Karin J Metzner

Karin J Metzner
University of Zurich | UZH · Division of Infectuous Dieseases and Hospital Epidemiology

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183
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Publications (183)
Article
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Viruses are the cause of a considerable burden to human, animal and plant health, while on the other hand playing an important role in regulating entire ecosystems. The power of new sequencing technologies combined with new tools for processing “Big Data” offers unprecedented opportunities to answer fundamental questions in virology. Virologists ha...
Article
Purpose of review: HIV-1 drug resistance (HIV DR) testing is routinely performed by genotyping plasma viruses using Sanger population sequencing. Next-generation sequencing (NGS) is increasingly replacing standardized Sanger sequencing. This opens up new opportunities, but also brings challenges. Recent findings: The number of NGS applications a...
Article
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Genomic safe harbors (GSH) are defined as sites in the host genome that allow stable expression of inserted transgenes while having no adverse effects on the host cell, making them ideal for use in basic research and therapeutic applications. Silencing and fluctuations in transgene expression would be highly undesirable effects. We have previously...
Article
CRISPR/dCas9-based activation systems (CRISPRa) enable sequence-specific gene activation and are therefore of particular interest for the ‘shock and kill’ cure approach against HIV-1 infections. This approach aims to activate the latent HIV-1 proviruses in infected cells and subsequently kill these cells. Several CRISPRa systems have been shown to...
Article
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HIV-1 reservoir size and dynamics are promising parameters to ensure the safe prescription of simplified maintenance antiretroviral therapy in chronically HIV-1 infected patients. In the SIMPL’HIV trial, HIV-1 DNA was quantified in peripheral blood mononuclear cells obtained at baseline and week 48 to investigate changes over time and evidence of a...
Article
Background: Studying HIV-1 superinfection is important to understand virus transmission, disease progression, and vaccine design. But detection remains challenging, with low sampling frequencies, and insufficient longitudinal samples. Methods: Using the Swiss HIV Cohort Study(SHCS), we developed a molecular epidemiology screening for superinfect...
Article
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We hypothesize that patterns of sexual behavior play a role in the conformation of transmission networks, i.e., the way you behave might influence whom you have sex with. If that was the case, behavioral grouping might in turn correlate with, and potentially predict transmission networking, e.g., proximity in a viral phylogeny. We rigorously presen...
Article
Background: HIV-1 replication capacity (RC) of transmitted/founder viruses may influence the further course of HIV-1 infection. Methods: Replication capacities (RCs) of 355 whole genome primary HIV-1 isolates derived from samples acquired during acute and recent primary HIV-1 infection (PHI) were determined using a novel high throughput infectio...
Article
Background Dolutegravir monotherapy (DTG-m) results in virological failure (VF) in some people living with HIV (PWH). We sought to identify the independent factors associated with the risk of VF and to explore the effect size heterogeneity between subgroups of PWH enrolled in DTG-m trials. Methods We searched for randomized clinical trials (RCT) e...
Article
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Little is known about whether and how variation in the HIV-1 genome affects its transmissibility. Assessing which genomic features of HIV-1 are under positive or negative selection during transmission is challenging, because very few virus particles are typically transmitted, and random genetic drift can dilute genetic signals in the recipient viru...
Article
Convergent evolution describes the process of different populations acquiring similar phenotypes or genotypes. Complex organisms with large genomes only rarely and only under very strong selection converge to the same genotype. In contrast, independent virus populations with very small genomes often acquire identical mutations. Here we test the hyp...
Preprint
Full-text available
We hypothesize that patterns of sexual behaviour play a role in the conformation of transmission networks. If that was the case, behavioural grouping might in turn correlate with transmission networks and have the potential to predict proximity in viral phylogenies. To address this hypothesis, we present an intuitive approach for quantifying intera...
Article
Objectives Chronic hepatitis C virus (HCV) infection affects the immune system. Whether elimination of HCV with direct-acting antivirals (DAA) restores immunity is unclear. We used mass cytometry to get a broad and in-depth assessment of blood cell populations of patients with chronic HCV prior to and after DAA therapy. Methods Before and 12 weeks...
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
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HIV-1 is capable of integrating its genome into that of its host cell. We examined the influence of the activation state of CD4+ T-cells, the effect of antiretroviral therapy (ART), and the clinical stage of HIV-1 infection on HIV-1 integration site features and selection. HIV-1 integration sites were sequenced from longitudinally sampled resting a...
Article
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HIV-1 replication capacity is an important characteristic to understand the replication competence of single variants or virus populations. It can further aid in the understanding of HIV-1 pathogenicity, disease progression, and drug resistance mutations. To effectively study RC, many assays have been established. However, there is still demand for...
Article
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Objectives In resource-limited settings, the World Health Organization recommends enhanced adherence counselling (EAC) for individuals with an unsuppressed HIV-1 viral load (VL) and to remeasure VL after three months to avoid unnecessary regimen switches. Only in case this follow-up VL remains unsuppressed, a regimen switch is indicated. We aimed t...
Article
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Motivation High-throughput sequencing technologies are used increasingly, not only in viral genomics research but also in clinical surveillance and diagnostics. These technologies facilitate the assessment of the genetic diversity in intra-host virus populations, which affects transmission, virulence, and pathogenesis of viral infections. However,...
Article
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An often-returning question for not only HIV-1, but also other organisms, is how predictable evolutionary paths are. The environment, mutational history, and random processes can all impact the exact evolutionary paths, but to which extent these factors contribute to the evolutionary dynamics of a particular system is an open question. Especially i...
Article
Objectives Understanding the drivers of HIV‐1 transmission is of importance for curbing the ongoing epidemic. Phylogenetic methods based on single viral sequences allow us to assess whether two individuals are part of the same viral outbreak, but cannot on their own assess who potentially transmitted the virus. We developed and assessed a molecular...
Article
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Background The extent of inappropriate prescribing observed in geriatric medicine has not been thoroughly evaluated in people ageing with HIV. We determined the prevalence of and risk factors for inappropriate prescribing in individuals aged ≥75 years enrolled in the Swiss HIV Cohort Study. Methods Retrospective review of medical records was perfo...
Article
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Background The persistence of the latent HIV-1 reservoir is a major obstacle to curing HIV-1 infection. HIV-1 integrates into the cellular genome and some targeted genomic loci are frequently detected in clonally expanded latently HIV-1 infected cells, for instance, the gene BTB domain and CNC homology 2 (BACH2) . Methods We investigated HIV-1 pro...
Article
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With the current widespread use of dolutegravir in low-income countries, the understanding of the impact of nucleoside reverse transcriptase inhibitor (NRTI-) associated mutations on the efficacy of dolutegravir-containing antiretroviral therapy (ART) is of utmost importance. We describe a rare case of a patient with pre-existing M184V/I mutation a...
Article
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Background Dolutegravir (DTG)–based dual therapy is becoming a new paradigm for both the initiation and maintenance of HIV treatment. The SIMPL’HIV study investigated the outcomes of virologically suppressed patients on standard combination antiretroviral therapy (cART) switching to DTG + emtricitabine (FTC). We present the 48-week efficacy and saf...
Article
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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 f...
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HIV-1 genetic diversity can be used to infer time since infection (TSI) and infection recency. We adapted this approach for HCV and identified genomic regions with informative diversity. We included 72 HCV/HIV-1 coinfected participants of the Swiss HIV Cohort Study, for whom reliable estimates of infection date and viral sequences were available. A...
Article
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Available therapies to treat patients infected with human immunodeficiency virus (HIV) aim at preventing viral replication but fail to eliminate the virus. Although transplantation of an allogeneic CCR5Δ32 homozygous stem cell grafts provided a cure for a few patients, this approach is not considered a general therapeutic strategy because of potent...
Article
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During chronic hepatitis C virus (HCV) infection, both CD4$^{+}$ and CD8$^{+}$ T-cells become functionally exhausted, which is reflected by increased expression of programmed cell death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and elevated anti-inflammatory interleukin 10 (IL-10) plasma levels. We studied 76...
Article
Objectives: In Cameroon, the integrase (IN) strand transfer inhibitor (INSTI) dolutegravir was recently introduced for the treatment of HIV-1 infection. Since pretreatment HIV-1 drug resistance can jeopardize the success of ART, and considering the high heterogeneity of circulating HIV-1 subtypes in Cameroon, we investigated the prevalence of pret...
