Publications by authors named "Matthieu Perreau"

65 Publications

Chimeric antigen receptor T-cell therapy for HIV cure.

Curr Opin HIV AIDS 2021 Mar;16(2):88-97

Lausanne University Hospital (CHUV), Department of Medicine, Division of Immunology and Allergy, Lausanne, Switzerland.

Purpose Of Review: Cell-based immunotherapies have made enormous progress over the last decade with the approval of several anti-CD19-chimeric antigen receptor (CAR)-T cell therapies for haemato-oncological diseases. CARs are synthetic receptors comprising an antigen-specific extracellular domain fused to a hinge, transmembrane and intracellular signalling domains. The success obtained with CD19 CAR-T cells rekindled interest in using CAR-T cells to treat HIV seropositive patients. The purpose of this review is to discuss historical and recent developments of anti-HIV CARs.

Recent Findings: Since the first description of CD4+-based CARs in the early 90s, new generations of anti-HIV CARs were developed. They target the hetero-trimeric glycoprotein gp120/gp41 and consist of either a CD4+ extracellular domain or a VH/VL segment derived from broadly neutralizing antibodies. Recent efforts were employed in multiplexing CAR specificities, intracellular signalling domains and T cells resistance to HIV.

Summary: Several new-anti HIV CAR-T cells were successfully tested in preclinical mice models and are now waiting to be evaluated in clinical trials. One of the key parameters to successfully using CAR-T cells in HIV treatment will depend on their capacity to control the HIV reservoir without causing off-targeting activities.
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http://dx.doi.org/10.1097/COH.0000000000000665DOI Listing
March 2021

Role of human Pegivirus infections in whole Plasmodium falciparum sporozoite vaccination and controlled human malaria infection in African volunteers.

Virol J 2021 01 26;18(1):28. Epub 2021 Jan 26.

Department of Medical Parasitology and Infection Biology, Clinical Immunology Unit, Swiss Tropical and Public Health Institute, Socinstr. 57, 4002, Basel, Switzerland.

Background: Diverse vaccination outcomes and protection levels among different populations pose a serious challenge to the development of an effective malaria vaccine. Co-infections are among many factors associated with immune dysfunction and sub-optimal vaccination outcomes. Chronic, asymptomatic viral infections can contribute to the modulation of vaccine efficacy through various mechanisms. Human Pegivirus-1 (HPgV-1) persists in immune cells thereby potentially modulating immune responses. We investigated whether Pegivirus infection influences vaccine-induced responses and protection in African volunteers undergoing whole P. falciparum sporozoites-based malaria vaccination and controlled human malaria infections (CHMI).

Methods: HPgV-1 prevalence was quantified by RT-qPCR in plasma samples of 96 individuals before, post vaccination with PfSPZ Vaccine and after CHMI in cohorts from Tanzania and Equatorial Guinea. The impact of HPgV-1 infection was evaluated on (1) systemic cytokine and chemokine levels measured by Luminex, (2) PfCSP-specific antibody titers quantified by ELISA, (3) asexual blood-stage parasitemia pre-patent periods and parasite multiplication rates, (4) HPgV-1 RNA levels upon asexual blood-stage parasitemia induced by CHMI.

Results: The prevalence of HPgV-1 was 29.2% (28/96) and sequence analysis of the 5' UTR and E2 regions revealed the predominance of genotypes 1, 2 and 5. HPgV-1 infection was associated with elevated systemic levels of IL-2 and IL-17A. Comparable vaccine-induced anti-PfCSP antibody titers, asexual blood-stage multiplication rates and pre-patent periods were observed in HPgV-1 positive and negative individuals. However, a tendency for higher protection levels was detected in the HPgV-1 positive group (62.5%) compared to the negative one (51.6%) following CHMI. HPgV-1 viremia levels were not significantly altered after CHMI.

Conclusions: HPgV-1 infection did not alter PfSPZ Vaccine elicited levels of PfCSP-specific antibody responses and parasite multiplication rates. Ongoing HPgV-1 infection appears to improve to some degree protection against CHMI in PfSPZ-vaccinated individuals. This is likely through modulation of immune system activation and systemic cytokines as higher levels of IL-2 and IL17A were observed in HPgV-1 infected individuals. CHMI is safe and well tolerated in HPgV-1 infected individuals. Identification of cell types and mechanisms of both silent and productive infection in individuals will help to unravel the biology of this widely present but largely under-researched virus.
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http://dx.doi.org/10.1186/s12985-021-01500-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837505PMC
January 2021

Immunological assessment of pediatric multisystem inflammatory syndrome related to COVID-19.

J Pediatric Infect Dis Soc 2020 Nov 12. Epub 2020 Nov 12.

Children's Hospital of Geneva, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.

Background: Recently, cases of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 have been reported worldwide. Negative RT-PCR testing associated with positive serology in most cases suggests a post-infectious syndrome. Because the pathophysiology of this syndrome is still poorly understood, extensive virological and immunological investigations are needed.

Methods: We report a series of four pediatric patients admitted to Geneva University Hospitals with persistent fever and laboratory evidence of inflammation meeting published definition of MIS-C related to COVID-19, to whom an extensive virological and immunological workup was performed.

Results: RT-PCRs on multiple anatomical compartments were negative whereas anti-SARS-CoV-2 IgA and IgG were strongly positive by ELISA and immunofluorescence. Both pseudo- and full virus neutralization assays showed the presence of neutralizing antibodies in all children, confirming a recent infection with SARS-CoV-2. Analyses of cytokine profiles revealed an elevation in all cytokines, as reported in adults with severe COVID-19. Although differing in clinical presentation, some features of MIS-C show phenotypic overlap with haemophagocytic lymphohistiocytosis (HLH). In contrast to patients with primary HLH, our patients showed normal perforin expression and NK cell degranulation. The levels of soluble IL-2 receptor (sIL-2R) correlated with the severity of disease, reflecting recent T-cell activation.

Conclusion: Our findings suggest that MIS-C related to COVID-19 is caused by a post-infectious inflammatory syndrome associated with elevation in all cytokines, and markers of recent T-cell activation (sIL-2R) occurring despite a strong and specific humoral response to SARS-CoV2. Further functional and genetic analyses are essential to better understand the mechanisms of host-pathogen interactions.
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http://dx.doi.org/10.1093/jpids/piaa142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717282PMC
November 2020

Heritability of the HIV-1 reservoir size and decay under long-term suppressive ART.

Nat Commun 2020 11 2;11(1):5542. Epub 2020 Nov 2.

Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.

