unitat VIH i irsiCaixa
Hospital Germans Trias i Pujol
Badalona
2. FLSida: Isabel Bravo, Pep Coll, Carla Estany, Cristina Herrero
BCN Checkpoint: Jorge Saz
IrsiCaixa: Bea Mothe, Jorge Carrillo, Christian Brander, Julià
Blanco, Bonaventura Clotet
Vall d’Hebron: Manel Crespo, Jordi Navarro, Ariadna Torrela
UVIC-UCC: Malu Calle
Marc Noguera
Yolanda
Guillén
Cristina
Rodríguez
Chiara
Mancuso
Muntsa
Rocafor
t
Maria
Casadell
à
Marion
a
Parera
Rocío
Bellid
o
Javier
River
a
Gràcies!
3. Diverse microbiomes, but also diverse
factors fueling the HIV pandemic
Europeans
Americans
Asians
N=33
Sanger
Danes
N=85
Illumina
US
N=145
454
Arumugam et al, Nature 2011 Piot et al, Lancet 2015
4. Brenchley J M et al. J Exp Med 2004;200:749-759
HIV infection destroys the GALT
% CD4+ T-cells
5. Microbial translocation in HIV
b
Secretory IgA
HEV
HEV
Increased TNF
production
Lossof tight
junctions
Decreased IgA
production
Increased TNF
and IFNg production;
failed ionic balance HIV infection
Villus
CD8+
Tcell in ltration
Crypt
Decreased ratio of
villusheight to
crypt depth
Abnormal enterocyte
di erentiation
CD4+
Tcell loss;
preferential
TH17 cell lossEnterocyte
apoptosis
small
at is
cal
din, a
uten. It
during
d foods.
trophy,
6. Immune senescence
Inflammageing
CV disease
Metabolic disorders
Osteoporosis
Chronic kidney
disease
Liver disease (NASH)
Cognitive problems
HIV persistence
Is there an HIV-associated disbyosis
perpetuating systemic inflammation?
GALT +
GI wall
damage
Bacterial
translocation
HIV
Disbyosis?
GUT BLOOD
Inflammation
Residual HIV
replication
Other
diseases, Tx
Other viral
infections
7. Barcelona: Test dataset
156 subjects
• 27 HIV negative, mostly MSM
• 129 HIV positive with ≠ phenotypes
• 100 (64%) MSM, 41 (26%) HTS, 15 (10%)
PWID
Stockholm: External Validation
83 subjects
• 7 HIV negative, all HTS
• 76 HIV positive (including 3 EC)
• 18 (22%) MSM, 55 (66%) HTS, 10 (12%)
PWID
Barcelona: Internal
Validation: same
analysis 1 month later
* Study reviewed by our Community Advisory
8. BCN patients
N=156
Microbiota
(16S, Shotgun
Illumina Sequencing)
Exome genotyping
Diet
HIV
negative
n=27
Elite control
n=8
Viremic
control
n=11
Naive
CD4>500
n=15
Early ART
n=13
Inmune
concordant
n=55
Inmune
discordant
n=18
Late
Presenter
n=11
• 18-60 years old
• BMI 18.5-30
• no ATB in last 3 months
(except LP)
• no surgery or active GI
diseases
No ART
VL< 50 c/mL >1year
No ART
VL 50-2000 c/mL >1year
No ART
VL >2000 c/mL
CD4+> 500 cells/mm3
ART within 6 mo from HIV-1 infection
ART > 2 years
VL <50 c/mL
CD4+ >500 cells/mm3
ART > 2 years
VL <50 c/mL
CD4+ <300 cells/mm3
No ART
CD4+ <200
13. Spearman correlation by genus abundance
Only significantvalues are shown,Holm’s-corrected p<0.05
14. Distribution of the study population
2 4 6 8 10
0.100.200.300.40
Silhouette coefficient
Number of clusters
Silhouettecoefficient
−1.0 −0.5 0.0 0.5
−0.50.00.5
NMDS + PAM (Bray−Curtis)
NMDS 1
NMDS2
ellipse: 95%
16. Risk Practice and HIV Status
16S rDNA sequencing (Bray-Curtis)
0.5
0.0
0.5
HIV_Status
