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A cure for HIV-1 remains unattainable as only one case has been reported, a decade ago 1 , 2 . The individual—who is known as the ‘Berlin patient’—underwent two allogeneic haematopoietic stem-cell transplantation (HSCT) procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5 (CCR5Δ32/Δ32) to treat his acute myeloid leukaemia. Total body irradiation was given with each HSCT. Notably, it is unclear which treatment or patient parameters contributed to this case of long-term HIV remission. Here we show that HIV-1 remission may be possible with a less aggressive and toxic approach. An adult infected with HIV-1 underwent allogeneic HSCT for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor. He experienced mild gut graft-versus-host disease. Antiretroviral therapy was interrupted 16 months after transplantation. HIV-1 remission has been maintained over a further 18 months. Plasma HIV-1 RNA has been undetectable at less than one copy per millilitre along with undetectable HIV-1 DNA in peripheral CD4 T lymphocytes. Quantitative viral outgrowth assays from peripheral CD4 T lymphocytes show no reactivatable virus using a total of 24 million resting CD4 T cells. CCR5-tropic, but not CXCR4-tropic, viruses were identified in HIV-1 DNA from CD4 T cells of the patient before the transplant. CD4 T cells isolated from peripheral blood after transplantation did not express CCR5 and were susceptible only to CXCR4-tropic virus ex vivo. HIV-1 Gag-specific CD4 and CD8 T cell responses were lost after transplantation, whereas cytomegalovirus-specific responses were detectable. Similarly, HIV-1-specific antibodies and avidities fell to levels comparable to those in the Berlin patient following transplantation. Although at 18 months after the interruption of treatment it is premature to conclude that this patient has been cured, these data suggest that a single allogeneic HSCT with homozygous CCR5Δ32 donor cells may be sufficient to achieve HIV-1 remission with reduced intensity conditioning and no irradiation, and the findings provide further support for the development of HIV-1 remission strategies based on preventing CCR5 expression. An adult infected with HIV-1 who underwent allogeneic haematopoietic stem-cell transplantation for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor achieved full remission of HIV-1 for 18 months after transplantation and 16 months after cessation of antiretroviral therapy.

Viruses are obligate parasites that rely on host cellular factors to replicate and spread. The endosomal sorting complexes required for transport (ESCRT) system, which is classically associated with sorting and downgrading surface proteins, is one of the host machineries hijacked by viruses across diverse families. Knowledge gained from research into ESCRT and viruses has, in turn, greatly advanced our understanding of many other cellular functions in which the ESCRT pathway is involved, e.g., cytokinesis. This review highlights the interplay between the ESCRT pathway and the viral factors of enveloped viruses with a special emphasis on retroviruses.

Microbial life inhabits deeply buried marine sediments, but the extent of this vast ecosystem remains poorly constrained. Here we provide evidence for the existence of microbial communities in ∼40° to 60°C sediment associated with lignite coal beds at ∼1.5 to 2.5 km below the seafloor in the Pacific Ocean off Japan. Microbial methanogenesis was indicated by the isotopic compositions of methane and carbon dioxide, biomarkers, cultivation data, and gas compositions. Concentrations of indigenous microbial cells below 1.5 km ranged from <10 to ∼104 cells cm–3. Peak concentrations occurred in lignite layers, where communities differed markedly from shallower subseafloor communities and instead resembled organotrophic communities in forest soils. This suggests that terrigenous sediments retain indigenous community members tens of millions of years after burial in the seabed.

Background HIV-1 does not encode a helicase and hijacks those of the cell for efficient replication. We and others previously showed that the DEAD box helicase, DDX5, is an essential HIV dependency factor. DDX5 was recently shown to be associated with the 7SK snRNP. Cellular positive transcription elongation factor b (P-TEFb) is bound in an inactive form with HEXIM1/2 on 7SK snRNP. The Tat/P-TEFb complex is essential for efficient processivity of Pol II in HIV-1 transcription elongation and Tat competes with HEXIM1/2 for P-TEFb. We investigated the precise role of DDX5 in HIV replication using siRNA mediated knockdown and rescue with DDX5 mutants which prevent protein–protein interactions and RNA and ATP binding. Results We demonstrate a critical role for DDX5 in the Tat/HEXIM1 interaction. DDX5 acts to potentiate Tat activity and can bind both Tat and HEXIM1 suggesting it may facilitate the dissociation of HEXIM1/2 from the 7SK-snRNP complex, enhancing Tat/P-TEFb availability. We show knockdown of DDX5 in a T cell line significantly reduces HIV-1 infectivity and viral protein production. This activity is unique to DDX5 and cannot be substituted by its close paralog DDX17. Overexpression of DDX5 stimulates the Tat/LTR promoter but suppresses other cellular and viral promoters. Individual mutations of conserved ATP binding, RNA binding, helicase related or protein binding motifs within DDX5 show that the N terminal RNA binding motifs, the Walker B and the glycine doublet motifs are essential for this function. The Walker A and RNA binding motifs situated on the transactivation domain are however dispensable. Conclusion DDX5 is an essential cellular factor for efficient HIV transcription elongation. It interacts with Tat and may potentiate the availability of P-TEFb through sequestering HEXIM1.

The central dogma of molecular biology describes the flow of genetic information from DNA to protein via an RNA intermediate. For many years, RNA has been considered simply as a messenger relaying information between DNA and proteins. Recent advances in next generation sequencing technology, bioinformatics, and non-coding RNA biology have highlighted the many important roles of RNA in virtually every biological process. Our understanding of RNA biology has been further enriched by a number of significant advances in probing RNA structures. It is now appreciated that many cellular and viral biological processes are highly dependent on specific RNA structures and/or sequences, and such reliance will undoubtedly impact on the evolution of both hosts and viruses. As a contribution to this special issue on host immunity and virus evolution, it is timely to consider how RNA sequences and structures could directly influence the co-evolution between hosts and viruses. In this manuscript, we begin by stating some of the basic principles of RNA structures, followed by describing some of the critical RNA structures in both viruses and hosts. More importantly, we highlight a number of available new tools to predict and to evaluate novel RNA structures, pointing out some of the limitations readers should be aware of in their own analyses.

As healthcare systems are adapting due to COVID-19, there has been an increased need for telehealth in the outpatient setting. Not all patients have been comfortable with this transition. We sought to determine the relationship between health literacy and technological comfort in our cancer patients. We conducted a survey of patients that presented to the oncology clinics at a single-center over a 2-month period. Patients were given a voluntary, anonymous, survey during their visit containing questions regarding demographics, health literacy and technological comfort. 344 surveys were returned (response-rate 64.3%). The median patient age was 61 years, 70% of responders were female and the most common race was White (67.3%). Increasing patient age, male gender, Black and Native-American race, decreased health literacy and lack of home broadband were associated with lower technological comfort score. In our cohort, patients with lower health literacy scores, older and male patients, or who have poor internet access showed a lower level of technological comfort. At risk patients can be identified and provided additional support in their use of telehealth services. •As healthcare systems adapt, there has been an increased use of telemedicine.•Patients with poor health literacy were likely to have reduced technological comfort.•It is important to identify these at-risk patients and assist them in utilizing telehealth services.

HIV-1 replicates via a low-fidelity polymerase with a high mutation rate; strong conservation of individual nucleotides is highly indicative of the presence of critical structural or functional properties. Identifying such conservation can reveal novel insights into viral behaviour. We analysed 3651 publicly available sequences for the presence of nucleic acid conservation beyond that required by amino acid constraints, using a novel scale-free method that identifies regions of outlying score together with a codon scoring algorithm. Sequences with outlying score were further analysed using an algorithm for producing local RNA folds whilst accounting for alignment properties. 11 different conserved regions were identified, some corresponding to well-known cis-acting functions of the HIV-1 genome but also others whose conservation has not previously been noted. We identify rational causes for many of these, including cis functions, possible additional reading frame usage, a plausible mechanism by which the central polypurine tract primes second-strand DNA synthesis and a conformational stabilising function of a region at the 5' end of env.

Our understanding of RNA structure has lagged behind that of proteins and most other biological polymers, largely because of its ability to adopt multiple, and often very different, functional conformations within a single molecule. Flexibility and multifunctionality appear to be its hallmarks. Conventional biochemical and biophysical techniques all have limitations in solving RNA structure and to address this in recent years we have seen the emergence of a wide diversity of techniques applied to RNA structural analysis and an accompanying appreciation of its ubiquity and versatility. Viral RNA is a particularly productive area to study in that this economy of function within a single molecule admirably suits the minimalist lifestyle of viruses. Here, we review the major techniques that are being used to elucidate RNA conformational flexibility and exemplify how the structure and function are, as in all biology, tightly linked.

Patients with hypertrophic cardiomyopathy (HCM) have exercise intolerance due to left ventricular outflow tract (LVOT) obstruction, mitral regurgitation, and left ventricular dysfunction. We sought to study predictors of outcomes in HCM patients undergoing cardiopulmonary stress testing (CPT). We studied 1,005 HCM patients (50 ± 14 years, 64% men, 77% on β-blockers) who underwent CPT with echocardiography. Clinical, echocardiographic, and exercise variables (peak oxygen consumption [VO2] and heart rate recovery [HRR] at first minute postexercise) were recorded. End point was a composite of death, appropriate defibrillator discharges, resuscitated sudden death, stroke, and heart failure admission. Mean left ventricular ejection fraction (LVEF), postexercise LVOT gradient, and peak VO2 were 62% ± 6%, 92 ± 51 mm Hg, and 21 ± 6 mL kg−1 min−1, respectively. Despite 789 patients (78%) being in New York Heart Association classes I to II, only 8% achieved >100% age-gender predicted peak VO2, whereas 77% and 15% achieved 50% to 100% and <50%, respectively. Left ventricular outflow tract gradient ≥30 mm Hg was observed in 83% patients, whereas 23% had abnormal HRR. More than 5.5 ± 4 years, there were 94 (9%) events; 511 (50%) patients underwent surgery for LVOT obstruction. Multivariable Cox proportional analysis demonstrated % age-gender predicted peak VO2 (hazard ratio [HR] 0.96 [0.93-0.98]), normal vs abnormal HRR (HR 0.48 [0.32-0.73]), higher LVEF (HR 0.96 [0.93-0.98]), surgery (0.53 [0.33-0.83]), and atrial fibrillation (HR 1.65 [1.04-2.60]) were associated with outcomes (all P < .05). In HCM patients undergoing CPT, a higher % of achieved age-gender predicted VO2 and surgical relief of LVOT obstruction were associated with better outcomes, whereas abnormal HRR, atrial fibrillation, and lower LVEF were associated with worse outcomes.

•A novel dual route vaccination using the MERS-CoV RBD sub-unit has been developed.•Murine antisera induced to the RBD protein , were neutralising in vitro.•MERS-CoV susceptibility was induced in naïve mice with Ad5hDPP4.•Passive transfer of anti-RBD sera protected susceptible mice.•Protected mice had a significantly reduced viral titre (P = 0.02) in their lungs. Murine antisera with neutralising activity for the coronavirus causative of Middle East respiratory syndrome (MERS) were induced by immunisation of Balb/c mice with the receptor binding domain (RBD) of the viral Spike protein. The murine antisera induced were fully-neutralising in vitro for two separate clinical strains of the MERS coronavirus (MERS-CoV). To test the neutralising capacity of these antisera in vivo, susceptibility to MERS-CoV was induced in naive recipient Balb/c mice by the administration of an adenovirus vector expressing the human DPP4 receptor (Ad5-hDPP4) for MERS-CoV, prior to the passive transfer of the RBD-specific murine antisera to the transduced mice. Subsequent challenge of the recipient transduced mice by the intra-nasal route with a clinical isolate of the MERS-CoV resulted in a significantly reduced viral load in their lungs, compared with transduced mice receiving a negative control antibody. The murine antisera used were derived from mice which had been primed sub-cutaneously with a recombinant fusion of RBD with a human IgG Fc tag (RBD-Fc), adsorbed to calcium phosphate microcrystals and then boosted by the oral route with the same fusion protein in reverse micelles. The data gained indicate that this dual-route vaccination with novel formulations of the RBD-Fc, induced systemic and mucosal anti-viral immunity with demonstrated in vitro and in vivo neutralisation capacity for clinical strains of MERS-CoV.