Virologic Failures on Initial Boosted-PI Regimen Infrequently Possess Low-Level Variants with Major PI Resistance Mutations by Ultra-Deep Sequencing

It is unknown whether HIV-positive patients experiencing virologic failure (VF) on boosted-PI (PI/r) regimens without drug resistant mutations (DRM) by standard genotyping harbor low-level PI resistant variants. CASTLE compared the efficacy of atazanavir/ritonavir (ATV/r) with lopinavir/ritonavir (LPV/r), each in combination with TVD in ARV-naïve subjects.To determine if VF on an initial PI/r-based regimen possess low-level resistant variants that may affect a subsequent PI-containing regimen.Patients experiencing VF on a Tenofovir/Emtricitabine+PI/r regimen were evaluated by ultra deep sequencing (UDS) for mutations classified/weighted by Stanford HIVdb. Samples were evaluated for variants to 0.4% levels. 36 VF subjects were evaluated by UDS; 24 had UDS for PI and RT DRMs. Of these 24, 19 (79.2%) had any DRM by UDS. The most common UDS-detected DRM were NRTI in 18 subjects: M184V/I (11), TAMs(7) & K65R(4); PI DRMs were detected in 9 subjects: M46I/V(5), F53L(2), I50V(1), D30N(1), and N88S(1). The remaining 12 subjects, all with VLs<10,000, had protease gene UDS, and 4 had low-level PI DRMs: F53L(2), L76V(1), I54S(1), G73S(1). Overall, 3/36(8.3%) subjects had DRMs identified with Stanford-HIVdb weights >12 for ATV or LPV: N88S (at 0.43% level-mutational load 1,828) in 1 subject on ATV; I50V (0.44%-mutational load 110) and L76V (0.52%-mutational load 20) in 1 subject each, both on LPV. All VF samples remained phenotypically susceptible to the treatment PI/r.Among persons experiencing VF without PI DRMs with standard genotyping on an initial PI/r regimen, low-level variants possessing major PI DRMs were present in a minority of cases, occurred in isolation, and did not result in phenotypic resistance. NRTI DRMs were detected in a high proportion of subjects. These data suggest that PIs may remain effective in subjects experiencing VF on a PI/r-based regimen when PI DRMs are not detected by standard or UDS genotyping

Differential Levels of Soluble Inflammatory Markers by Human Immunodeficiency Virus Controller Status and Demographics

Background. Human immunodeficiency virus (HIV)-1 elite controllers (ECs) represent an ideal population to study the effects of HIV persistence on chronic inflammation in the absence of antiretroviral therapy (ART). Methods. Twenty inflammatory markers measured in cohorts of ECs, HIV suppressed noncontrollers, and HIV-uninfected controls were compared using rank-based tests and partial least squares discriminant analysis (PLSDA). Spearman correlations were determined among the inflammatory markers, residual viremia by the single-copy assay, and CD4+ T cell slope. Results. Significant differences were seen between cohorts in 15 of the soluble inflammatory markers. Human immunodeficiency virus-1 ECs were found to have the highest levels for all of the markers with the exception of RANTES. In particular, median levels of 7 inflammatory markers (soluble CD14 [sCD14], interferon [IFN]-γ, IFN-γ-inducible protein [IP]-10, interleukin [IL]-4, IL-10, sCD40L, and granulocyte-macrophage colony-stimulating factor) were twice as high in the HIV-1 ECs compared with either of the HIV-suppressed or uninfected groups. Multivariate PLSDA analysis of inflammatory markers improved differentiation between the patient cohorts, discerning gender differences in inflammatory profile amongst individuals on suppressive ART. Soluble markers of inflammation in ECs were not associated with either levels of residual HIV-1 viremia or CD4+ T cell decline. Conclusions. Despite maintaining relatively low levels of viremia, HIV-1 ECs had elevated levels of a set of key inflammatory markers. Additional studies are needed to determine whether ECs may benefit from ART and to further evaluate the observed gender differences

Serotonin Reduction in Post-acute Sequelae of Viral Infection

Post-acute sequelae of COVID-19 (PASC, Long COVID ) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes

It’s The Region, Stupid: The Real Dangers of U.S. Failure in Afghanistan-Pakistan