negative
positive
Risk_Group
hts
msm
pwid
Genus level
−1.0
−0.5
0.0
0.5
1.0
NMDS2
HIV_Status
negative
positive
Risk_Group
hts
msm
pwid
Species level
−0.5
0.0
0.5
−1.5 −1.0 −0.5 0.0 0.5 1.0
NMDS1
NMDS2
Genus level − Month 0
−0.5
0.0
0.5
−2 −1 0 1
NMDS1
NMDS2
Genus level − Month 1
N=155
Ellipse 95%
N=108
Ellipse 95%
17. Concordance BCN0 – BCN1
−1.0 −0.5 0.0 0.5
−0.50.00.51.0
Procrustes errors
Dimension 1
Dimension2
PROTEST Statistics:
Procrustes Sum of Squares (m2): 0.3475
Correlation in a symmetric Procrustes
rotation: 0.8078
Significance: 0.001
Permutation: free
Number of permutations: 999
Jackson, D. A. Protest - A Procrustean
Randomization Test of Community
Environment Concordance. Ecoscience 2,
297–303 (1995).
18. Distribution of the study population
frequency
0.00.20.40.60.81.0
Distance from Bacteroides representative
Prevotella
Faecalibacterium
Bacteroides
Lachnospiraceae_unclassified
Succinivibrio
Alloprevotella
Ruminococcaceae_unclassified
Blautia
Parabacteroides
Alistipes
Others
No MSM
MSM
Positive
Negative
Cluster 1 (Bacteroides)
Cluster2 (Prevotella)
Distance fom Bacteroides representative
22. Diet evaluation
2 complementary questionnaires given to the study
participant. Dietitian/nutritionist explained the
questionnaires before and reviewed them after
completion
• Nutrient amounts & energy intake
• Short-term questionnaire
• Prospective consecutive 3 to 5 day registry (including one
weekend day) of all food & drinks specifying as much as
possible ways of preparation & amounts
• Energy and nutritional calculations: Software ADN
(“Anàlisi de Dades Nutricionals”), v1.0 beta 2. Compiles
existing & validated nutritional composition tables.
• Food consumption frequency assessment
• Mid-term questionnaire
• Analysed as portions of food/week
• Capitulo 6: Métodos de valoración del consumo alimentario. En: Nutrición y Dietética Clínica. J. Salas-Salvadó, A. Bonada, R. Trallero, ME Saló, R. Burgos. 2ª edición.
Elsevier Masson. 2008
• Anex 12. Cuestionarios para realizar una historia dietetica. En: Nutrición aplicada y dietoterapia. M. Muñoz, J. Aranceta, I.Garcia-Jalón. 2ª edición. Ediciones Universidad de
Navarra, EUNSA. Pamplona 2004.
Nutritional data were transformed to adjust for
total energy consumption by fitting a linear
model and taking residuals as new nutritional
values (mean= 0 and SD=1)
E.g.: The relative contribution of 100 gr of proteins is
different if the total energy intake is 5000 kJ or 9000 kJ
Energy Folate
Increased energy intake MSM
vs. Non-MSM and Prevotella
vs. Bacteroides. P<0.01 in both
comparisons
35. -0.1 1.0
n/a n/a
1.0 1.0
n/a n/a
10.5 0.006
n/a n/a
0.87** 0.5
n/a n/a
-3.6 0.3
n/a n/a
0.8 0.3
n/a n/a
6.92 0.02
n/a n/a
1.62 0.7
n/a n/a
2.7 0.4
n/a n/a
0.77** 0.2
n/a n/a
5.25 0.2
n/a n/a
1.8 0.7
n/a n/a
0.6 0.8
n/a n/a
Figure 4. Several genes important in neutrophil
function were significantly upregulated among
MSM who engaged in CRAI ≤24 hours prior
indica ng a possible role for neutrophils in response to
CRAI.
