Non-mac-tropic HIV-1 R5 viruses are predominantly transmitted and persist in immune tissue even in AIDS patients who carry highly mac-tropic variants in the brain. Non-mac-tropic R5 envelopes (Envs) require high CD4 levels for infection contrasting with highly mac-tropic Envs, which interact more efficiently with CD4 and mediate infection of macrophages that express low CD4. Non-mac-tropic R5 Envs predominantly target T-cells during transmission and in immune tissue where they must outcompete mac-tropic variants. Here, we investigated whether Env+ pseudoviruses bearing transmitted/founder (T/F), early and late disease non-mac-tropic R5 envelopes mediated more efficient infection of CD4+ T-cells compared to those with highly mac-tropic Envs. Results: Highly mac-tropic Envs mediated highest infectivity for primary T-cells, Jurkat/CCR5 cells, myeloid dendritic cells, macrophages, and HeLa TZM-bl cells, although this was most dramatic on macrophages. Infection of primary T-cells mediated by all Envs was low. However, infection of T-cells was greatly enhanced by increasing virus attachment with DEAE dextran and spinoculation, which enhanced the three Env+virus groups to similar extents. Dendritic cell capture of viruses and trans-infection also greatly enhanced infection of primary T-cells. In trans-infection assays, non-mac-tropic R5 Envs were preferentially enhanced and those from late disease mediated levels of T-cell infection that were equivalent to those mediated by mac-tropic Envs. Conclusions: Our results demonstrate that T/F, early or late disease non-mac-tropic R5 Envs do not preferentially mediate infection of primary CD4+ T-cells compared to highly mac-tropic Envs from brain tissue. We conclude that non-macrophage-tropism of HIV-1 R5 Envs in vitro is determined predominantly by a reduced capacity to target myeloid cells via low CD4 rather than a specific adaptation for T-cells entry that precludes macrophage infection.
by
Ramireddy Bommireddy;
Shannon Stone;
Noopur Bhatnagar;
Pratima Kumari;
Luis E. Munoz;
Judy Oh;
Ki-Hye Kim;
Jameson T. L. Berry;
Kristen M. Jacobsen;
Lahcen Jaafar;
Swe-Htet Naing;
Allison N. Blackerby;
Tori Van der Gaag;
Chloe N. Wright;
Lilin Lai;
Christopher D. Pack;
Sampath Ramachandiran;
Mehul Suthar;
Sang-Moo Kang;
Mukesh Kumar;
Shaker J. C. Reddy;
Periasamy Selvaraj
Several approaches have produced an effective vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since millions of people are exposed to influenza virus and SARS-CoV-2, it is of great interest to develop a two-in-one vaccine that will be able to protect against infection of both viruses. We have developed a hybrid vaccine for SARS-CoV-2 and influenza viruses using influenza virus-like particles (VLP) incorporated by protein transfer with glycosylphosphatidylinositol (GPI)-anchored SARS-CoV-2 RBD fused to GM-CSF as an adjuvant. GPI-RBD-GM-CSF fusion protein was expressed in CHO-S cells, purified and incorporated onto influenza VLPs to develop the hybrid vaccine. Our results show that the hybrid vaccine induced a strong antibody response and protected mice from both influenza virus and mouse-adapted SARS-CoV-2 challenges, with vaccinated mice having significantly lower lung viral titers compared to naive mice. These results suggest that a hybrid vaccine strategy is a promising approach for developing multivalent vaccines to prevent influenza A and SARS-CoV-2 infections.
Here, we report the results of a late boost and three additional series of simian immunodeficiency virus (SIV) challenges in seven DNA/modified vaccinia virus Ankara (MVA)-vaccinated rhesus macaques who resisted a first series of rectal challenges. During 29 additional challenges delivered over 2.3 years, all animals became infected. However, 13 blips of virus in six macaques and anamnestic Env-specific rectal IgA responses in three of the six suggested that local control of infections was occurring during the serial challenge.
