PLOS Pathogens

The HIV reservoir is a population of 1-10 million anatomically dispersed, latently infected memory CD4+ T cells in which an HIV DNA molecule is quiescently integrated into human chromosomal DNA. When antiretroviral therapy (ART) is stopped and HIV replication initiates in one of these cells, systemic viral spread resumes, rekindling progression to AIDS. Therefore, HIV latency prevents cure. The HIV reservoir contains clones: identical HIV sequences that are integrated within identical human chro...

The latent reservoir of HIV persists for decades in people living with HIV (PWH) on antiretroviral therapy (ART). To determine if persistence arises from the natural dynamics of memory CD4+ T cells harboring HIV, we compared the clonal dynamics of HIV proviruses to that of memory CD4+ T cell receptors (TCR{beta}) from the same PWH and from HIV-seronegative people. We show that clonal dominance of HIV proviruses and antigen-specific CD4+ T cells are similar but that the fields understanding of th...

Seasonal influenza is a primary public health burden in the USA and globally. Annual vaccination programs are designed on the basis of circulating influenza viral strains. However, the effectiveness of the seasonal influenza vaccine is highly variable between seasons and among individuals. A number of factors are known to influence vaccination effectiveness including age, sex, and comorbidities. Here, we sought to determine whether whole blood gene expression profiling prior to vaccination is in...

Genome sequencing from wastewater has emerged as an accurate and cost-effective tool for identifying SARS-CoV-2 variants. However, existing methods for analyzing wastewater sequencing data are not designed to detect novel variants that have not been characterized in humans. Here, we present an unsupervised learning approach that clusters co-varying and time-evolving mutation patterns leading to the identification of SARS-CoV-2 variants. To build our model, we sequenced 3,659 wastewater samples c...

Monitoring SARS-CoV-2 genetic diversity is strongly indicated because diversifying selection may lead to the emergence of novel variants resistant to naturally acquired or vaccine-induced immunity. To date, most data on SARS-CoV-2 genetic diversity has come from the sequencing of clinical samples, but such studies may suffer limitations due to costs and throughput. Wastewater-based epidemiology may provide an alternative and complementary approach for monitoring communities for novel variants. G...

Leprosy is a chronic disease of the skin and peripheral nerves caused by Mycobacterium leprae. A major public health and clinical problem are leprosy reactions, which are inflammatory episodes that often contribute to nerve damage and disability. Type I reversal reactions (T1R) can occur after microbiological cure of leprosy and affect up to 50% of leprosy patients. Early intervention to prevent T1R and, hence, nerve damage, is a major focus of current leprosy control efforts. In a prospective s...

SARS-CoV-2 genomic surveillance in wastewater enables the identification of cryptic lineages, often with numerous mutations not observed in circulating variants. Here, we discovered a unique cryptic SARS-CoV-2 lineage (designated NJ) from New Jersey wastewater that carries many rare mutations and exhibits the highest binding affinity to the hACE2 receptor among all tested SARS-CoV-2 variant RBDs, including the latest Omicron lineages. Moreover, NJ shows extensive evasion against all five major c...

Rapid evolution of SARS-CoV-2 has resulted in the emergence of numerous variants, posing significant challenges to public health surveillance. Clinical genome sequencing, while valuable, has limitations in capturing the full epidemiological dynamics of circulating variants in the general population. This study utilized receptor-binding domain (RBD) amplicon sequencing of wastewater samples to monitor the SARS-CoV-2 community dynamics and evolution in El Paso, TX. Over 17 months, we identified 91...

BackgroundSARS-CoV-2 infection may lead to Post-COVID Syndrome (PCS), characterized by debilitating symptoms like persistent fatigue, cardiovascular symptoms, and cognitive dysfunction. Persistent endothelial dysfunction (ED) is a potential driver of ongoing symptoms. Yet, the underlying biological mechanisms remain unclear. MethodsIn this prospective observational study, we characterized 41 PCS patients and 24 healthy controls (HC, matched out of n = 204, recruited before the pandemic) and inv...

Neutrophils are essential for defense against pathogens but excessive activation in systemic infections can drive immunopathology. We show that neutrophil degranulation can induce endothelial dysfunction via degradation of the glycocalyx and increase of endothelial permeability. To identify targetable pathways regulating neutrophil degranulation in severe inflammation, we compared the proteomes of neutrophils isolated from patients with severe malaria and sepsis. We found significant upregulatio...