Figure 5. Gene Set Enrichment Analysis using the MSigDB
database (www.broadinstitute.org/gsea/msigdb/collection.jsp )
was conducted to identify significant immunologic pathways that
were differentially expressed in the rectal mucosa comparing
MSM who engaged in CRAI ≤24 hours prior and MSM who
abstained from CRAI for ≥ 72 hours. Pathways of interest
included DNA Replication (A), TH17 vs. naïve CD4 T cells (B),
and Reactome Antigen Processing and Cross Presentation (C).
p=0.011
A
B C
e MSM engaging in CRAI showed a distinct mRNA gene expression and CD8+ T lymphocyte profile as
engaged in anal intercourse.
te inflammatory response to CRAI, possibly driven by neutrophils and monocytes, that may be the result of
g intercourse with exposure to pro-inflammatory semen and the gut microbiota.
e frequency of IFNg producing CD8+ T cells increased, suggesting a pro-inflammatory microenvironment.
enses and inflammation, also likely play an important role in the acute and chronic response.
determine how these factors may impact HIV susceptibility or mucosal vaccine response in the rectal
The Effect of Condomless Receptive Anal Intercourse on the Rectal Mucosa in MSM
Colleen F. Kelley MD, MPH; Chandni Duphare, Hyun-Woo Lee; Kirk Easley; Jing Yang; Gregory Tharp;
Mark J. Mulligan MD; Patrick S. Sullivan DVM, PhD; Steven Bosinger PhD; Rama R. Amara PhD
Center for AIDS Research at Emory University, Atlanta, GA, USA
q The risk of HIV transmission per exposure event for receptive
anal intercourse is 1.38%, more than 12-fold higher than other
routes of sexual transmission. Nearly 70% of HIV transmissions
among MSM are attributed to rectal exposure.
q The vast majority of mucosal HIV transmission research has
been conducted in the female genital tract or in non-human
primates and extrapolated to rectal transmission among MSM.
q Sexual intercourse with semen exposure is known to cause an
inflammatory reaction with influx of HIV target cells in the
female genital tract.
q Therefore, we conducted a study to examine the rectal mucosal
effects of condomless receptive anal intercourse (CRAI) in
MSM
BACKGROUND:
METHODS:
Colleen F. Kelley MD, MPH
The Hope Clinic
500 Irvin Ct. Ste. 200
Decatur, GA 30030
colleen.kelley@emory.edu
404-712-1823
Acknowledgements: K23AI108335 (Kelley) and Emory CFAR P30 AI050409
Poster #286
q We enrolled 41 HIV negative MSM who were engaging in CRAI
with an HIV negative partner and 21 men who had never engaged
in anal intercourse (controls) into this study.
q Peripheral blood and rectal biopsy samples were collected from 2
time points separated by a median of 9 weeks. MSM abstained
from CRAI for ≥72 hours prior to visit 1. MSM engaged in CRAI
≤24 hours prior to visit 2.
q PBMCs were isolated by Ficoll density and rectal MMCs by
collagenase digestion. Cells were stained with surface antibodies
for CD4+ and CD8+ cell phenotyping and stimulated with PMA/
Ionamycin (Figure 1) to evaluate cytokine expression and
analyzed with Flowjo software. Linear mixed effects models were
used to examine differences in CD4+ and CD8+ cellular
phenotype and cytokine expression between MSM engaging in
CRAI and controls.
q From a subset of subjects (18 MSM and 10 controls), RNA was
extracted from one rectal pinch biopsy and sequenced with
Illumina HiSeq. Data were analyzed with DESeq to examine
differential mRNA gene expression and Gene Set Enrichment
Analysis with MSigDB database.
RESULTS:
CONCLUSIONS:
Figure 1. Representative gating strategy for PBMCs and rectal MMCs for CD4+ and CD8+ cell phenotyping (A) and mitogen
stimulation (B) to evaluate cytokine expression.
A.