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Adam Trickey;
Margaret T. May;
M. John Gill;
Sophie Grabar;
Janne Vehreschild;
Ferdinand W.N.M. Wit;
Fabrice Bonnet;
Matthias Cavassini;
Sophie Abgrall;
Juan Berenguer;
Christoph Wyen;
Peter Reiss;
Katharina Grabmeier-Pfistershammer;
Jodie Guest;
Leah Shepherd;
Ramon Teira;
Antonella d'Arminio Monforte;
Julia del Amo;
Amy Justice;
Dominique Costagliola;
Jonathan A. C. Sterne
People living with HIV (PLHIV) are more likely than the general population to develop AIDS-defining malignancies (ADMs) and several non-ADMs (NADMs). Information is lacking on survival outcomes and cause-specific mortality after cancer diagnosis among PLHIV. We investigated causes of death within 5 years of cancer diagnosis in PLHIV enrolled in European and North American HIV cohorts starting antiretroviral therapy (ART) 1996–2015, aged ≥16 years, and subsequently diagnosed with cancer. Cancers were grouped: ADMs, viral NADMs and nonviral NADMs. We calculated cause-specific mortality rates (MR) after diagnosis of specific cancers and compared 5-year survival with the UK and France general populations. Among 83,856 PLHIV there were 4,436 cancer diagnoses. Of 603 deaths after ADM diagnosis, 292 (48%) were due to an ADM. There were 467/847 (55%) and 74/189 (39%) deaths that were due to an NADM after nonviral and viral NADM diagnoses, respectively. MR were higher for diagnoses between 1996 and 2005 versus 2006–2015: ADMs 102 (95% CI 92–113) per 1,000 years versus 88 (78–100), viral NADMs 134 (106–169) versus 111 (93–133) and nonviral NADMs 264 (232–300) versus 226 (206–248). Estimated 5-year survival for PLHIV diagnosed with liver (29% [19–39%]), lung (18% [13–23%]) and cervical (75% [63–84%]) cancer was similar to general populations. Survival after Hodgkin's lymphoma diagnosis was lower in PLHIV (75% [67–81%]). Among ART-treated PLHIV diagnosed with cancer, MR and causes of death varied by cancer type, with mortality highest for liver and lung cancers. Deaths within 5 years of NADM diagnoses were more likely to be from cancer than AIDS.
Objective
To perform an ecological study to analyze the geospatial distribution of neurosurgeons ≥60 years old and compare these data with the spread of 2019 novel coronavirus disease (COVID-19) across the United States.
Methods
Data regarding distribution of COVID-19 cases were collected from the Environmental Systems Research Institute, and demographic statistics were collected from the American Association of Medical Colleges 2019 State Workforce Reports. These figures were analyzed using geospatial mapping software.
Results
As of July 5, 2020, the 10 states with the highest number of COVID-19 cases showed older neurosurgical workforce proportions (the proportion of active surgeons ≥60 years old) of 20.6%–38.9%. Among states with the highest number of COVID-19 deaths, the older workforce proportions were 25.0%–43.4%. Connecticut demonstrated the highest with 43.4% of neurosurgeons ≥60 years old.
Conclusions
Regional COVID-19 hotspots may coincide with areas where a substantial proportion of the neurosurgical workforce is ≥60 years old. Continuous evaluation and adjustment of local and national clinical practice guidelines are warranted throughout the pandemic era.