The HIV-1 reservoir is the major hurdle to curing HIV-1. However, the impact of the viral genome on the HIV-1 reservoir, i.e. its heritability, remains unknown. We investigate the heritability of the HIV-1 reservoir size and its long-term decay by analyzing the distribution of those traits on viral phylogenies from both partial-pol and viral near full-length genome sequences. We use a unique nationwide cohort of 610 well-characterized HIV-1 subtype-B infected individuals on suppressive ART for a median of 5.4 years. We find that a moderate but significant fraction of the HIV-1 reservoir size 1.5 years after the initiation of ART is explained by genetic factors. At the same time, we find more tentative evidence for the heritability of the long-term HIV-1 reservoir decay. Our findings indicate that viral genetic factors contribute to the HIV-1 reservoir size and hence the infecting HIV-1 strain may affect individual patients' hurdle towards a cure.
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http://dx.doi.org/10.1038/s41467-020-19198-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608612PMC
November 2020

Host Genomics of the HIV-1 Reservoir Size and Its Decay Rate During Suppressive Antiretroviral Treatment.

J Acquir Immune Defic Syndr 2020 Dec;85(4):517-524

School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

Background: The primary hurdle for the eradication of HIV-1 is the establishment of a latent viral reservoir early after primary infection. Here, we investigated the potential influence of human genetic variation on the HIV-1 reservoir size and its decay rate during suppressive antiretroviral treatment.

Setting: Genome-wide association study and exome sequencing study to look for host genetic determinants of HIV-1 reservoir measurements in patients enrolled in the Swiss HIV Cohort Study, a nation-wide prospective observational study.

Methods: We measured total HIV-1 DNA in peripheral blood mononuclear cells from study participants, as a proxy for the reservoir size at 3 time points over a median of 5.4 years, and searched for associations between human genetic variation and 2 phenotypic readouts: the reservoir size at the first time point and its decay rate over the study period. We assessed the contribution of common genetic variants using genome-wide genotyping data from 797 patients with European ancestry enrolled in the Swiss HIV Cohort Study and searched for a potential impact of rare variants and exonic copy number variants using exome sequencing data generated in a subset of 194 study participants.

Results: Genome-wide and exome-wide analyses did not reveal any significant association with the size of the HIV-1 reservoir or its decay rate on suppressive antiretroviral treatment.

Conclusions: Our results point to a limited influence of human genetics on the size of the HIV-1 reservoir and its long-term dynamics in successfully treated individuals.
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http://dx.doi.org/10.1097/QAI.0000000000002473DOI Listing
December 2020

Predictors of virological failure and time to viral suppression of first line integrase inhibitor based antiretroviral treatment.

Clin Infect Dis 2020 Oct 24. Epub 2020 Oct 24.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.

Background: Integrase strand transfer inhibitors (InSTIs) are recommended for first-line treatment of HIV-infection. We identified risk factors, including baseline minor InSTI resistance mutations, for treatment failure of InSTI-based regimens.

Methods: We studied time to treatment failure and time to viral suppression among 1419 drug-naive patients in the Swiss HIV Cohort Study.We performed Cox regression models adjusted for demographic factors, baseline HIV RNA/CD4 cell counts, AIDS defining events and the type of InSTI.In 646 patients with a baseline genotypic resistance test of the integrase, we studied the impact of minor integrase resistance mutations.

Results: We observed 121 virological failures during 18'447 person-years of follow-up. A baseline viral load ≥100'000 cps/mL (multivariable Hazard Ratio (mHR): 2.2, 95% CI: 1.3-3.6) and an AIDS defining event (mHR: 1.8, 95% CI: 1.1-3.0) were associated with treatment failure. CD4 counts between 200-500 cells/µL (mHR: 0.5, 95% CI: 0.3-0.8) and >500 cells/µL (mHR: 0.4, 95% CI: 0.2-0.7) were protective. Median [IQR] time to viral suppression was 50 [29,107] days. Time to suppression was shorter in lower viral load strata (mHR: 0.7, 95% CI: 0.6-0.8) and in dolutegravir-based therapy (mHR: 1.2, 95% CI: 1.0-1.4). Minor resistance mutations were found at baseline in 104/646 (16%) patients with no effect on treatment outcome.

Conclusion: Among drug-naïve HIV-infected individuals treated with InSTI-based regimens, factors associated with treatment failure, in particular high viral load and low CD4 counts remain similar to older treatments. Minor InSTI resistance mutations had no impact in this large observational cohort.
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http://dx.doi.org/10.1093/cid/ciaa1614DOI Listing
October 2020

Personalized Cytokine-Directed Therapy With Tocilizumab for Refractory Immune Checkpoint Inhibitor-Related Cholangiohepatitis.

J Thorac Oncol 2021 Feb 19;16(2):318-326. Epub 2020 Sep 19.

Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; University Hospital of Lausanne, Lausanne, Switzerland; Vaccine and Immunotherapy Center, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. Electronic address:

Introduction: For patients with corticosteroid (CS)-refractory immune checkpoint inhibitor-related cholangiohepatitis (irCH), no consensus exists regarding treatment, and outcomes remain poor. We evaluated the possibility of personalized treatment according to the patient's cytokine profile and the immunohistopathologic assessment of the predominant immune infiltrate type of liver tissue.

Methods: NSCLCs with CS-refractory irCH were analyzed by immunohistochemistry of liver biopsy specimen, serum cytokine panel, and assessment of peripheral blood mononuclear cell immune cell monitoring by mass cytometry.

Results: A total of three consecutive patients with irCH were identified. We found a predominant T-cell infiltrate and an interferon-gamma or T helper 1 proinflammatory cytokine profile. Here, we report for the first time that a T-cell-targeted therapy with the interleukin (IL)-6 receptor-neutralizing antibody tocilizumab, which inhibits signaling downstream of interferon-gamma and several other Janus kinase-dependent cytokines, is an effective single cytokine-directed therapy for CS-refractory irCH. Three patients with severe, CS-refractory irCH who were treated with tocilizumab were found to have persistent clinical and biological remission.

Conclusions: Dysregulation of the IL-6/T-cell axis may contribute to the pathogenesis of CS-refractory irCH. Our observations suggest that IL-6 blockade seems to have promise in the treatment of CS-refractory irCH. The results from our three patients need to be confirmed in a larger patient population.
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http://dx.doi.org/10.1016/j.jtho.2020.09.007DOI Listing
February 2021

Cancer and HIV-1 Infection: Patterns of Chronic Antigen Exposure.

Front Immunol 2020 30;11:1350. Epub 2020 Jun 30.

Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland.