Infection with SARS-CoV-2 induces COVID-19, an inflammatory disease that is usually self-limited, but depending on patient conditions may culminate with critical illness and patient death. The virus triggers activation of intracellular sensors, such as the NLRP3 inflammasome, which promotes inflammation and aggravates the disease. Thus, identification of host components associated with NLRP3 inflammasome is key for understanding the physiopathology of the disease. Here, we reported that SARS-CoV...

In the current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19), a better understanding of the underlying mechanisms is essential to reduce morbidity and mortality and treat post-COVID-19 disease. Here, we analyzed alterations of sphingolipids and their metabolizing enzymes in 125 men and 74 women tested positive for SARS-CoV-2 and hospitalized with mild, moderate or severe symptoms or after convalescence. The activities of acid and neutral sphingomy...

Leprosy is a chronic infectious disease of the skin and peripheral nerves with a strong genetic predisposition. Recent genome-wide approaches have identified numerous common variants associated with leprosy, almost all in the Chinese population. We conducted the first family-based genome-wide association study of leprosy in 622 affected offspring from Vietnam, followed by replication in an independent sample of 1189 leprosy cases and 671 controls of the same ethnic origin. The most significant r...

Patients suffering from sickle cell disease (SCD) present with multifactorial pathology, and a detailed understanding of it may help to develop novel therapeutics. In this study, the plasma elemental (24Mg, 44Ca, 57Fe, 63Cu, 66Zn, 77Se, 85Rb, 208Pb, and 39K) levels of SCD patients (n=10, male: 50%) and control groups (trait and healthy; n=10 each; male: 50%) were profiled using inductively coupled plasma mass spectrometry (ICP-MS). Additionally, comparative global erythrocyte metabolomics of SCD...

While antiretroviral therapy (ART) has significantly improved disease prognosis in people with HIV (PWH), understanding the biological mechanisms underlying plasma HIV-1 RNA viral load (VL) can inform additional strategies to slow HIV/AIDS disease progression. Here, we integrated multi-omic datasets and used two machine learning network biology tools (GRIN and MENTOR) to identify biological mechanisms associated with VL across 10 cohorts from multiple omics data sets. We integrated the following...

Concurrent epidemics of respiratory viruses provide avenues for intricate virus-virus interactions, yet how molecular-level viral interactions patterns shape viral ecology and epidemic dynamics remain enigmatic. Here, we present real-world virus crosstalk by comprehensively analyzing diagnostic data from a large cohort (37,415 respiratory illness cases pre-COVID-19 pandemic, 22,239 cases thereafter), mainly infants/toddlers, sourced from the same local hospital. Such high-risk group cohort allow...

BackgroundLipids are involved in the interaction between viral infection and the host metabolic and immunological response. Several studies comparing the lipidome of COVID-19-positive hospitalized patients vs. healthy subjects have already been reported. It is largely unknown, however, whether these differences are specific to this disease. The present study compared the lipidomic signature of hospitalized COVID-19-positive patients with that of healthy subjects, and with COVID-19-negative patie...

Defining causal variation by fine-mapping can be more effective in multi-ethnic genetic studies, particularly in regions such as the MHC with highly population-specific structure. To enable such studies, we constructed a large (N=21,546) high resolution HLA reference panel spanning five global populations based on whole-genome sequencing data. Expectedly, we observed unique long-range HLA haplotypes within each population group. Despite this, we demonstrated consistently accurate imputation at G...

BackgroundSynchronized circadian rhythms play a key role in coordinating physiologic health. Desynchronized circadian rhythms may predispose individuals to disease or be indicative of underlying disease. Intensive care unit (ICU) patients likely experience desynchronized circadian rhythms due to disruptive environmental conditions in the ICU and underlying pathophysiology. This observational pilot study was undertaken to determine if circadian rhythms are altered in ICU patients relative to heal...

BackgroundSusceptibility to SARS-CoV-2 infections is highly variable, ranging from asymptomatic and mild infections in most, to deadly outcome in few. This individual difference in susceptibility and outcome could be mediated by a cross protective pre-immunity, but the nature of this pre-immunity has remained elusive. MethodsAntibody epitope sequence similarities and cross-reactive T cell peptides were searched for between SARS-CoV-2 and other pathogens. We established an ELISA test, a Luminex ...