by
Kimberly Skrobarcek;
Yi Mu;
Lisa G. Winston;
Geoff Brousseau;
Carol Lyons;
Monica Farley;
Rebecca Perlmutter;
Stacy Holzbauer;
Erin C. Phipps;
Ghinwa Dumyati;
Zintars G. Beldavs;
Marion Kainer;
Alice Guh
Background: Traditionally a hospital-acquired pathogen, Clostridium difficile is increasingly recognized as an important cause of diarrhea in community settings. Health disparities in C. difficileinfection (CDI) have been reported, but little is known about the social determinants of health that influence community-associated (CA) CDI incidence. We sought to identify socioeconomic status (SES) factors associated with increased CA-CDI incidence. Methods: Population-based CDI surveillance is conducted in 35 U.S. counties through the Centers for Disease Control and Prevention’s Emerging Infections Program. A CA-CDI case is defined as a positive C. difficile stool specimen collected as an outpatient or within three days of hospitalization in a person aged ≥ 1 year who did not have a positive test in the prior 8 weeks or an overnight stay in a healthcare facility in the prior 12 weeks. ArcGIS software was used to geocode 2014–2015 CA-CDI case addresses to a 2010 census tract (CT). Incidence rate was calculated using 2010 Census population denominators. CT-level SES factors were obtained from the 2011–2015 American Community Survey 5-year estimates and divided into deciles. To account for CT-level clustering effects, separate generalized linear mixed models with negative binomial distribution were used to evaluate the association between each SES factor and CA-CDI incidence, adjusted by age, sex and race. Results: Of 9686 CA-CDI cases, 9417 (97%) had addresses geocoded to a CT; of these, 62% were female, 82% were white, and 35% were aged ≥65 years. Annual CA-CDI incidence was 42.9 per 100,000 persons. After adjusting for age, sex and race, CT-level SES factors significantly associated with increased CA-CDI incidence included living under the poverty level (rate ratio [RR] 1.12; 95% confidence interval [CI] 1.09–1.53), crowding in homes (RR 1.11; 95% CI 1.01–1.21), low education (RR 1.11; 95% CI 1.07–1.15), low income (RR 1.15; 95% CI 1.12–1.17), having public health insurance (RR 1.21; 95% CI 1.18–1.24), receiving public assistance income (RR 1.69; 95% CI 1.55–1.84), and unemployment (RR 1.14; 95% CI 1.07–1.22). Conclusion: Areas with lower SES have modestly increased CA-CDI incidence. Understanding the mechanisms by which SES factors impact CA-CDI incidence could help guide prevention efforts in these higher-risk areas.
Background
Multi-tablet regimens (MTRs) are associated with increased adverse events and non-adherence. Single tablet regimens (STRs) plus boosted protease inhibitors (PIs) are a simplification option for MTR-treated patients; however, data is needed to validate this therapeutic strategy.
Methods
This retrospective analysis included all HIV-1 infected patients seen at a single center from March 2016 to December 2017 who were switched from twice-daily (BID) regimens or regimens containing ≥ 3 pills daily to elvitegravir/cobicistat/emtricitabine/tenofovir-alafenamide (E/C/F/TAF) plus darunavir (DRV) or rilpivirine/emtricitabine/tenofovir-alafenamide (RPV/F/TAF) plus DRV boosted with ritonavir or cobicistat (DRV/r-c). Eligible patients had baseline HIV-1 RNA<200 copies/mL and were followed for 48 weeks. The primary endpoint was HIV-1 RNA≥50 copies/mL at Week 48. Adherence and safety data were recorded throughout the study.
Results
Of 61 patients included, median age was 53 years, the median number of pills taken daily (range) was 5 (3–9), 80% were taking BID regimens, 97% had baseline HIV-1 RNA<50 copies/mL, 56 (92%) were switched to E/C/F/TAF plus DRV and 5 (8%) to RPV/F/TAF plus DRV/r-c. At Week 48, 2 patients (3%) had HIV-1 RNA≥ 50 copies/mL, both were treated with E/C/F/TAF plus DRV and neither had evidence of treatment-emergent resistance. Fifty-nine (97%) had an HIV-1 RNA<50 copies/mL. Adverse drug reactions (ADRs) occurred in 3/61 (5%) (all Grade 2) leading to 3/61 (5%) ADR-related discontinuations.
Conclusion
In this real-world cohort of MTR-treated patients, switching to a TAF-based STR plus boosted PI maintained virologic control in 97% and was well-tolerated, supporting potential use of this strategy for regimen simplification.