The main role of the human immune system is to eliminate cells presenting foreign antigens and abnormal patterns, while maintaining self-tolerance. However, when facing highly variable pathogens or antigens very similar to self-antigens, this system can fail in completely eliminating the anomalies, leading to the establishment of chronic pathologies. Prototypical examples of immune system defeat are cancer and Human Immunodeficiency Virus-1 (HIV-1) infection. In both conditions, the immune system is persistently exposed to antigens leading to systemic inflammation, lack of generation of long-term memory and exhaustion of effector cells. This triggers a negative feedback loop where effector cells are unable to resolve the pathology and cannot be replaced due to the lack of a pool of undifferentiated, self-renewing memory T cells. In addition, in an attempt to reduce tissue damage due to chronic inflammation, antigen presenting cells and myeloid components of the immune system activate systemic regulatory and tolerogenic programs. Beside these homologies shared between cancer and HIV-1 infection, the immune system can be shaped differently depending on the type and distribution of the eliciting antigens with ultimate consequences at the phenotypic and functional level of immune exhaustion. T cell differentiation, functionality, cytotoxic potential and proliferation reserve, immune-cell polarization, upregulation of negative regulators (immune checkpoint molecules) are indeed directly linked to the quantitative and qualitative differences in priming and recalling conditions. Better understanding of distinct mechanisms and functional consequences underlying disease-specific immune cell dysfunction will contribute to further improve and personalize immunotherapy. In the present review, we describe relevant players of immune cell exhaustion in cancer and HIV-1 infection, and enumerate the best-defined hallmarks of T cell dysfunction. Moreover, we highlight shared and divergent aspects of T cell exhaustion and T cell activation to the best of current knowledge.
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http://dx.doi.org/10.3389/fimmu.2020.01350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344140PMC
June 2020

Phylogenetic Cluster Analysis Identifies Virological and Behavioral Drivers of HIV Transmission in MSM.

Clin Infect Dis 2020 Apr 17. Epub 2020 Apr 17.

Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.

Background: Identifying local outbreaks and their drivers is a key step towards curbing HIV transmission and potentially achieving HIV elimination. Such outbreaks can be identified as transmission clusters extracted from phylogenetic trees constructed of densely sampled viral sequences. In this study, we combined phylogenetic transmission clusters with extensive data on virological suppression and behavioral risk of cluster members to quantify the drivers of ongoing transmission over ten years.

Methods: Using the comprehensive Swiss HIV Cohort Study and its drug-resistance database, we reconstructed phylogenetic trees for each year between 2007-2017. We identified HIV transmission clusters dominated by men who have sex with men(MSM) and determined their annual growth. We used Poisson regression to assess if cluster-growth was associated with a per-cluster-infectivity and behavioral-risk score.

Results: Both infectivity and behavioral risk scores were significantly higher in growing MSM transmission clusters compared to non-growing clusters (p≤0.01). The fraction of transmission clusters without infectious members acquiring new infections increased significantly over the study period. The infectivity score was significantly associated with per-capita incidence of MSM transmission clusters in eight years, while the behavioral risk score was significantly associated with per-capita incidence of MSM transmission clusters in three years.

Conclusions: We present a phylogenetic method to identify hotspots of ongoing transmission among MSM. Our results demonstrate the effectiveness of treatment as prevention at the population level. However, the significantly increasing number of new infections among transmission clusters without infectious members highlight a relative shift from diagnosed to undiagnosed individuals as drivers of HIV transmission in Swiss MSM.
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http://dx.doi.org/10.1093/cid/ciaa411DOI Listing
April 2020

Blood and Lymph Node Dissemination of Clonal Genome-Intact Human Immunodeficiency Virus 1 DNA Sequences During Suppressive Antiretroviral Therapy.

J Infect Dis 2020 07;222(4):655-660

Infectious Disease Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.

The majority of cells with latent human immunodeficiency virus 1 infection are located in lymphoid tissues that are difficult to access. In the current study, we used single-genome near-full-length proviral sequencing to evaluate intact and defective proviruses in blood and lymph node CD4 T cells enriched for specific functional polarizations. We observed minor variations between the frequencies of proviral sequences within individual CD4 T-cell subsets and across tissue compartments. However, we noted multiple clonal clusters of identical intact or defective proviral sequences from distinct compartments and CD4 T-cell subpopulations, suggesting frequent interchanges between viral reservoir cells in blood and tissues.
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http://dx.doi.org/10.1093/infdis/jiaa137DOI Listing
July 2020

Differences in social and mental well-being of long-term survivors among people who inject drugs and other participants in the Swiss HIV Cohort Study: 1980-2018.

Antivir Ther 2020 ;25(1):43-54

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: People living with HIV who were diagnosed before highly active antiretroviral therapy became available in 1996 and who survived at least 15 years after HIV diagnosis, termed long-term survivors (LTS), form a particularly vulnerable population. We study social, clinical and mental factors of LTS in the Swiss HIV Cohort Study, with a particular focus on people who inject drugs (PWID).

Methods: We quantified differences between PWID LTS, and men who have sex with men (MSM) and heterosexual (HET) LTS. Using phylogenetic methods, we distinguished between heterosexual LTS who most likely shared a social network with PWID at the time of infection, termed clusteredHET, and those who did not, termed HET not clustered (HETnc). The analysis was performed using data collected at least 15 years post diagnosis.

Results: Overall, 1,663 of 5,686 (29.2%) PWID were LTS. We found significant differences between PWID LTS and MSM/HETnc LTS regarding self-reported depression (59.4% versus 43.3%; odds ratio [OR]=1.8; P<0.001), incarceration (30.6% versus 7.0%; OR=6.9; P<0.001) and full work ability (25.4% versus 59.0%; OR=0.27; P<0.001). ClusteredHET were less vulnerable with respect to these variables than PWID LTS but more at risk compared with MSM/HETnc LTS, indicating that clusteredHET are closer to PWID with regard to social and mental aspects compared with all MSM/HETnc.

Conclusions: Even more than 15 years post HIV diagnosis, special care for HIV-positive PWID is needed, with emphasis on mental health and social integration of PWID LTS.
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http://dx.doi.org/10.3851/IMP3347DOI Listing
January 2020

T-cell exhaustion in HIV infection.

Immunol Rev 2019 11;292(1):149-163

Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.

The T-cell response is central in the adaptive immune-mediated elimination of pathogen-infected and/or cancer cells. This activated T-cell response can inflict an overwhelming degree of damage to the targeted cells, which in most instances leads to the control and elimination of foreign invaders. However, in conditions of chronic infection, persistent exposure of T cells to high levels of antigen results in a severe T-cell dysfunctional state called exhaustion. T-cell exhaustion leads to a suboptimal immune-mediated control of multiple viral infections including the human immunodeficiency virus (HIV). In this review, we will discuss the role of T-cell exhaustion in HIV disease progression, the long-term defect of T-cell function even in aviremic patients on antiretroviral therapy (ART), the role of exhaustion-specific markers in maintaining a reservoir of latently infected cells, and exploiting these markers in HIV cure strategies.
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http://dx.doi.org/10.1111/imr.12823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003858PMC
November 2019

Lymph node migratory dendritic cells modulate HIV-1 transcription through PD-1 engagement.

PLoS Pathog 2019 07 22;15(7):e1007918. Epub 2019 Jul 22.

Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.

T-follicular helper (Tfh) cells, co-expressing PD-1 and TIGIT, serve as a major cell reservoir for HIV-1 and are responsible for active and persistent HIV-1 transcription after prolonged antiretroviral therapy (ART). However, the precise mechanisms regulating HIV-1 transcription in lymph nodes (LNs) remain unclear. In the present study, we investigated the potential role of immune checkpoint (IC)/IC-Ligand (IC-L) interactions on HIV-1 transcription in LN-microenvironment. We show that PD-L1 (PD-1-ligand) and CD155 (TIGIT-ligand) are predominantly co-expressed on LN migratory (CD1chighCCR7+CD127+) dendritic cells (DCs), that locate predominantly in extra-follicular areas in ART treated individuals. We demonstrate that TCR-mediated HIV production is suppressed in vitro in the presence of recombinant PD-L1 or CD155 and, more importantly, when LN migratory DCs are co-cultured with PD-1+/Tfh cells. These results indicate that LN migratory DCs expressing IC-Ls may more efficiently restrict HIV-1 transcription in the extra-follicular areas and explain the persistence of HIV transcription in PD-1+/Tfh cells after prolonged ART within germinal centers.
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http://dx.doi.org/10.1371/journal.ppat.1007918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675123PMC
July 2019

Determinants of HIV-1 reservoir size and long-term dynamics during suppressive ART.

Nat Commun 2019 07 19;10(1):3193. Epub 2019 Jul 19.

Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, 8091, Zurich, Switzerland.

The HIV-1 reservoir is the major hurdle to a cure. We here evaluate viral and host characteristics associated with reservoir size and long-term dynamics in 1,057 individuals on suppressive antiretroviral therapy for a median of 5.4 years. At the population level, the reservoir decreases with diminishing differences over time, but increases in 26.6% of individuals. Viral blips and low-level viremia are significantly associated with slower reservoir decay. Initiation of ART within the first year of infection, pretreatment viral load, and ethnicity affect reservoir size, but less so long-term dynamics. Viral blips and low-level viremia are thus relevant for reservoir and cure studies.
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http://dx.doi.org/10.1038/s41467-019-10884-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642170PMC
July 2019

HIV Transmission Chains Exhibit Greater HLA-B Homogeneity Than Randomly Expected.

J Acquir Immune Defic Syndr 2019 08;81(5):508-515

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: HIV's capacity to escape immune recognition by human leukocyte antigen (HLA) is a core component of HIV pathogenesis. A better understanding of the distribution of HLA class I in HIV-infected patients would improve our knowledge of pathogenesis in relation to the host HLA type and could better improve therapeutic strategies against HIV.

Materials And Methods: Three hundred one to 325 transmission pairs and 469-496 clusters were identified for analysis among Swiss HIV Cohort Study (SHCS) participants using HIV pol sequences from the drug resistance database. HLA class I data were compiled at 3 specificity levels: 4-digit, 2-digit alleles, and HLA-B supertype. The analysis tabulated HLA-I homogeneity as 2 measures: the proportion of transmission pairs, which are HLA concordant, and the average percentage of allele matches within all clusters. These measures were compared with the mean value across randomizations with randomly assorted individuals.

Results: We repeated the analysis for different HLA classification levels and separately for HLA-A, -B, and -C. Subanalyses by the risk group were performed for HLA-B. HLA-B showed significantly greater homogeneity in the transmission chains (2-digit clusters: 0.291 vs. 0.251, P value = 0.009; supertype clusters: 0.659 vs. 0.611, P value = 0.002; supertype pairs: 0.655 vs. 0.608, P value = 0.014). Risk group restriction caused the effect to disappear for men-who-have-sex-with-men but not for other risk groups. We also examined if protective HLA alleles B27 and B57 were under- or overrepresented in the transmission chains, although this yielded no significant pattern.

Conclusions: The HLA-B alleles of patients within HIV-1 transmission chains segregate in homogenous clusters/pairs, potentially indicating preferential transmission among HLA-B concordant individuals.
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http://dx.doi.org/10.1097/QAI.0000000000002077DOI Listing
August 2019

Emergence of Drug Resistance in the Swiss HIV Cohort Study Under Potent Antiretroviral Therapy Is Observed in Socially Disadvantaged Patients.

Clin Infect Dis 2020 01;70(2):297-303

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich.

Background: The rate of acquired human immunodeficiency virus type 1 (HIV-1) drug resistance (ADR) has fallen dramatically since introduction of combined antiretroviral therapy (cART) in Switzerland. However, clinical experience indicates that there are still patients at risk of newly acquiring drug resistance despite having access to cART. Here, we characterized risk factors for ADR, to improve patient care and prevent emergence of drug resistance and treatment failure.

Methods: We performed a case-control study to identify risk factors for ADR in all patients starting their first cART in the Swiss HIV Cohort Study (SHCS) since 1996. The SHCS is highly representative and includes >75% of patients receiving ART in Switzerland. To this end, we implemented a systematic medical chart review to obtain more detailed information on additional parameters, which are not routinely collected in the SHCS. The collected data were analyzed using univariable and multivariable conditional logistic regression.

Results: We included in our study 115 cases and 115 matched controls. Unemployment (multivariable odds ratio [mOR], 2.9 [95% confidence interval {CI}, 1.3-6.4]; P = .008), African origin (mOR, 3.0 [95% CI, 1.0-9.2]; P = .047), comedication with anti-infectives (mOR, 3.7 [95% CI, 1.0-12.6]; P = .045), and symptoms of mental illness (mOR, 2.6 [95% CI, 1.2-5.5]; P = .012) were associated with ADR in the multivariable model.

Conclusions: Although ADR has become very rare with cART due to new potent therapies, patients in socially challenging life situations or presenting with mental health issues are at higher risk for drug resistance. Prompt identification and adequate support of these patients before ADR will prevent treatment failure and HIV-1 transmission.
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http://dx.doi.org/10.1093/cid/ciz178DOI Listing
January 2020

A Systematic Phylogenetic Approach to Study the Interaction of HIV-1 With Coinfections, Noncommunicable Diseases, and Opportunistic Diseases.

J Infect Dis 2019 06;220(2):244-253

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Switzerland.