Table 2. Results of rectal MMC phenotyping for MSM engaging in CRAI and men who never engaged in AI
(controls) demonstrate overall lower CD38 expression on CD4+ T cells in MSM engaging in CRAI and higher
Ki67 expression on CD8+ T cells. Upon mitogen stimulation, rectal CD8+ T cells from MSM engaging in CRAI
overall produced higher levels of IFNγ and TNFα compared to controls. With the exception of a decline in
CD38 expression on CD4+ T cells, there were no significant differences with timing of CRAI among MSM. Data
were analyzed by repeated measure modeling controlling for time, time*group interaction, and technician.
Immunologic
Indices
n
Baseline
Mean
(95% CI)
n CRAI mean
(95%CI)
Overall model-
based mean
p-
value
CRAI:
V1 vs. V2
mean
difference
or ratio**
p-
value
Rectal Memory
CD4+ cells
%CCR5+
CRAI 41 61.0(56.7,65.3) 38 62.8(58.4,67.1) 61.9(58.4,65.4) -0.1 1.0
Control 21 60.2(54.3,66.1) 17 64.2(56.5,71.9) 62.0(56.9,67.1) 1.0 n/a n/a
*%Ki67+
CRAI 41 2.5(2.0,3.0) 38 2.5(1.9,3.3) 2.5(2.0,3.0) 1.0 1.0
Control 21 2.1(1.4,3.2) 17 1.9(1.4,2.6) 2.0(1.5,2.6) 0.2 n/a n/a
%CD38
CRAI 40 45.0(38.2,51.9) 36 34.5(28.8,40.2) 39.7(34.6,44.8) 10.5 0.006
Control 21 49.1(41.5,56.7) 17 50.0(38.6,61.4) 49.5(42.4,56.7) 0.03 n/a n/a
*%CCR5+Ki67+
CRAI 41 1.5(1.2,1.8) 38 1.7(1.3,2.3) 1.58(1.31,1.91) 0.87** 0.5
Control 21 1.4(0.9,2.1) 17 1.2(0.8,1.7) 1.28(0.92,1.78) 0.3 n/a n/a
%α4β7+
CRAI 38 57.0(51.7,62.4) 38 53.8(48.1,59.4) 55.4(51.5,59.3) -3.6 0.3
Control 21 58.0(51.7,64.3) 17 60.0(49.7,70.2) 59.0(53.1,64.9) 0.3 n/a n/a
Rectal Memory
CD8+ cells
*%Ki67+
CRAI 41 3.7(3.0,4.7) 38 4.5(3.3,6.2) 4.1(3.3,5.0) 0.8 0.3
Control 21 3.5(2.3,5.1) 17 2.0(1.4,3.0) 2.6(1.9,3.7) 0.04 n/a n/a
%CD38+
CRAI 40 71.1(66.2,76.0) 36 64.2(57.7,70.7) 67.6(62.6,72.6) 6.92 0.02
Control 21 69.4(60.9,77.9) 17 70.4(61.0,79.9) 69.9(63.2,76.6) 0.5 n/a n/a
Stimulated rectal
CD4+ cells
%IFNγ+
CRAI 35 21.6(17.9,25.3) 32 22.6(18.8,26.5) 22.1(19.2,25.1) 1.62 0.7
Control 18 16.8(12.1,21.5) 16 24.2(18.1,30.3) 20.5(16.5,24.5) 0.5 n/a n/a
%TNFα+
CRAI 35 30.8(25.7,35.9) 32 33.6(28.2,39.0) 32.2(28.5,35.9) 2.7 0.4
Control 18 27.1(20.1,34.1) 16 31.9(25.1,38.8) 29.5(25.2,33.9) 0.4 n/a n/a
*%IL-17+
CRAI 35 2.0(1.7,2.7) 32 2.5(1.8,3.6) 2.2(1.7,2.9) 0.77** 0.2
Control 18 1.4(0.9,2.3) 16 1.7(1.1,2.6) 1.6(1.1,2.2) 0.1 n/a n/a
Stimulated rectal
CD8+ cells
%IFNγ+
CRAI 34 58.3(51.3,65.2) 32 53.0(45.7,60.3) 55.6(50.1,61.2) 5.25 0.2
Control 18 37.6(28.5,46.7) 16 45.0(33.1,56.7) 41.3(33.3,49.3) 0.005 n/a n/a
%TNFα+
CRAI 33 40.8(34.4,47.2) 32 39.0(32.5,45.5) 39.9(35.1,44.7) 1.8 0.7
Control 18 31.3(21.9,40.6 16 32.5(24.7,40.3) 31.2(26.1,37.6) 0.04 n/a n/a
%IFNγ+TNFα+
CRAI 33 25.8(20.9,30.8) 32 25.2(19.2,31.2) 25.5(21.0,30.0) 0.6 0.8
Control 17 14.2(7.9,20.4) 14 17.9(11.6,24.3) 16.1(11.4,20.7) 0.005 n/a n/a
* report the geometric mean (95%CI) **ratio of visit 1 and 2 geometric means reported
Figure 2. Global mRNA gene expression data from 1 rectal pinch
biopsy was generated by RNASeq and analyzed with DESeq.