Article
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 (ART). Setting: Genome-wide association stud...
Article
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Objectives: To determine the impact of pretreatment low-abundance HIV-1 drug-resistant variants (LA-DRVs) on virological failure (VF) among HIV-1/TB-co-infected individuals treated with NNRTI first-line ART. Methods: We conducted a case-control study of 170 adults with HIV-1/TB co-infection. Cases had at least one viral load (VL) ≥1000 RNA copie...
Article
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HIV and EBV are human pathogens that cause a considerable burden to worldwide health. In combination, these viruses are linked to AIDS-associated lymphomas. We found that EBV, which transforms B cells, renders them susceptible to HIV-1 infection in a CXCR4 and CD4-dependent manner in vitro and that CXCR4-tropic HIV-1 integrates into the genome of t...
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The long-term consequences of T cell responses’ impairment in chronic HCV infection are not entirely characterized, although they may be essential in the context of the clinical course of infection, re-infection, treatment-mediated viral clearance and vaccine design. Furthermore, it is unclear whether a complete reinvigoration of HCV-specific T cel...
Preprint
Full-text available
High-throughput sequencing technologies are used increasingly, not only in viral genomics research but also in clinical surveillance and diagnostics. These technologies facilitate the assessment of the genetic diversity in intra-host virus populations, which affects transmission, virulence, and pathogenesis of viral infections. However, there are t...
Preprint
Full-text available
The persistence of the latent HIV−1 reservoir is a major obstacle to cure HIV−1 infection. HIV−1 integrates into the cellular genome and some targeted genomic loci are frequently detected in clonally expanded latently HIV−1 infected cells, for instance, the gene BTB domain and CNC homology 2 (BACH2) . We investigated HIV−1 promoter activity after i...
Article
Full-text available
Objective There is limited data on abdominal obesity and the influence of genetics on weight change after antiretroviral therapy (ART) initiation. We assessed body mass index (BMI) and waist hip ration (WHR) change over time in the Swiss HIV Cohort study (SHCS). Methods Mixed-effects models characterizing BMI and WHR change over time in 1090 SHCS...
Preprint
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Introduction A major hurdle to HIV-1 eradication is the establishment of a latent viral reservoir early after primary infection. Several factors are known to influence the HIV-1 reservoir size and decay rate on suppressive antiretroviral treatment (ART), but little is known about the role of human genetic variation. Methods We measured the reservoi...
Article
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Background: The presence of high-abundance drug-resistant HIV-1 jeopardizes the success of antiretroviral therapy (ART). Despite numerous investigations, the clinical impact of low-abundance drug-resistant HIV-1 variants (LA-DRVs) present at levels <15-25% of the virus population in antitretroviral (ARV) drug-naïve individuals remains controversia...
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Introduction: In many countries, mortality due to suicide is higher among people living with HIV than in the general population. We aimed to analyse trends in suicide mortality before and after the introduction of triple combination antiretroviral therapy (cART), and to identify risk factors associated with death from suicide in Switzerland. Meth...
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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%...
Article
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One of the most intriguing puzzles in biology is the degree to which evolution is repeatable. The repeatability of evolution, or parallel evolution, has been studied in a variety of model systems, but has rarely been investigated with clinically relevant viruses. To investigate parallel evolution of HIV-1, we passaged two replicate HIV-1 population...
Article
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BACKGROUND Scale-up of direct-acting antiviral therapy is expected to abate hepatitis C virus (HCV) incidence among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). International transmission could influence this process. We classified HCV infections in HIV-positive MSM as either domestically or internationally acquired,...
Article
Objectives Late presentation (LP) to HIV care disproportionally affects individuals from sub‐Saharan Africa (SSA). We explored the reasons for late presentation to care among this group of patients in the Swiss HIV Cohort Study. Methods The prevalence of LP was compared between patients from Western Europe (WE) and those from SSA enrolled between...
Article
Background: HIV-1 genetic diversity increases over the course of infection, and can be used to infer time since infection (TSI) and consequently also infection recency, crucial quantities for HIV-1 surveillance and the understanding of viral pathogenesis. Methods: We considered 313 HIV-infected individuals for whom reliable estimates of infectio...