To systematically test whether coinfections spread along the HIV-1 transmission network and whether similarities in HIV-1 genomes predict AIDS-defining illnesses and comorbidities, we analyzed the distribution of these variables on the HIV phylogeny of the densely sampled Swiss HIV Cohort Study. By combining different statistical methods, we could detect, quantify, and explain the clustering of diseases. Infectious conditions such as hepatitis C, but also Kaposi sarcoma, clustered significantly, suggesting transmission of these infections along the HIV-1 transmission network. The clustering of patients with neurocognitive complaints could not be completely explained by the clustering of patients with similar demographic risk factors, which suggests a potential impact of viral genetics. In summary, the consistent and robust signal for coinfections and comorbidities highlights the strong interaction of HIV-1 and other infections and shows the potential of combining phylogenetic methods to identify disease traits that are likely to be related to virus genetic factors.
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http://dx.doi.org/10.1093/infdis/jiz093DOI Listing
June 2019

Viral Diversity Based on Next-Generation Sequencing of HIV-1 Provides Precise Estimates of Infection Recency and Time Since Infection.

J Infect Dis 2019 06;220(2):254-265

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich.

Background: Human immunodeficiency virus type 1 (HIV-1) genetic diversity increases over the course of infection and can be used to infer the time since infection and, consequently, infection recency, which are crucial for HIV-1 surveillance and the understanding of viral pathogenesis.

Methods: We considered 313 HIV-infected individuals for whom reliable estimates of infection dates and next-generation sequencing (NGS)-derived nucleotide frequency data were available. Fractions of ambiguous nucleotides, obtained by population sequencing, were available for 207 samples. We assessed whether the average pairwise diversity calculated using NGS sequences provided a more exact prediction of the time since infection and classification of infection recency (<1 year after infection), compared with the fraction of ambiguous nucleotides.

Results: NGS-derived average pairwise diversity classified an infection as recent with a sensitivity of 88% and a specificity of 85%. When considering only the 207 samples for which fractions of ambiguous nucleotides were available, the NGS-derived average pairwise diversity exhibited a higher sensitivity (90% vs 78%) and specificity (95% vs 67%) than the fraction of ambiguous nucleotides. Additionally, the average pairwise diversity could be used to estimate the time since infection with a mean absolute error of 0.84 years, compared with 1.03 years for the fraction of ambiguous nucleotides.

Conclusions: Viral diversity based on NGS data is more precise than that based on population sequencing in its ability to predict infection recency and provides an estimated time since infection that has a mean absolute error of <1 year.
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http://dx.doi.org/10.1093/infdis/jiz094DOI Listing
June 2019

HIV Infection Functionally Impairs Mycobacterium tuberculosis-Specific CD4 and CD8 T-Cell Responses.

J Virol 2019 03 19;93(5). Epub 2019 Feb 19.

Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

Human immunodeficiency virus (HIV) infection is the major risk factor predisposing for progression from latent tuberculosis infection (LTBI) to tuberculosis disease (TB). Since long-term-treated aviremic HIV-infected individuals remained at higher risk of developing TB than HIV-uninfected individuals, we hypothesized that progression from LTBI to pulmonary TB (PTB) might be due not only to CD4 T-cell depletion but also to -specific CD4 T-cell functional impairment. To test this hypothesis, -specific T-cell frequencies and cytokine profiles were investigated in untreated Tanzanian individuals suffering from LTBI ( = 20) or PTB ( = 67) and compared to those of untreated /HIV-coinfected individuals suffering from LTBI ( = 15) or PTB ( = 10). We showed that HIV infection significantly reduced the proportion of Th2 (interleukin 4 [IL-4]/IL-5/IL-13) producing -specific CD4 T cells and IL-2-producing -specific CD4 and CD8 T cells in individuals with LTBI or PTB (0.05). Interestingly, the loss of IL-2 production was associated with a significant increase of PD-1 expression on -specific CD4 and CD8 T cells (0.05), while the loss of Th2 cytokine production was associated with a significant reduction of Gata-3 expression in memory CD4 T cells (0.05). Finally, we showed that the serum levels of IL-1α, IL-6, C-reactive protein (CRP), IL-23, and IP-10 were significantly reduced in /HIV-coinfected individuals with PTB compared to those in HIV-negative individuals with PTB (0.05), suggesting that HIV infection significantly suppresses -induced systemic proinflammatory cytokine responses. Taken together, this study suggests that in addition to depleting -specific CD4 T cells, HIV infection significantly impairs functionally favorable -specific CD4 T-cell responses in Tanzanian individuals with LTBI or PTB. and human immunodeficiency virus (HIV) infections are coendemic in several regions of the world, and /HIV-coinfected individuals are more susceptible to progression to tuberculosis disease. We therefore hypothesized that HIV infection would potentially impair -specific protective immunity in individuals suffering from latent tuberculosis infection (LTBI) or active pulmonary tuberculosis (PTB). In this study, we demonstrated that /HIV-coinfected individuals have fewer circulating -specific CD4 T cells and that those that remained were functionally impaired in both LTBI and PTB settings. In addition, we showed that HIV infection significantly interferes with -induced systemic proinflammatory cytokine/chemokine responses. Taken together, these data suggest that HIV infection impairs functionally favorable -specific immunity.
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http://dx.doi.org/10.1128/JVI.01728-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384080PMC
March 2019

Importance of routine viral load monitoring: higher levels of resistance at ART failure in Uganda and Lesotho compared with Switzerland.

J Antimicrob Chemother 2019 02;74(2):468-472

Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Objectives: Emerging resistance to antiretroviral drugs may jeopardize the achievements of improved access to ART. We compared the prevalence of different resistance mutations in HIV-infected adults with virological failure in a cohort with regular routine viral load (VL) monitoring (Switzerland) and cohorts with limited access to VL testing (Uganda and Lesotho).

Methods: We considered individuals who had genotypic resistance testing (GRT) upon virological failure (≥1000 copies/mL) and were on ART consisting of at least one NNRTI and two NRTIs. From Lesotho, individuals with two subsequent VLs ≥1000 copies/mL despite enhanced adherence counselling (n = 58) were included in the analysis. From Uganda, individuals with a single VL ≥1000 copies/mL (n = 120) were included in the analysis. From the Swiss HIV Cohort Study (SHCS), a population without history of monotherapy or dual therapy with the first GRT upon virological failure (n = 61) was selected.

Results: We found that 50.8% of individuals in the SHCS, 72.5% in Uganda and 81.0% in Lesotho harboured HIV with high-level resistance to at least two drugs from their current regimen. Stanford resistance scores were higher in Uganda compared with Switzerland for all drugs used in first-line treatment except zidovudine and tenofovir (P < 0.01) and higher in Lesotho compared with Uganda for all drugs used in first-line treatment except zidovudine (P < 0.01).

Conclusions: Frequent VL monitoring and possibly pretreatment GRT as done in the SHCS pays off by low levels of resistance even when treatment failure occurs. The high-level resistance patterns in Lesotho compared with Uganda could reflect a selection of strains with multiple resistance during enhanced adherence counselling.
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http://dx.doi.org/10.1093/jac/dky436DOI Listing
February 2019

Effect of national HIV testing recommendations and local interventions on HIV testing practices in a Swiss university hospital: a retrospective analysis between 2012 and 2015.

