Dataset Information

HHV-6B detection and host gene expression implicate HHV-6B as pulmonary pathogen after hematopoietic cell transplant.

ABSTRACT: Limited understanding of the immunopathogenesis of human herpesvirus 6B (HHV-6B) has prevented its acceptance as a pulmonary pathogen after hematopoietic cell transplant (HCT). In this prospective multicenter study of patients undergoing bronchoalveolar lavage (BAL) for pneumonia after allogeneic HCT, we test blood and BAL fluid (BALF) for HHV-6B DNA and mRNA transcripts associated with lytic infection and perform RNA-seq on paired blood. Among 116 participants, HHV-6B DNA is detected in 37% of BALs, 49% of which also have HHV-6B mRNA detection. We establish HHV-6B DNA viral load thresholds in BALF that are highly predictive of HHV-6B mRNA detection and associated with increased risk for overall mortality and death from respiratory failure. Participants with HHV-6B DNA in BALF exhibit distinct host gene expression signatures, notable for enriched interferon signaling pathways in participants clinically diagnosed with idiopathic pneumonia. These data implicate HHV-6B as a pulmonary pathogen after allogeneic HCT.

SUBMITTER: Hill JA

PROVIDER: S-EPMC10791683 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

HHV-6B detection and host gene expression implicate HHV-6B as pulmonary pathogen after hematopoietic cell transplant.

Hill Joshua A JA Lee Yeon Joo YJ Vande Vusse Lisa K LK Xie Hu H Chung E Lisa EL Waghmare Alpana A Cheng Guang-Shing GS Zhu Haiying H Huang Meei-Li ML Hill Geoffrey R GR Jerome Keith R KR Leisenring Wendy M WM Zerr Danielle M DM Gharib Sina A SA Dadwal Sanjeet S Boeckh Michael M

Nature communications 20240116 1

Limited understanding of the immunopathogenesis of human herpesvirus 6B (HHV-6B) has prevented its acceptance as a pulmonary pathogen after hematopoietic cell transplant (HCT). In this prospective multicenter study of patients undergoing bronchoalveolar lavage (BAL) for pneumonia after allogeneic HCT, we test blood and BAL fluid (BALF) for HHV-6B DNA and mRNA transcripts associated with lytic infection and perform RNA-seq on paired blood. Among 116 participants, HHV-6B DNA is detected in 37% of ...[more]

PMID: 38228644

Similar Datasets

Project description:BackgroundHuman herpesvirus 6B (HHV-6B) frequently reactivates following allogeneic stem cell transplant (alloHCT). Consensus guidelines note that haploidentical alloHCT may represent a high-risk population for which there is little evidence; this warrants further investigation.MethodsIn this single-center retrospective study, we evaluated 188 consecutive adult patients receiving haploidentical alloHCT between 11/2014 and 11/2020 and compared outcomes between patients with HHV-6B reactivation receiving targeted antiviral therapy and those who were clinically observed.ResultsOf the 58 included patients, 21 (36.2%) received antiviral therapy for HHV-6B reactivation with foscarnet (n = 19) or ganciclovir (n = 2). There were no differences in patient or disease characteristics between treated and observed patients. Treated patients were more likely to have high-level DNAemia (85.7% vs 40.5%; P < .001) and had higher peak viral quantitative measurements (median log10, 4.65 vs 3.84; P < .001). The median time to clearance from plasma (interquartile range) was 13 (7.25-20.00) days for all patients and was not significantly different between groups. There were no differences in episodes of encephalitis, grade III/IV acute graft-vs-host disease (GVHD), or time to neutrophil or platelet engraftment among treated vs observed patients. Day 100 nonrelapse mortality was not significantly different in the multivariate analysis; however, the presence of central nervous system symptoms was strongly associated with worse survival (hazard ratio, 4.11; 95% CI, 1.27-13.34; P = .018).ConclusionsWe did not observe a difference in clinical outcomes between the treated and observed groups of patients with HHV-6B reactivation following haploidentical alloHCT. With the rising use of haploidentical transplant and post-transplant cyclophosphamide GVHD prevention platforms, prospective studies are needed to further characterize the risk and outcomes associated with HHV-6B reactivation and therapy.