Article
Full-text available
Background Scale-up of direct-acting antiviral(DAA) therapy is expected to abate HCV incidence among HIV-positive men-who-have-sex-with-men(MSM). Treatment programs in neighbouring countries may influence each other’s outcomes through international transmission. We aimed at classifying HCV infections in HIV-positive MSM as either domestically or in...
Article
Background: Patients who start combination antiretroviral therapy (cART) during primary human immunodeficiency virus type 1 (HIV-1) infection show a smaller HIV-1 latent reservoir, less immune activation, and less viral diversity compared to patients who start cART during chronic infection. We conducted a pilot study to determine whether these pro...
Article
Targeted genome editing in blood and immune cells enable new therapeutic applications, especially for infectious diseases. We present a GMP-compliant protocol to manufacture CCR5-edited CD34+ hematopoietic stem and precursor cells (HSPCs) with the goal to cure patients suffering from chronic infection with human immunodeficiency virus type 1 (HIV1)...
Preprint
Full-text available
Convergent evolution describes the process of different populations acquiring similar phenotypes or genotypes. Complex organisms with large genomes only rarely and only under very strong selection converge to the same genotype. In contrast, independent virus populations with very small genomes often acquire identical mutations. Here we test the hyp...
Article
Full-text available
Understanding the determinants of broadly neutralizing antibody (bNAb) evolution is crucial for the development of bNAb-based HIV vaccines1. Despite emerging information on cofactors that promote bNAb evolution in natural HIV-1 infections, in which the induction of bNAbs is genuinely rare2, information on the impact of the infecting virus strain on...
Article
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Long-lived latently HIV-1-infected cells represent a barrier to cure. We developed a dual-fluorescence HIV-1-based vector containing a pair of genetic insulators flanking a constitutive fluorescent reporter gene to study HIV-1 latency. The protective effects of these genetic insulators are demonstrated through long-term (up to 394 days) stable fluo...
Article
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Objectives Dolutegravir (DTG) is a highly effective integrase inhibitor with a strong genetic resistance barrier and a potential role in simplified HIV maintenance treatment. We assessed the feasibility of DTG maintenance monotherapy and measured HIV reservoirs on DTG monotherapy. Methods An interventional, open‐label, single‐arm study including e...
Article
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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 so...
Article
Objectives: To determine the most recent prevalence, transmission patterns and risk factors of transmitted drug-resistance mutations (TDRMs) in Cameroon, we initiated a multicentre study monitoring HIV-1 drug resistance in newly HIV-1-diagnosed individuals using a novel next-generation sequencing (NGS) assay applicable to fingerprick dried blood s...
Article
Pegylated interferon-alpha (pIFN-α) is suggested to lower HIV-1 DNA load in antiretroviral therapy (ART) treated patients. We studied the kinetics of total HIV-1 DNA levels in 40 HIV-1/hepatitis C (HCV) coinfected patients, treated with pIFN-α for HCV and categorized into three groups according to start of ART: Chronic HIV-1 infection (n=22), acute...
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Following publication of the original article [1], the authors were alerted by a colleague of a column duplication in Table 1. Since the summary row was correct, though, the interpretation and the conclusion of the article were not affected.
Article
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Background: Sequence-specific PCR is the most common approach for virus identification in diagnostic laboratories. However, as specific PCR only detects pre-defined targets, novel virus strains or viruses not included in routine test panels will be missed. Recently, advances in high-throughput sequencing allow for virus-sequence-independent identi...
Article
A single virus is capable of infecting and replicating in a single cell. Recent advances across single-cell omics technologies – genomics, epigenomics, transcriptomics, epitranscriptomics, proteomics, and metabolomics – will offer unprecedented opportunities to gain more insights into the various aspects of the life cycle of viruses and their impac...
Article
Objectives: Here we examined the hypothesis that some stable HIV-infected partnerships can be found in cohort studies, as the patients frequently attend the clinic visits together. Methods: Using mathematical approximations and shuffling to derive the probabilities of sharing a given number of visits by chance, we identified and validated couple...
Article
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A hallmark of HIV-1 infection is the continuously declining number of the virus’ predominant target cells, activated CD4⁺ T cells. With diminishing CD4⁺ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial. To explore evolutionary pa...
Data
Overview Env mutation in clones isolated from CD4low and reversion culturing. (TIF)