BMJ Open 2018 10 3;8(10):e021203. Epub 2018 Oct 3.

Infectious Diseases Service, Lausanne University Hospital, Lausanne, Switzerland.

Objectives: Despite HIV testing recommendations published by the Federal Office of Public Health (FOPH) since 2007, many individuals living with HIV are diagnosed late in Switzerland. The aim of this study is to examine the effect of the 2013 FOPH HIV testing recommendations on HIV testing rates.

Setting: Ten clinical services at Lausanne University Hospital, Lausanne, Switzerland.

Participants: Patients attending between 1 January 2012 and 31 December 2015.

Design: Retrospective analysis using two existing hospital databases. HIV testing rates calculated as the percentage of tests performed (from the Immunology Service database) per number of patients seen (from the central hospital database).

Primary And Secondary Outcome Measures: The primary outcome was testing rate change following the 2013 FOPH testing recommendations, comparing testing rates 2 years before and 2 years after their publication. Secondary outcomes were demographic factors of patients tested or not tested for HIV.

Results: 147 884 patients were seen during the study period of whom 9653 (6.5%) were tested for HIV, with 34 new HIV diagnoses. Mean testing rate increased from 5.6% to 7.8% after the recommendations (p=0.001). Testing rate increases were most marked in services involved in clinical trials on HIV testing, whose staff had attended training seminars on testing indications and practice. Testing rates were lower among older (aged >50 years), female and Swiss patients compared with younger, male and non-Swiss patients, both globally (p=0.001) and in specific clinical services.

Conclusions: This simple two-database tool demonstrates clinical services in which HIV testing practice can be optimised. Improved testing rates in services involved in clinical trials on testing suggest that local engagement complements the effect of national recommendations. While, overall, HIV testing rates increased significantly over time, testing rates were lower among patients with similar demographic profiles to individuals diagnosed late in Switzerland.
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http://dx.doi.org/10.1136/bmjopen-2017-021203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194398PMC
October 2018

Inferring the age difference in HIV transmission pairs by applying phylogenetic methods on the HIV transmission network of the Swiss HIV Cohort Study.

Virus Evol 2018 Jul 18;4(2):vey024. Epub 2018 Sep 18.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, Rämistrasse 100, Zürich, Switzerland.

Age-mixing patterns are of key importance for understanding the dynamics of human immunodeficiency virus (HIV)-epidemics and target public health interventions. We use the densely sampled Swiss HIV Cohort Study (SHCS) resistance database to study the age difference at infection in HIV transmission pairs using phylogenetic methods. In addition, we investigate whether the mean age difference of pairs in the phylogenetic tree is influenced by sampling as well as by additional distance thresholds for including pairs. HIV-1 -sequences of 11,922 SHCS patients and approximately 240,000 Los Alamos background sequences were used to build a phylogenetic tree. Using this tree, 100 per cent down to 1 per cent of the tips were sampled repeatedly to generate pruned trees ( = 500 for each sample proportion), of which pairs of SHCS patients were extracted. The mean of the absolute age differences of the pairs, measured as the absolute difference of the birth years, was analyzed with respect to this sample proportion and a distance criterion for inclusion of the pairs. In addition, the transmission groups men having sex with men (MSM), intravenous drug users (IDU), and heterosexuals (HET) were analyzed separately. Considering the tree with all 11,922 SHCS patients, 2,991 pairs could be extracted, with 954 (31.9 per cent) MSM-pairs, 635 (21.2 per cent) HET-pairs, 414 (13.8 per cent) IDU-pairs, and 352 (11.8 per cent) HET/IDU-pairs. For all transmission groups, the age difference at infection was significantly (P < 0.001) smaller for pairs in the tree compared with randomly assigned pairs, meaning that patients of similar age are more likely to be pairs. The mean age difference in the phylogenetic analysis, using a fixed distance of 0.05, was 9.2, 9.0, 7.3 and 5.6 years for MSM-, HET-, HET/IDU-, and IDU-pairs, respectively. Decreasing the cophenetic distance threshold from 0.05 to 0.01 significantly decreased the mean age difference. Similarly, repeated sampling of 100 per cent down to 1 per cent of the tips revealed an increased age difference at lower sample proportions. HIV-transmission is age-assortative, but the age difference of transmission pairs detected by phylogenetic analyses depends on both sampling proportion and distance criterion. The mean age difference decreases when using more conservative distance thresholds, implying an underestimation of age-assortativity when using liberal distance criteria. Similarly, overestimation of the mean age difference occurs for pairs from sparsely sampled trees, as it is often the case in sub-Saharan Africa.
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http://dx.doi.org/10.1093/ve/vey024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143731PMC
July 2018

Immunogenicity and safety of double versus standard dose of the seasonal influenza vaccine in solid-organ transplant recipients: A randomized controlled trial.

Vaccine 2018 10 1;36(41):6163-6169. Epub 2018 Sep 1.

Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland; Transplantation Centre, Department of Surgery and Anaesthesiology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.

Background: The use of vaccines with higher doses of antigen is an attractive strategy to improve the immunogenicity of influenza vaccination in transplant recipients. However, the effect of vaccination with a double-dose (DD) containing 30 µg of antigen in this population remains unknown.

Methods: We performed a randomized controlled trial to compare the immunogenicity and safety of DD (30 µg) vs. standard dose (SD, 15 µg) of a trivalent inactivated influenza vaccine in kidney and liver transplant recipients. Immunogenicity was assessed by hemagglutination-inhibition assay. Vaccine response was defined as seroconversion to at least one viral strain 2 weeks after vaccination and seroprotection as a titer ≥40.

Results: Sixty-three kidney and 16 liver transplant recipients were enrolled. Forty patients received the DD and 39 the SD vaccine. Overall, 40% of patients in the DD compared to 26% in the SD group (P = 0.174) responded to vaccine. In the DD arm, more patients were seroprotected to all viral strains after vaccination (88% vs 69%, P = 0.048). Post vaccination geometric mean titers of antibodies were 131.9 vs. 89.7 (P = 0.187) for H1N1, 185.4 vs. 138.7 (P = 0.182) for H3N2, and 96.6 vs. 68.8 (P = 0.081) for influenza B with the DD vs. SD. In both groups, most of the adverse events were mild and no vaccine-related severe adverse events were observed.

Conclusion: Double-dose influenza vaccine is safe and may increase antibody response in transplant recipients. In this population, DD vaccination could be an alternative when high-dose vaccine is not available. NCT02746783.
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http://dx.doi.org/10.1016/j.vaccine.2018.08.057DOI Listing
October 2018

TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs.

J Clin Invest 2018 10 27;128(10):4387-4396. Epub 2018 Aug 27.

Lineberger Comprehensive Cancer Center, and.