Project description:Human betaherpesviruses 6A and 6B (HHV-6A and HHV-6B) are highly prevalent in human populations. The genomes of these viruses can be stably integrated at the telomeres of human chromosomes and be vertically transmitted (inherited chromosomally integrated HHV-6A/HHV-6B, iciHHV-6A/iciHHV-6B). We reconstructed the population structures of HHV-6A and HHV-6B, showing that HHV-6A diverged less than HHV-6B genomes from the projected common ancestral population. Thus, HHV-6B genomes experienced stronger drift, as also supported by calculation of nucleotide diversity and Tajima's D. Analysis of ancestry proportions indicated that HHV-6A exogenous viruses and iciHHV-6A derived most of their genomes from distinct ancestral sources. Conversely, ancestry proportions were similar in exogenous HHV-6B viruses and iciHHV-6B. In line with previous indications, this suggests the distinct exogenous viral populations that originated iciHHV-6B in subjects with European and Asian ancestry are still causing infections in the corresponding geographic areas. Notably, for both iciHHV-6A and iciHHV-6B, we found that European and American sequences tend to have high proportions of ancestry from viral populations that experienced considerable drift, suggesting that they underwent one or more bottlenecks followed by population expansion. Finally, analysis of HHV-6B exogenous viruses sampled in Japan indicated that proportions of ancestry components of most of these viruses are different from the majority of those sampled in the USA. More generally, we show that, in both viral species, both integrated and exogenous viral genomes have different ancestry components, partially depending on geographic location. It would be extremely important to determine whether such differences account for the diversity of HHV-6A/HHV-6B-associated clinical symptoms and epidemiology. Also, the sequencing of additional exogenous and integrated viral genomes will be instrumental to confirm and expand our conclusions, which are based on a relatively small number of genomes, sequenced with variable quality, and with unequal sampling in terms of geographic origin.

Project description:Within the family Herpesviridae, sub-family β-herpesvirinae, and genus Roseolovirus, there are only three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered as two variants of the same virus (i.e., HHV6). Despite high overall genetic sequence identity (~90%), HHV-6A and HHV-6B are now recognized as two distinct viruses. Sequence divergence (e.g., >30%) in key coding regions and significant differences in physiological and biochemical profiles (e.g., use of different receptors for viral entry) underscore the conclusion that HHV-6A and HHV-6B are distinct viruses of the β-herpesvirinae. Despite these viruses being implicated as causative agents in several nervous system disorders (e.g., multiple sclerosis, epilepsy, and chronic fatigue syndrome), the mechanisms of action and relative contributions of each virus to neurological dysfunction are unclear. Unresolved questions regarding differences in cell tropism, receptor use and binding affinity (i.e., CD46 versus CD134), host neuro-immunological responses, and relative virulence between HHV-6A versus HHV-6B prevent a complete characterization. Although it has been shown that both HHV-6A and HHV-6B can infect glia (and, recently, cerebellar Purkinje cells), cell tropism of HHV-6A versus HHV-6B for different nerve cell types remains vague. In this study, we show that both viruses can infect different nerve cell types (i.e., glia versus neurons) and different neurotransmitter phenotypes derived from differentiated human neural stem cells. As demonstrated by immunofluorescence, HHV-6A and HHV-6B productively infect VGluT1-containing cells (i.e., glutamatergic neurons) and dopamine-containing cells (i.e., dopaminergic neurons). However, neither virus appears to infect GAD67-containing cells (i.e., GABAergic neurons). As determined by qPCR, expression of immunological factors (e.g., cytokines) in cells infected with HHV-6A versus HHV6-B also differs. These data along with morphometric and image analyses of infected differentiated neural stem cell cultures indicate that while HHV-6B may have greater opportunity for transmission, HHV-6A induces more severe cytopathic effects (e.g., syncytia) at the same post-infection end points. Cumulatively, results suggest that HHV-6A is more virulent than HHV-6B in susceptible cells, while neither virus productively infects GABAergic cells. Consistency between these in vitro data and in vivo experiments would provide new insights into potential mechanisms for HHV6-induced epileptogenesis.

Dataset Information

HHV-6B detection and host gene expression implicate HHV-6B as pulmonary pathogen after hematopoietic cell transplant.

Publications

HHV-6B detection and host gene expression implicate HHV-6B as pulmonary pathogen after hematopoietic cell transplant.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets