Brad T Sherman

Leidos Biomedical Research, Inc., National Institutes of Health · Laboratory of Human Retrovirology and Immunoinformatics

Pneumocystis jirovecii is an important opportunistic pathogen associated with AIDS and other immunodeficient conditions. Currently, very little is known about its nuclear and mitochondrial genomes. In this study, we sequenced the complete mitochondrial genome (mtDNA) of this organism and its closely related species Pneumocystis carinii and Pneumocy...

The database for annotation, visualization and integrated discovery (DAVID), which can be freely accessed at http://david.abcc.ncifcrf.gov/, is a web-based online bioinformatics resource that aims to provide tools for the functional interpretation of large lists of genes/proteins. It has been used by researchers from more than 5000 institutes world...

DAVID bioinformatics resources consists of an integrated biological knowledgebase and analytic tools aimed at systematically extracting biological meaning from large gene/protein lists. This protocol explains how to use DAVID, a high-throughput and integrated data-mining environment, to analyze gene lists derived from high-throughput genomic experi...

Functional analysis of large gene lists, derived in most cases from emerging high-throughput genomic, proteomic and bioinformatics scanning approaches, is still a challenging and daunting task. The gene-annotation enrichment analysis is a promising high-throughput strategy that increases the likelihood for investigators to identify biological proce...

Functional annotation of differentially expressed genes is a necessary and critical step in the analysis of microarray data. The distributed nature of biological knowledge frequently requires researchers to navigate through numerous web-accessible databases gathering information one gene at a time. A more judicious approach is to provide query-base...

Motivation The Database for Annotation, Visualization and Integrated Discovery (DAVID) is a web-based bioinformatics system for the functional interpretation of large lists of genes/proteins generated from high-throughput assays. It has been cited in 72,287 papers since its debut in 2003 as of July 23, 2024. The analysis is usually limited to the s...

Background Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in type 1 IFN genes may contribute to disease progression. This study assessed the impact of variations at the gene and pathway level of type 1 IFN on HIV-1 viral load (VL)....

Herpes Simplex Virus type 1 (HSV-1) infects humans and causes a variety of clinical manifestations. Many HSV-1 genomes have been sequenced with high-throughput sequencing technologies and the annotation of these genome sequences heavily relies on the known genes in reference strains. Consequently, the accuracy of reference strain annotation is crit...

Reservoirs of HIV maintained in anatomic compartments during antiretroviral therapy prevent HIV eradication. However, mechanisms driving their persistence and interventions to control them remain elusive. Here we report the presence of an inducible HIV reservoir within antigen-specific CD4⁺T cells in the central nervous system of a 59-year-old male...

Background: There is an incompletely understood increased risk for cardiovascular disease (CVD) among people living with HIV (PLWH). We investigated if a collection of biomarkers were associated with CVD among PLWH. Mendelian randomization (MR) was used to identify potentially causal associations. Methods: Data from follow-up in 4 large trials a...

Background: Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19. Objective: To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma ant...

Motivation: The existence of quasispecies in the viral population causes difficulties for disease prevention and treatment. High-throughput sequencing provides opportunity to determine rare quasispecies and long sequencing reads covering full genomes reduce quasispecies determination to a clustering problem. The challenge is high similarity of qua...

DAVID is a popular bioinformatics resource system including a web server and web service for functional annotation and enrichment analyses of gene lists. It consists of a comprehensive knowledgebase and a set of functional analysis tools. Here, we report all updates made in 2021. The DAVID Gene system was rebuilt to gain coverage of more organisms,...

Herpes simplex virus type 2 (HSV-2) is a common causative agent of genital tract infections. Moreover, HSV-2 and HIV infection can mutually increase the risk of acquiring another virus infection. Due to the high GC content and highly repetitive regions in HSV-2 genomes, only the genomes of four strains have been completely sequenced (HG52, 333, SD9...

Background: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment. Objective: To evaluate the a priori hypothesis that bamlanivimab has greater...

Citation: Yang, J.; Hao, M.; Khan, M.A.; Rehman, M.T.; Highbarger, H.C.; Chen, Q.; Goswami, S.; Sherman, B.T.; Rehm, C.A.; Dewar, R.L.; et al. Abstract: We have recently reported that a recombinant HIV-1NL4.3 containing Met-to-Ile change at codon 50 of integrase (IN) (IN:M50I) exhibits suppression of the virus release below 0.5% of WT HIV, and the...

BACKGROUND Bamlanivimab, a neutralizing monoclonal antibody given in combination with remdesivir, did not improve outcomes among hospitalized COVID-19 patients based on an early futility assessment. In this final study report, we evaluate an a priori hypothesis that greater benefit of bamlanivimab would be identified in those without detectable end...

The authors wish to make the following corrections to this paper [...]

Interleukin-27 (IL-27) is a pleiotropic cytokine that influences the innate and adaptive immune systems. It inhibits viral infection and regulates the expression of microRNAs (miRNAs). We recently reported that macrophages differentiated from human primary monocytes in the presence of IL-27 and human AB serum resisted human immunodeficiency virus (...

Objectives: Interleukin-27 (IL-27) is known as an anti-HIV cytokine. We have recently demonstrated that IL-27-pretreatment promotes phytohaemagglutinin (PHA)-stimulated CD4(+) T cells into HIV-1-resistant cells by inhibiting uncoating step. Purpose: To further characterize the function of the HIV resistant T cells, we investigated profiles of mi...

Objectives: Elevated levels of interleukin-6 (IL-6), D-dimer, and C-reactive protein (hsCRP) are associated with increased incidence of comorbid disease and mortality among people living with HIV (PLWH). Prior studies suggest a genetic basis for these biomarker elevations in the general population. The study objectives are to identify the genetic...

HIV-1 proviruses persist in the CD4 ⁺ T cells of HIV-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels <40 copies/mL. Greater than 95% of these proviruses detected in circulating peripheral blood mononuclear cells (PBMCs) are referred to as “defective” by virtue of having large inte...

Macrophages play an essential role in the immune system. Recent studies have shown that long non-coding RNAs (lncRNAs) can regulate genes encoding products involved in the immune response. Interleukin (IL)-27 is a member of the IL-6/IL-12 family of cytokines with broad anti-viral effects that inhibits human immunodeficiency virus (HIV) type-1 and h...

Herpes simplex virus 1 (HSV-1) strain McKrae is highly virulent and relatively neuroinvasive in animal models compared with other wild-type HSV-1 strains. To identify the genetic determinants that lead to the unique phenotypes of the McKrae strain, we sequenced its genome with PacBio single-molecule real-time (SMRT) technology and resolved the comp...

Herpes simplex virus type 1 (HSV-1) strain MacIntyre has a severe defect in the anterograde spread after replication in the nucleus. To better understand and identify the genetic determinants that lead to the unique phenotypes of the MacIntyre strain, we sequenced its genome with PacBio single-molecule real-time sequencing technology and resolved t...

Background: HIV-infected patients with poor virologic control and multi-drug resistant virus have limited therapeutic options. The current study was undertaken to evaluate the safety, immunologic effects, and antiviral activity of peripheral lymphocytes transferred from an elite controller, whose immune system is able to control viral replication...

The impact of variation in host genetics on replication of HIV-1 in demographically diverse populations remains uncertain. Here, we perform a genome-wide screen for associations of single nucleotide polymorphisms (SNP) to viral load (VL) in antiretroviral therapy-naïve participants (n=2,440) with varying demographics from the Strategic Timing of An...

After initiating antiretroviral therapy (ART), a rapid decline in HIV viral load is followed by a long period of undetectable viremia. Viral outgrowth assay suggests the reservoir continues to decline slowly. Here, we use full-length sequencing to longitudinally study the proviral landscape of four subjects on ART to investigate the selective press...

Background HIV-1 set-point viral load (SPVL) is predictive of disease progression and shows variability across HIV-1-positive (HIV+) persons. Various factors may influence SPVL including viral features, environmental exposure and host genetics. To identify single nucleotide polymorphisms (SNPs) associated with SPVL, we performed a genome-wide assoc...

After initiating antiretroviral therapy (ART), a rapid decline in plasma viremia is followed by reservoir stabilization. Viral outgrowth assay suggests the reservoir continues to decline slowly, but variation over time and among individuals complicates our understanding of selective pressures during ART. We used full-length sequencing to study more...

We have previously demonstrated that Interleukin-27 differentially regulates the expression of seven novel microRNAs. Here we elucidate the functional significance of these novel microRNAs. Of the seven microRNAs, over expression of miRNA-6852 (miR-SX4) mimic induces cell cycle arrest at G2/M phase and induces necrosis in HEK293 and panel of cervic...

Many of the infectious diseases which have jeopardized and still are a threat to public health are caused by RNA viruses, including HIV, HCV, Influenza virus, Ebola virus and Zika virus. Because of a high rate of mutations and recombination events, rapidly evolving RNA viruses prevail within a host as a collection of closely related variants, refer...

We previously identified Ku70, a subunit of a DNA repair protein complex, as a cytosolic DNA sensor that induces the production of interferon-λ1 (IFN-λ1) by human primary cells and cell lines. IFN-λ1 is a type III IFN and has similar antiviral activity to that of the type I IFNs (IFN-α and IFN-β). We observed that human embryonic kidney (HEK) 293T...

MicroRNAs (miRNAs) regulate gene expression and thereby influence cell fate and function. Recent studies suggest that an abundant class of miRNAs play important roles in immune cells, such as T cells, natural killer (NK) cells, B cells, and dendritic cells (DCs). Interleukin (IL)-27 is a member of the IL-12 family of cytokines with broad anti-viral...

Objective IL-15 has been postulated to play an important role in HIV-1 infection, yet there are conflicting reports regarding its expression levels in these patients. We sought to measure the level of IL-15 in a large, well characterised cohort of HIV-1 infected patients and correlate this with well known markers of inflammation, including CRP, D-d...

Correlation between IL-15 level and HIV viral load in patients treated with ART. HIV-1 infected patients with ART were divided into 4 groups based on viral load and comparisons were made with IL-15 level using the Mann-Whitney test. (TIFF)

Information of each patient’s viral load, CD4 counts and AIDS defining illness. (XLSX)

ART treatment regimen for each patient. PO: oral administration, SQ: subcutaneous injection, QID: once a day, TID: three times a day, BID: twice a day, QHS: at every bed time. (XLSX)

The multivariate analysis for those who were on ART. (DOCX)

The multivariate analysis for those who were ART naïve. (DOCX)

β-glucans, which can activate innate immune responses, are a major component in the cell wall of the cyst form of Pneumocystis. In the current study we examined whether β-1,3 glucans are masked by surface proteins in Pneumocystis, and what role β-glucans play in Pneumocystis-associated inflammation. For 3 species, including P. jirovecii, which caus...

Background Gene isoforms are commonly found in both prokaryotes and eukaryotes. Since each isoform may perform a specific function in response to changing environmental conditions, studying the dynamics of gene isoforms is important in understanding biological processes and disease conditions. However, genome-wide identification of gene isoforms is...

Pneumocystis jirovecii is a major cause of life-threatening pneumonia in immunosuppressed patients including transplant recipients and those with HIV/AIDS, yet surprisingly little is known about the biology of this fungal pathogen. Here we report near complete genome assemblies for three Pneumocystis species that infect humans, rats and mice. Pneum...

Supplementary Figures 1-15, Supplementary Tables 1-5, Supplementary Notes 1-7, Supplementary Methods and Supplementary References

Pneumocystis genes involved in DNA recombination.

Pneumocystis peptidase family.

Pneumocystis genes encoding ATPase.

Pneumocystis genes involved in carbohydrate metabolism.

Pneumocystis genes involved in lipid metabolism.

Pneumocystis genes involved in proteasome.

Pneumocystis genes involved in glucan metabolism.

Pneumocystis genes involved in spliceosome.

Pneumocystis genes with alternative splicing.

Pneumocystis genes involved in mating and meiosis.

Pneumocystis genes involved in cell signaling and stress responses.

Pneumocystis genes encoding histone deacetylase.

Transcription factors in Pneumocystis and other fungi.

Pneumocystis genes involved in nucleotide metabolism.

Pneumocystis genes involved in cofactor metabolism.

Pneumocystis genes involved in oxidative phophorylation.

Members of the msg superfamily in three Pneumocystis species.

Pneumocystis genes involved in amino acid metabolism.

Pneumocystis genes involved in clathrin-dependent endocytosis.

Glycopeptide mapping of P. carinii Msg protein digests.

Oligonucleotide primer and probe sequences used in PCR and DNA hybridization.

Pneumocystis RRM-domain-containing proteins.

Pneumocystis transporters.

Fungal genes involved in chitin metabolism.

Pneumocystis genes involved in glycan metabolism.

GSEA of categories enriched in genes highly expressed during Pneumocystis infection.

Pneumocystis genes involved in anaerobic growth.