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Nucleocapsid antibody assays can be used to estimate SARS-CoV-2 infection prevalence in regions implementing spike-based COVID-19 vaccines. However, poor sensitivity of nucleocapsid antibody assays in detecting infection after vaccination has been reported. We derived a lower cutoff for identifying previous infections in a large blood donor cohort (N = 142,599) by using the Ortho VITROS Anti-SARS-CoV-2 Total-N Antibody assay, improving sensitivity while maintaining specificity >98%. We validated sensitivity in samples donated after self-reported swab-confirmed infections diagnoses. Sensitivity for first infections in unvaccinated donors was 98.1% (95% CI 98.0–98.2) and for infection after vaccination was 95.6% (95% CI 95.6–95.7) based on the standard cutoff. Regression analysis showed sensitivity was reduced in the Delta compared with Omicron period, in older donors, in asymptomatic infections,

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive demyelinating disease of the spinal cord due to chronic inflammation. Hallmarks of disease pathology include dysfunctional anti-viral responses and the infiltration of HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ T cells in the central nervous system. HAM/TSP individuals exhibit CD4+ and CD8+ T cells with elevated co-expression of multiple inhibitory immune checkpoint proteins (ICPs), but ICP blockade strategies can only partially restore CD8+ T-cell effector function. Exosomes, small extracellular vesicles, can enhance the spread of viral infections and blunt anti-viral responses. Here, we evaluated the impact of exosomes isolated from HTLV-1-infected cells and HAM/TSP patient sera on dendritic cell (DC) and T-cell phenotypes and function. We observed that exosomes derived from HTLV-infected cell lines (OSP2) elicit proinflammatory cytokine responses in DCs, promote helper CD4+ T-cell polarization, and suppress CD8+ T-cell effector function. Furthermore, exosomes from individuals with HAM/TSP stimulate CD4+ T-cell polarization, marked by increased Th1 and regulatory T-cell differentiation. We conclude that exosomes in the setting of HAM/TSP are detrimental to DC and T-cell function and may contribute to the progression of pathology with HTLV-1 infection.

Abstract Background HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors. Patients and methods We recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification. Results We found that systemic IL-6 was positively correlated with both age (r = 0.50, p

Background In 2017, San Francisco’s initiative to locally eliminate hepatitis C virus (HCV) as a public health threat, End Hep C SF, generated an estimate of city-wide HCV prevalence in 2015, but only incorporated limited information about population HCV treatment. Using additional data and updated methods, we aimed to update the 2015 estimate to 2019 and provide a more accurate estimate of the number of people with untreated, active HCV infection overall and in key subgroups–people who inject drugs (PWID), men who have sex with men (MSM), and low socioeconomic status transgender women (low SES TW). Methods Our estimates are based on triangulation of data from blood bank testing records, cross-sectional and longitudinal observational studies, and published literature. We calculated subpopulation estimates based on biological sex, age and/or HCV risk group. When multiple sources of data were available for subpopulation estimates, we calculated an average using inverse variance weighting. Plausible ranges (PRs) were conservatively estimated to convey uncertainty. Results The total number of people estimated to have anti-HCV antibodies in San Francisco in 2019 was 22,585 (PR:12,014–44,152), with a citywide seroprevalence of 2.6% (PR:1.4%–5.0%)–similar to the 2015 estimate of 21,758 (PR:10,274–42,067). Of all people with evidence of past or present infection, an estimated 11,582 (PR:4,864–35,094) still had untreated, active HCV infection, representing 51.3% (PR:40.5%–79.5%) of all people with anti-HCV antibodies, and 1.3% (PR:0.6%–4.0%) of all San Franciscans. PWID comprised an estimated 2.8% of the total population of San Francisco, yet 73.1% of people with anti-HCV antibodies and 90.4% (n = 10,468, PR:4,690–17,628) of untreated, active HCV infections were among PWID. MSM comprised 7.8% of the total population, yet 11.7% of people with anti-HCV antibodies and 1.0% (n = 119, PR:0–423) of those with untreated active infections. Low SES TW comprised an estimated 0.1% of the total population, yet 1.4% of people with HCV antibodies and 1.6% (n = 183, PR:130–252) of people with untreated active infections. Conclusions Despite the above-average number (2.6%) of people with anti-HCV antibodies, we estimate that only 1.3% (PR:0.6%–4.0%) of all San Francisco residents have untreated, active HCV infection–likely a reflection of San Francisco’s robust efforts to diagnose infection among high-risk groups and initiate curative treatment with as many people as possible. While plausible ranges of infections are wide, these findings indicate that while the overall number of people with anti-HCV antibodies may have increased slightly, the number of people with active HCV infection may have decreased slightly since 2015. This estimate improves upon the 2015 calculations by directly estimating the impact of curative treatment citywide and in subgroups. However, more research is needed to better understand the burden of HCV disease among other subgroups at high risk, such as Blacks/African Americans, people with a history of injection drug use (but not injecting drugs in the last 12 months), people who are currently or formerly incarcerated, and people who are currently or formerly unhoused.

BackgroundHuman T-Cell Lymphotropic Viruses (HTLV) type 1 and type 2 account for an estimated 5 to 10 million infections worldwide and are transmitted through breast feeding, sexual contacts and contaminated cellular blood components. HTLV-associated syndromes are considered as neglected diseases for which there are no vaccines or therapies available, making it particularly important to ensure the best possible diagnosis to enable proper counselling of infected persons and avoid secondary transmission. Although high quality antibody screening assays are available, currently available confirmatory tests are costly and have variable performance, with high rates of indeterminate and non-typable results reported in many regions of the world. The objective of this project was to develop and validate a new high-performance multiplex immunoassay for confirmation and discrimination of HTLV-1 and HTLV-2 strains.Methodology/principal findingsThe multiplex platform was used first as a tool to identify suitable antigens and in a second step for assay development. With data generated on over 400 HTLV-positive blood donors sourced from USA and French blood banks, we developed and validated a high-precision interpretation algorithm. The Multi-HTLV assay demonstrated very high performance for confirmation and strain discrimination with 100% sensitivity, 98.1% specificity and 100% of typing accuracy in validation samples. The assay can be interpreted either visually or automatically with a colorimetric image reader and custom algorithm, providing highly reliable results.Conclusions/significanceThe newly developed Multi-HTLV is very competitive with currently used confirmatory assays and reduces considerably the number of indeterminate results. The multiparametric nature of the assay opens new avenues to study specific serological signatures of each patient, follow the evolution of infection, and explore utility for HTLV disease prognosis. Improving HTLV diagnostic testing will be critical to reduce transmission and to improve monitoring of seropositive patients.

Background: Test-seeking is associated with HIV in Brazilian blood donors. This study sought to investigate the frequency with which three different donor groups: deferred donors, accepted donors who tested HIV positive [HIV (+)], and accepted donors who tested infectious disease markers negative [IDM (−)], came to the blood bank at the suggestion of a health care professional. Study design and methods: Donors deferred for reporting high-risk behaviors and participants in an HIV risk factor case-control study completed a confidential audio computer-assisted self-interview (ACASI) that included two questions related to health care professionals and test-seeking. Results: Of 4013 enrolled deferred donors, 468 (11.8%) reported a health care professional suggested donation as a way to be tested for infection. Of 341 HIV (+) and 791 IDM (−) participants, 43 (12.6%) and 11 (1.4%), respectively, reported a health care professional suggested donation as a way to be tested for infection. Physicians were the most frequently reported source of referral: [(61.5% of deferred, 69.1% of HIV (+), and 9.1% of IDM (−) donors)]. Conclusion: HIV (+) donors and deferred donors were 10 times more likely to report test-seeking behavior by suggestion of health care professional than IDM (−) donors. If true, efforts should be made to educate health care professionals and blood donors on how to safeguard the blood supply, emphasizing that HIV testing should be done at volunteer testing centers rather than at the blood centers. Keywords: Blood donation, Healthcare professionals, Test-seeking

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develops in 1–5% of HTLV-1-infected individuals. Previous studies by us and others have shown that the expression of negative immune checkpoint receptors (NCRs) is significantly increased on CD8 T cells in various chronic viral infections and are associated with poor anti-viral immunity. We have previously identified the differential expression of NCRs on CD8 T cells in blood from patients with HAM/TSP and in central nervous system (CNS) tissues of HTLV-1 infected humanized mice and defined the association with neurological complications. In this study, we determined the co-expression patterns of several key NCRs (PD-1, TIGIT, TIM-3, and LAG-3) and their cognate ligands in HTLV-1 infection and assessed how combination strategies targeting these pathways would impact HTLV-1-specific CD8 T-cell effector functions as an approach to reduce CNS disease outcomes. We found that global CD8 T cells from HAM/TSP patients co-express multiple NCRs at significantly higher frequencies than asymptomatic carriers (AC). Moreover, NCR ligands (PVR and PD-LI) on both plasmacytoid and myeloid dendritic cells were also expressed at higher frequencies in HAM/TSP compared to AC. In both AC and HAM/TSP subjects, combination dual PD-L1/TIGIT or triple PD-L1/TIGIT/TIM-3 blockade with monoclonal antibodies resulted in increases in intracellular cytokine expression in CD8 T cells after virus stimulation, particularly CD107a, a marker of degranulation, and TNF-α, a key cytokine that can directly inhibit viral replication. Interestingly, almost all blockade combinations resulted in reduced IL-2+ HTLV-1-specific CD8 T cell frequencies in HAM/TSP subjects, but not in AC. These results define a novel combinatorial NCR immunotherapeutic blockade strategy to reduce HAM/TSP disease burden.

Chikungunya virus (CHIKV) caused large epidemics throughout the Caribbean in 2014. We conducted nucleic acid amplification testing (NAAT) for CHIKV RNA (n = 29,695) and serologic testing for IgG against CHIKV (n = 1,232) in archived blood donor samples collected during and after an epidemic in Puerto Rico in 2014. NAAT yields peaked in October with 2.1% of donations positive for CHIKV RNA. A total of 14% of NAAT-reactive donations posed a high risk for virus transmission by transfusion because of high virus RNA copy numbers (104–109 RNA copies/mL) and a lack of specific IgM and IgG responses. Testing of minipools of 16 donations would not have detected 62.5% of RNA-positive donations detectable by individual donor testing, including individual donations without IgM and IgG. Serosurveys before and after the epidemic demonstrated that nearly 25% of blood donors in Puerto Rico acquired CHIKV infections and seroconverted during the epidemic.

Short or damaged telomeres have been implicated in degenerative conditions. We hypothesized that analysis of telomere length (TL) in human T-cell lymphotropic virus (HTLV) infection and HTLV-associated neuropathy might provide clues to the etiology of HTLV-associated disease and viral dynamics. A subset of 45 human T-cell lymphotropic virus type 1 (HTLV-1), 45 human T-cell lymphotropic virus type 2 (HTLV-2), and 45 seronegative subjects was selected from the larger HTLV Outcomes Study (HOST) cohort, matched on age, sex and race/ethnicity. Telomere-to-single-copy gene (T/S) ratio (a measure of TL) and HTLV-1 and HTLV-2 proviral loads were measured in peripheral blood mononuclear cells (PBMCs) using quantitative PCR (qPCR). Vibration sensation measured by tuning fork during neurologic examinations performed as part of the HOST study allowed for an assessment of peripheral neuropathy. TL was compared between groups using t-tests, linear and logistic regression. Mean T/S ratio was 1.02 ± 0.16 in HTLV-1, 1.03 ± 0.17 in HTLV-2 and 0.99 ± 0.18 in HTLV seronegative subjects (p = 0.322). TL was not associated with HTLV-1 or -2 proviral load. Shorter TL was significantly associated with impaired vibration sense in the HTLV-2 positive group only. Overall, we found no evidence that telomere length was affected by chronic HTLV-1 and HTLV-2 infection. That TL was only associated with peripheral neuropathy in the HTLV-2-positive group is intriguing, but should be interpreted cautiously. Studies with larger sample size and telomere length measurement in lymphocyte subsets may clarify the relationship between TL and HTLV-infection.