Activation of HIV-1 reservoirs and induction of anti-HIV-1 T cells are critical to control HIV-1 rebound after combined antiretroviral therapy (cART). Here we evaluated in humanized mice (hu-mice) with persistent HIV-1 infection the therapeutic effect of TLR3 agonist and a CD40-targeting HIV-1 vaccine, which consists of a string of 5 highly conserved CD4+ and CD8+ T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol fused to the C-terminus of a recombinant anti-human CD40 antibody (αCD40.HIV5pep). We show that αCD40.HIV5pep vaccination coadministered with poly(I:C) adjuvant induced HIV-1-specific human CD8+ and CD4+ T cell responses in hu-mice. Interestingly, poly(I:C) treatment also reactivated HIV-1 reservoirs. When administrated in therapeutic settings in HIV-1-infected hu-mice under effective cART, αCD40.HIV5pep with poly(I:C) vaccination induced HIV-1-specific CD8+ T cells and reduced the level of cell-associated HIV-1 DNA (or HIV-1 reservoirs) in lymphoid tissues. Most strikingly, the vaccination significantly delayed HIV-1 rebound after cART cessation. In summary, the αCD40.HIV5pep with poly(I:C) vaccination approach both activates replication of HIV-1 reservoirs and enhances the anti-HIV-1 T cell response, leading to a reduced level of cell-associated HIV-1 DNA or reservoirs. Our proof-of-concept study has significant implication for the development of CD40-targeting HIV-1 vaccine to enhance anti-HIV-1 immunity and reduce HIV-1 reservoirs in patients with suppressive cART.
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http://dx.doi.org/10.1172/JCI99005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159955PMC
October 2018

Humoral immune response to adenovirus induce tolerogenic bystander dendritic cells that promote generation of regulatory T cells.

PLoS Pathog 2018 08 20;14(8):e1007127. Epub 2018 Aug 20.

Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France.

Following repeated encounters with adenoviruses most of us develop robust humoral and cellular immune responses that are thought to act together to combat ongoing and subsequent infections. Yet in spite of robust immune responses, adenoviruses establish subclinical persistent infections that can last for decades. While adenovirus persistence pose minimal risk in B-cell compromised individuals, if T-cell immunity is severely compromised reactivation of latent adenoviruses can be life threatening. This dichotomy led us to ask how anti-adenovirus antibodies influence adenovirus T-cell immunity. Using primary human blood cells, transcriptome and secretome profiling, and pharmacological, biochemical, genetic, molecular, and cell biological approaches, we initially found that healthy adults harbor adenovirus-specific regulatory T cells (Tregs). As peripherally induced Tregs are generated by tolerogenic dendritic cells (DCs), we then addressed how tolerogenic DCs could be created. Here, we demonstrate that DCs that take up immunoglobulin-complexed (IC)-adenoviruses create an environment that causes bystander DCs to become tolerogenic. These adenovirus antigen loaded tolerogenic DCs can drive naïve T cells to mature into adenovirus-specific Tregs. Our study reveals a mechanism by which an antiviral humoral responses could, counterintuitively, favor virus persistence.
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http://dx.doi.org/10.1371/journal.ppat.1007127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117092PMC
August 2018

IRF5 Is a Key Regulator of Macrophage Response to Lipopolysaccharide in Newborns.

Front Immunol 2018 11;9:1597. Epub 2018 Jul 11.

Clinic of Neonatology, Department of Woman-Mother-Child, Lausanne University Hospital, Lausanne, Switzerland.

Infections are a leading cause of mortality and morbidity in newborns. The high susceptibility of newborns to infection has been associated with a limited capacity to mount protective immune responses. Monocytes and macrophages are involved in the initiation, amplification, and termination of immune responses. Depending on cues received from their environment, monocytes differentiate into M1 or M2 macrophages with proinflammatory or anti-inflammatory and tissue repair properties, respectively. The purpose of this study was to characterize differences in monocyte to macrophage differentiation and polarization between newborns and adults. Monocytes from umbilical cord blood of healthy term newborns and from peripheral blood of adult healthy subjects were exposed to GM-CSF or M-CSF to induce M1 or M2 macrophages. Newborn monocytes differentiated into M1 and M2 macrophages with similar morphology and expression of differentiation/polarization markers as adult monocytes, with the exception of CD163 that was expressed at sevenfold higher levels in newborn compared to adult M1 macrophages. Upon TLR4 stimulation, newborn M1 macrophages produced threefold to sixfold lower levels of TNF than adult macrophages, while production of IL-1-β, IL-6, IL-8, IL-10, and IL-23 was at similar levels as in adults. Nuclear levels of IRF5, a transcription factor involved in M1 polarization, were markedly reduced in newborns, whereas the NF-κB and MAP kinase pathways were not altered. In line with a functional role for IRF5, adenoviral-mediated IRF5 overexpression in newborn M1 macrophages restored lipopolysaccharide-induced TNF production. Altogether, these data highlight a distinct immune response of newborn macrophages and identify IRF5 as a key regulator of macrophage TNF response in newborns.
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http://dx.doi.org/10.3389/fimmu.2018.01597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050365PMC
July 2018

CD32 and PD-1 Lymph Node CD4 T Cells Support Persistent HIV-1 Transcription in Treated Aviremic Individuals.

J Virol 2018 10 26;92(20). Epub 2018 Sep 26.

Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

A recent study conducted in blood has proposed CD32 as the marker identifying the "elusive" HIV reservoir. We have investigated the distribution of CD32 CD4 T cells in blood and lymph nodes (LNs) of HIV-1-uninfected subjects and viremic untreated and long-term-treated HIV-1-infected individuals and their relationship with PD-1 CD4 T cells. The frequency of CD32 CD4 T cells was increased in viremic compared to treated individuals in LNs, and a large proportion (up to 50%) of CD32 cells coexpressed PD-1 and were enriched within T follicular helper (Tfh) cells. We next investigated the role of LN CD32 CD4 T cells in the HIV reservoir. Total HIV DNA was enriched in CD32 and PD-1 CD4 T cells compared to CD32 and PD-1 cells in both viremic and treated individuals, but there was no difference between CD32 and PD-1 cells. There was no enrichment of latently infected cells with inducible HIV-1 in CD32 versus PD-1 cells in antiretroviral therapy (ART)-treated individuals. HIV-1 transcription was then analyzed in LN memory CD4 T cell populations sorted on the basis of CD32 and PD-1 expression. CD32 PD-1 CD4 T cells were significantly enriched in cell-associated HIV RNA compared to CD32 PD-1 (averages of 5.2-fold in treated individuals and 86.6-fold in viremics), CD32 PD-1 (2.2-fold in treated individuals and 4.3-fold in viremics), and CD32 PD-1 (2.2-fold in ART-treated individuals and 4.6-fold in viremics) cell populations. Similar levels of HIV-1 transcription were found in CD32 PD-1 and CD32 PD-1 CD4 T cells. Interestingly, the proportion of CD32 and PD-1 CD4 T cells negatively correlated with CD4 T cell counts and length of therapy. Therefore, the expression of CD32 identifies, independently of PD-1, a CD4 T cell population with persistent HIV-1 transcription and coexpression of CD32 and PD-1, the CD4 T cell population with the highest levels of HIV-1 transcription in both viremic and treated individuals. The existence of long-lived latently infected resting memory CD4 T cells represents a major obstacle to the eradication of HIV infection. Identifying cell markers defining latently infected cells containing replication-competent virus is important in order to determine the mechanisms of HIV persistence and to develop novel therapeutic strategies to cure HIV infection. We provide evidence that PD-1 and CD32 may have a complementary role in better defining CD4 T cell populations infected with HIV-1. Furthermore, CD4 T cells coexpressing CD32 and PD-1 identify a CD4 T cell population with high levels of persistent HIV-1 transcription.
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http://dx.doi.org/10.1128/JVI.00901-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158413PMC
October 2018