Principal components analysis showed distinct separation between
MSM who abstained from CRAI for ≥ 72 hours (blue ellipse) and
MSM who engaged in CRAI ≤ 24 hours prior (red ellipse). Data from
both control visits (green and purple ellipses) clustered together
demonstrating similarity in mRNA gene expression over time in the absence
of CRAI.
Figure 3. Fifty-four genes were differen ally expressed (q<0.05,
0.5<FC<1.5) between MSM who abstained from CRAI for ≥ 72 hours
and controls, including those implicated in ssue remodeling (CAPN8,
CAM1, COL6A3, COL8A1, LOX, PAPPA, MMP3), cell prolifera on (C8orf4,
EDNRB, FGF7, HGF, ZNRD1, FGFBP1) and immune ac va on (CD109,
CD80, CRLF1, LILRA3, LILRA6, MASP1, OASL). An addi onal 19 unique
genes were differen ally expressed when comparing MSM who engaged
CRAI ≤24 hours prior vs. MSM who abstained from CRAI for ≥72 hours and
also implicated genes important in ssue remodeling (HYAL1, MMP1), cell
prolifera on (AGR2, CDC6, CGREF1, WDR4) and immune ac va on
(S100A9). *genes were downregulated
Figure 4. Several genes important in neutrophil
function were significantly upregulated among
MSM who engaged in CRAI ≤24 hours prior
indica ng a possible role for neutrophils in response to
CRAI.
Figure 5. Gene Set Enrichment Analysis using the MSigDB
database (www.broadinstitute.org/gsea/msigdb/collection.jsp )
was conducted to identify significant immunologic pathways that
were differentially expressed in the rectal mucosa comparing
MSM who engaged in CRAI ≤24 hours prior and MSM who
abstained from CRAI for ≥ 72 hours. Pathways of interest
included DNA Replication (A), TH17 vs. naïve CD4 T cells (B),
and Reactome Antigen Processing and Cross Presentation (C).
p=0.011
A
B C
q The rectal mucosa of HIV negative MSM engaging in CRAI showed a distinct mRNA gene expression and CD8+ T lymphocyte profile as
compared to men who have never engaged in anal intercourse.
q Our data show evidence of an acute inflammatory response to CRAI, possibly driven by neutrophils and monocytes, that may be the result of
microtrauma/mucosal injury during intercourse with exposure to pro-inflammatory semen and the gut microbiota.
q With chronic exposure to CRAI, the frequency of IFNg producing CD8+ T cells increased, suggesting a pro-inflammatory microenvironment.
Th17 cells, critical for mucosal defenses and inflammation, also likely play an important role in the acute and chronic response.
q Further research will be needed to determine how these factors may impact HIV susceptibility or mucosal vaccine response in the rectal
mucosa of HIV negative MSM and how the gut microbiota may contribute.
Table 1. Description of the study population. MSM engaging in CRAI were slightly older than
MSM who never engaged in AI (controls). Almost all MSM engaging in CRAI reported use of
lubricants for sex and many reported enema use.