BACKGROUND: COVID-19 testing policies for symptomatic children attending U.S. schools or daycare vary, and whether isolated symptoms should prompt testing is unclear. We evaluated children presenting for SARS-CoV-2 testing to determine if the likelihood of having a positive SARS-CoV-2 test differed between participants with one versus ≥2 symptoms, and to examine the predictive capability of isolated symptoms. METHODS: Participants ≤ 18 years presenting for clinical SARS-CoV-2 molecular testing in six sites in urban/suburban/rural Georgia (July-October, 2021; delta variant predominant) were queried about individual symptoms. Participants were classified into three groups: asymptomatic, one symptom only, or ≥2 symptoms. SARS-CoV-2 test results and clinical characteristics of the three groups were compared. Sensitivity, specificity, and positive/negative predictive values (PPV/NPV) for isolated symptoms were calculated by fitting a saturated Poisson model. RESULTS: Of 602 participants, 21.8% tested positive and 48.7% had a known or suspected close contact. Children reporting one symptom (n=82; OR=6.00, 95% CI: 2.70-13.33) and children reporting ≥2 symptoms (n=365; OR=5.25: 2.66-10.38) were significantly more likely to have a positive COVID-19 test than asymptomatic children (n=155), but they were not significantly different from each other (OR=0.88: 0.52-1.49). Sensitivity/PPV were highest for isolated fever (33%/57%), cough (25%/32%), and sore throat (21%/45%); headache had low sensitivity (8%) but higher PPV (33%). Sensitivity/PPV of isolated congestion/rhinorrhea were 8%/9%. CONCLUSIONS: With high delta variant prevalence, children with isolated symptoms were as likely as those with multiple symptoms to test positive for COVID-19. Isolated fever, cough, sore throat, or headache, but not congestion/rhinorrhea, offered highest predictive value.
Mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) occurs in utero, intrapartum, and through breastfeeding, with a cumulative rate of transmission of 35 to 40%. As a result, ∼400,000 children become infected each year. Little is known about mother-to-infant transmission (MTIT) during natural simian immunodeficiency virus (SIV) infection of sooty mangabeys (SMs) that typically is nonpathogenic despite high viral loads. In this study, we retrospectively investigated the rates of MTIT in a large colony of naturally SIV-infected SMs using serological (anti-SIV antibody by enzyme-linked immunosorbent assay [ELISA] and Western blot analysis) and virological (SIVsmm real-time reverse transcription-PCR) methods. We examined 161 SM infants born to SIV-infected mothers and found that 150 (93.2%) were infected by non-MTIT (n = 120) or remained uninfected (n = 30). The remaining 11 SM infants (6.8%) were defined as acquiring SIV by presumptive MTIT based on (i) the presence of anti-SIV antibodies without seroreversion and (ii) a viral load of >500 copies/ml of serum in the first year of life. SM infants infected with SIV by presumptive MTIT did not show any increased morbidity or mortality, indicating that the infection is nonpathogenic even when acquired early in life. Interestingly, viral loads of SIV-infected SM infants with presumptive MTIT were 2-log lower than those of SIV-infected adult SMs living in the same colony (i.e., ∼1,000 and 100,000 copies/ml, respectively). These results indicate that MTIT is substantially less frequent in naturally SIV-infected SMs than in HIV-1-infected humans and results in nonpathogenic infection associated with low SIV viremia. Evolutionary pressure to reduce MTIT may have contributed to the restriction of SIV pathogenesis in natural hosts.
Influenza viruses initiate infection by attaching to sialic acid receptors on the surface of host cells. It has been recognized for some time that avian influenza viruses usually bind to terminal sialic acid that is linked in the α2-3 configuration to the next sugar while human viruses show preference for α2-6 linked sialic acid. With developments in synthetic chemistry and chemo-enzymatic methods of synthesizing quite complex glycans, it has become clear that the binding specificity extends beyond the sialic acid, and this has led to considerable interest in developing glycan reagents that could be used either as a diagnostic tool for particular influenza viruses, or to identify cells that are susceptible to infection by certain influenza viruses. Here we describe the use of the Consortium for Functional Glycomics Glycan Array to investigate binding specificity of influenza hemagglutinin and cleavage by neuraminidase, using seasonal and pandemic H1N1 influenza viruses as examples, and compare the results with published data using other array methods.