Streaming video requires RealPlayer to view.The University Archives has determined that this item is of continuing value to OSU's history.Jonathan Landay is senior national security and intelligence correspondent for McClatchy Newspapers. He is a veteran foreign affairs reporter and has written on U.S. defense, intelligence and foreign policies for nearly 25 years. Landay speaks frequently on national security matters, particularly the Balkans. During his visit to Ohio State, he will speak about Pakistan and the war in Afghanistan. Landay has experience in South Asia, Iraq, the Balkans and Washington. He previously worked for United Press International where he covered the final four years of the Soviet occupation of Afghanistan, the conflicts in Punjab, Kashmir and Sri Lanka, and the 1989 crackdown on pro-democracy demonstrators in Beijing's Tiananmen Square. He also covered the collapse and wars of former Yugoslavia for UPI and later for the Christian Science Monitor. After moving to Washington, D.C. in December 1994 to write on defense and foreign affairs for The Christian Science Monitor, he joined Knight Ridder Newspapers, now McClatchy Newspapers. Landay writes regularly on issues such as the Iranian and North Korean nuclear programs, the U.S. missile defense program, U.S. intelligence matters and U.S. interrogation and detainee policy. He covered the 2001 U.S.-led intervention in Afghanistan, including the Battle of Tora Bora, and in 2003, he spent four months in northern Iraq covering preparations for the U.S.-led invasion and later, the invasion itself. He returns frequently to report in Pakistan and in Afghanistan, where he embeds with U.S. forces. Landay has been nominated three times for a Pulitzer Prize for his investigative work with Warren P. Strobel and Bureau Chief John Walcott on the Bush administration's use of exaggerated and bogus pre-war intelligence on Iraq and the lack of post-invasion stability operations planning. The team won numerous awards including the 2003 Raymond Clapper Memorial Award, the National Headliner Award for How the Bush Administration Went to War in Iraq, a 2005 Award of Distinction from Northwestern University's Medill School of Journalism for Iraqi Exiles Fed Exaggerated Tips to News Media, and a 2007 Edward Weintal Prize from Georgetown University's Institute for the Study of Diplomacy. Their reporting was also showcased in Buying the War, a documentary produced by Bill Moyers for PBS in 2007. Landay earned his B.A. in journalism from George Washington University. He is a keen cyclist and plays lead guitar and writes original music for a local rhythm and blues band called Nobody's Business.Ohio State University. Mershon Center for International Security StudiesEvent Web page, streaming video, event photos, articl

The History, Management, and Ecology of The Leadmine Mountain and Heins Farm Conservation Properties

The Leadmine Mountain and Heins Farm conservation properties make up over 900 acres of land in Sturbridge, Massachusetts, and are managed by the town Conservation Commission. The Commission has a goal of introducing features onto these properties to educate the public on the history, management, and ecology of the land. However, with no specific information on what to include, this project was able to provide a compilation of information to serve as a basis for development of effective educational strategies

Metamorphic Manufacturing v2

Metamorphic manufacturing is a type of digital fabrication wherein robotic systems are employed to incrementally deform material into the desired shape. This approach has the potential to reduce material waste compared to subtractive methods such as CNC milling and can achieve material properties superior to what is possible with additive methods like 3D printing. The aim of this project is to develop a prototype metamorphic manufacturing system capable of shaping plasticine clay. Utilizing the 6-axis ABB IRB 1600 robotic arm equipped with a custom end-effector and interchangeable tools, a system was constructed to achieve this objective. A LiDAR camera was explored to capture accurate 3D models of the Plasticine workpiece as it is being shaped. Automated tool-changing was also explored to allow for a fully automatic workflow

Association of Selected Phenotypic Markers of Lymphocyte Activation and Differentiation with Perinatal Human Immunodeficiency Virus Transmission and Infant Infection

This study of a subset of women and infants participating in National Institutes of Health Pediatric AIDS Clinical Trials Group protocol 185 evaluated lymphocyte phenotypic markers of immune activation and differentiation to determine their association with the likelihood of human immunodeficiency virus (HIV) transmission from the women to their infants and the potential for early identification and/or prognosis of infection in the infants. Lymphocytes from 215 human immunodeficiency virus type 1 (HIV)-infected women and 192 of their infants were analyzed by flow cytometry with an extended three-color panel of monoclonal antibodies. Women who did not transmit to their infants tended to have higher CD4(+) T cells. Most notably, levels of total CD8(+) T cells and CD8(+) CD38(+) cells made significant independent contributions to predicting the risk of mother-to-child transmission. Adjusting for HIV-1 RNA level at entry, a one percentage-point increase in these marker combinations was associated with a nine percent increase in the likelihood of maternal transmission. Total as well as naïve CD4(+) T cells were significantly higher in uninfected than infected infants. Total CD8(+) cells, as well as CD8(+)cells positive for HLA-DR(+), CD45 RA(+) HLA-DR(+), and CD28(+) HLA-DR(+) were elevated in infected infants. Detailed immunophenotyping may be helpful in predicting which pregnant HIV-infected women are at increased risk of transmitting HIV to their infants. Increasing differences in lymphocyte subsets between infected and uninfected infants became apparent as early as six weeks of age. Detailed immunophenotyping may be useful in supporting the diagnosis of HIV infection in infants with perinatal HIV exposure