Characteristic MSM engaging in
CRAI
(n=41)
Men never engaged
in AI
(n=21)
p-value
Median age in years
(25th
, 75th
)
28 (25.5, 33.9) 24 (23.5, 30.0) 0.02
Race n(%)
White 33 (80.0) 14 (66.7)
Black 6 (14.6) 2 (9.5)
Other 2 (4.9) 5 (23.8) 0.11
Lubricant use n(%) 39 (95.1) n/a
Enema use n(%) 18 (43.9) n/a
Median CRAI episodes
in previous month
(25th
, 75th
)
5 (4,8) n/a
!
B. Rectal MMC
s mula ons with
PMA/Ionamycin
IFNγ IL-2 IL-4 IL-17 IL-21 TNFα
CD3
Cytokine
IFNγ IL-2 IL-4 IL-17 IL-21 TNFα
Cytokine
CD4+
CD8+
Non-s mulated
S mulated
Non-s mulated
S mulated
Forward
sca er
Sidescaer
Live/Dead
Sidescaer
Sidescaer
CD3 CD8
CD4
12
92.9
50.1
66.8
20
0.242 0.0191
0.0573
0.0319 0.0382 0.102
0.341 0.149
0.0213
0.107 0.0426 0.256
27 27.1
1.21
4.3 0.411 36.4
50.6 9.8
0.98
2.43 0.948 32.4
CD3
69.3
Lymphocytes
99.8
99.6
46.2
27.3
44
56 65.234.7
17.3
0.0715 25.4
74.10.422
0.136 18.2
81.40.357
0.0143 1.75
97.80.479
0.1 17.3
82.20.393
1.22 0.543
18.379.9
0.563 0.449
36.762.3
40.5 16.1
2122.4
Blood
23.4 88
73.6
33.2
16.1
82.4
17.6 8217.8
Rectal
MMCs
24.6
0.508 64.2
34.11.16
0.145 40
58.31.52
0.0483 4.54
93.71.62
0.628 46.8
51.51.04
2.22 2.37
38.756.6
0.501 2.71
80.915.9
8.72 59.6
247.72
Live/Dead
Sidescaer
Sidescaer
CD45Forward
sca er
Sidescaer
CD8
CD4
CD45RO
CCR7
CD4+ Cells CD8+ Cells
CD45RO
CCR7
Gated on total memory CD4+ cells (excluding CCR7+CD45RO-)
Gated on total memory CD8+ cells
(excluding CCR7+CD45RO-)
Gated on total memory CD4+ cells (excluding CCR7+CD45RO-)
Gated on total memory CD8+ cells
(excluding CCR7+CD45RO-)
CD45RO
α4β7
CD45RO
CCR5
CD45RO
Ki67
CD45RO
CD38
CCR5
Ki67
CD45RO
Ki67
CD45RO
CD38
Forward
sca er
Sidescaer
Live/Dead
Sidescaer
Sidescaer
CD45 CD8
CD4
CD45RO
CCR7
CD45RO
CCR7
CD45RO
α4β7
CD45RO
CCR5
CD45RO
Ki67
CD45RO
CD38
CCR5
Ki67
CD45RO
Ki67
CD45RO
CD38
A B
“Evidence of an acute inflammatory response to CRAI, possibly driven by
neutrophils and monocytes, that may be the resuly of microtrauma/mucosal
injury during intercourse with exposure to pro-inflammatory semen and the gut
microbiota”
DNA replication
Reactome & Antigen processingTh17 vs naive CD4+ cells
36. Conclusions
• Human activities are potential confounders of microbiome studies: sexual
practice seems to be one of them.
• The fecal microbiota of gay men in Europe is richer and has a distinct
composition.
• HIV-1 infection is independently associated with reduced gut bacterial
richness, more so in immune discordant subjects.
• Low gene counts correlate with immune, inflammatory and metablic
parameters
• Interventions to increase gut bacterial richness might offer novel avenues to
improve HIV-1-associated immune dysfunction.
37. "There are trillions of bacterial cells living on my body, but I still
get lonely sometimes."
Gràcies!