The Cumulative Impact of Harm Reduction on the Swiss HIV Epidemic: Cohort Study, Mathematical Model, and Phylogenetic Analysis.

Open Forum Infect Dis 2018 May 19;5(5):ofy078. Epub 2018 May 19.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Switzerland.

Background: Human immunodeficiency virus (HIV) transmission among injecting drug users (IDUs) is increasing in the United States due to the recent opioid epidemic and is the leading mode of transmission in Eastern Europe.

Methods: To evaluate the overall impact of HIV harm reduction, we combined (1) data from the Swiss HIV Cohort Study and public sources with (2) a mathematical model expressed as a system of ordinary differential equations. The model reconstructs the national epidemic from the first case in 1980 until 2015. Phylogenetic cluster analysis of HIV-1 pol sequences was used to quantify the epidemic spillover from IDUs to the general population.

Results: Overall, harm reduction prevented 15903 (range, 15359-16448) HIV infections among IDUs until the end of 2015, 5446 acquired immune deficiency syndrome (AIDS) deaths (range, 5142-5752), and a peak HIV prevalence of 50.7%. Introduction of harm reduction 2 years earlier could have halved the epidemic, preventing 3161 (range, 822-5499) HIV infections and 1468 (range, 609-2326) AIDS deaths. Suddenly discontinuing all harm reduction in 2005 would have resulted in outbreak re-emergence with 1351 (range, 779-1925) additional HIV cases. Without harm reduction, the estimated additional number of heterosexuals infected by HIV-positive IDUs is estimated to have been 2540 (range, 2453-2627), which is equivalent to the total national reported incidence among heterosexuals in the period of 2007 to 2015.

Conclusions: Our results suggest that a paramount, population-level impact occurred because of the harm reduction package, beyond factors that can be explained by a reduction in risk behavior and a decrease in the number of drug users over time.
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http://dx.doi.org/10.1093/ofid/ofy078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965087PMC
May 2018

Hyperglycaemia is inversely correlated with live M. bovis BCG-specific CD4 T cell responses in Tanzanian adults with latent or active tuberculosis.

Immun Inflamm Dis 2018 06 11;6(2):345-353. Epub 2018 Apr 11.

Swiss Tropical and Public Health Institute, Basel, Switzerland.

Introduction: The rising prevalence of Diabetes mellitus (DM) in high TB-endemic countries may adversely affect sustainability of TB control since DM constitutes a risk factor for development of active tuberculosis (TB). The impact of DM on TB specific adaptive immune responses remains poorly addressed, particularly in people living in Sub-Saharan countries. We performed a functional characterization of TB specific cellular immune response in Tanzanian subjects with active or latent Mycobacterium tuberculosis (Mtb) infection stratified by their diabetic status.

Methods: HIV negative active TB patients (≥18 years) with Xpert MTB/RIF positive pulmonary TB were included before starting TB treatment in Dar es Salaam, Tanzania between April and December 2013. HIV negative healthy controls latently infected with TB but without past TB history were also included. Active and latent TB patients were stratified in two groups according to their diabetic status. Peripheral Blood Mononuclear cells were stimulated with either live M. bovis BCG or Mtb-specific peptide pools and analyzed by intracellular cytokine staining and polychromatic flow cytometry.

Results: Our results show a lower frequency of IFN-γ CD4 T cells in patients with active TB and DM compared to patients with active TB only after live M. bovis BCG (p = 0.04) but not after Mtb peptide pools re-stimulation. Irrespective of TB status, level of glycaemia is selectively inversely correlated with IFN-γ and TNF-α CD4 T cell production (p = 0.02 and p = 0.03) after live M. bovis BCG stimulation.

Conclusions: These results support the hypothesis that hyperglycaemia negatively impacts antigen processing and/or presentation of whole mycobacteria delaying secretion of key cytokines involved in TB immunity.
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http://dx.doi.org/10.1002/iid3.222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946156PMC
June 2018

Blood CXCR3 CD4 T Cells Are Enriched in Inducible Replication Competent HIV in Aviremic Antiretroviral Therapy-Treated Individuals.

Front Immunol 2018 5;9:144. Epub 2018 Feb 5.

Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.

We recently demonstrated that lymph nodes (LNs) PD-1/T follicular helper (Tfh) cells from antiretroviral therapy (ART)-treated HIV-infected individuals were enriched in cells containing replication competent virus. However, the distribution of cells containing inducible replication competent virus has been only partially elucidated in blood memory CD4 T-cell populations including the Tfh cell counterpart circulating in blood (cTfh). In this context, we have investigated the distribution of (1) total HIV-infected cells and (2) cells containing replication competent and infectious virus within various blood and LN memory CD4 T-cell populations of conventional antiretroviral therapy (cART)-treated HIV-infected individuals. In the present study, we show that blood CXCR3-expressing memory CD4 T cells are enriched in cells containing inducible replication competent virus and contributed the most to the total pool of cells containing replication competent and infectious virus in blood. Interestingly, subsequent proviral sequence analysis did not indicate virus compartmentalization between blood and LN CD4 T-cell populations, suggesting dynamic interchanges between the two compartments. We then investigated whether the composition of blood HIV reservoir may reflect the polarization of LN CD4 T cells at the time of reservoir seeding and showed that LN PD-1 CD4 T cells of viremic untreated HIV-infected individuals expressed significantly higher levels of CXCR3 as compared to CCR4 and/or CCR6, suggesting that blood CXCR3-expressing CD4 T cells may originate from LN PD-1 CD4 T cells. Taken together, these results indicate that blood CXCR3-expressing CD4 T cells represent the major blood compartment containing inducible replication competent virus in treated aviremic HIV-infected individuals.
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http://dx.doi.org/10.3389/fimmu.2018.00144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807378PMC
March 2019