scholarly journals Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19

2020 ◽  
Author(s):  
Bruce K. Patterson ◽  
Harish Seethamraju ◽  
Kush Dhody ◽  
Michael J. Corley ◽  
Kazem Kazempour ◽  
...  
Keyword(s):  
Viral Load ◽  
Plasma Viral Load ◽  
Randomized Clinical Trials ◽  
Severe Disease ◽  
Myeloid Cell ◽  
Receptor Occupancy ◽  
Plasma Viremia ◽  
Rapid Reduction ◽  
Ccr5 Receptor ◽  
Novel Approach

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is now pandemic with nearly three million cases reported to date1. Although the majority of COVID-19 patients experience only mild or moderate symptoms, a subset will progress to severe disease with pneumonia and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation2. Emerging results indicate a dysregulated immune response characterized by runaway inflammation, including cytokine release syndrome (CRS), as the major driver of pathology in severe COVID-193,4. With no treatments currently approved for COVID-19, therapeutics to prevent or treat the excessive inflammation in severe disease caused by SARS-CoV-2 infection are urgently needed. Here, in 10 terminally-ill, critical COVID-19 patients we report profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Following compassionate care treatment with the CCR5 blocking antibody leronlimab, we observed complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. Consistent with reduction of plasma IL-6, single-cell RNA-sequencing revealed declines in transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes. These results demonstrate a novel approach to resolving unchecked inflammation, restoring immunologic deficiencies, and reducing SARS-CoV-2 plasma viral load via disruption of the CCL5-CCR5 axis, and support randomized clinical trials to assess clinical efficacy of leronlimab-mediated inhibition of CCR5 for COVID-19.

scholarly journals Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19

2020 ◽  
Author(s):  
Bruce Pattterson ◽  
Harish Seetthamraju ◽  
Kush Dhody ◽  
Michael Corley ◽  
Kazem Kazempour ◽  
...  
Keyword(s):  
Viral Load ◽  
Plasma Viral Load ◽  
Randomized Clinical Trials ◽  
Severe Disease ◽  
Myeloid Cell ◽  
Receptor Occupancy ◽  
Plasma Viremia ◽  
Rapid Reduction ◽  
Ccr5 Receptor ◽  
Novel Approach

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is now pandemic with nearly three million cases reported to date1. Although the majority of COVID-19 patients experience only mild or moderate symptoms, a subset will progress to severe disease with pneumonia and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation2. Emerging results indicate a dysregulated immune response characterized by runaway inflammation, including cytokine release syndrome (CRS), as the major driver of pathology in severe COVID-193,4. With no treatments currently approved for COVID-19, therapeutics to prevent or treat the excessive inflammation in severe disease caused by SARS-CoV-2 infection are urgently needed. Here, in 10 terminally-ill, critical COVID-19 patients we report profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Following compassionate care treatment with the CCR5 blocking antibody leronlimab, we observed complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. Consistent with reduction of plasma IL-6, single-cell RNA-sequencing revealed declines in transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes. These results demonstrate a novel approach to resolving unchecked inflammation, restoring immunologic deficiencies, and reducing SARS-CoV-2 plasma viral load via disruption of the CCL5-CCR5 axis, and support randomized clinical trials to assess clinical efficacy of leronlimab-mediated inhibition of CCR5 for COVID-19.

scholarly journals CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao L. Chang ◽  
Helen L. Wu ◽  
Gabriela M. Webb ◽  
Meenakshi Tiwary ◽  
Colette Hughes ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Progression ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Plasma Concentrations ◽  
Receptor Occupancy ◽  
Plasma Viremia ◽  
High Background ◽  
Ccr5 Receptor

CCR5 plays a central role in infectious disease, host defense, and cancer progression, thereby making it an ideal target for therapeutic development. Notably, CCR5 is the major HIV entry co-receptor, where its surface density correlates with HIV plasma viremia. The level of CCR5 receptor occupancy (RO) achieved by a CCR5-targeting therapeutic is therefore a critical predictor of its efficacy. However, current methods to measure CCR5 RO lack sensitivity, resulting in high background and overcalculation. Here, we report on two independent, flow cytometric methods of calculating CCR5 RO using the anti-CCR5 antibody, Leronlimab. We show that both methods led to comparable CCR5 RO values, with low background on untreated CCR5+CD4+ T cells and sensitive measurements of occupancy on both blood and tissue-resident CD4+ T cells that correlated longitudinally with plasma concentrations in Leronlimab-treated macaques. Using these assays, we found that Leronlimab stabilized cell surface CCR5, leading to an increase in the levels of circulating and tissue-resident CCR5+CD4+ T cells in vivo in Leronlimab-treated macaques. Weekly Leronlimab treatment in a chronically SIV-infected macaque led to increased CCR5+CD4+ T cells levels and fully suppressed plasma viremia, both concomitant with full CCR5 RO on peripheral blood CD4+ T cells, demonstrating that CCR5+CD4+ T cells were protected from viral replication by Leronlimab binding. Finally, we extended these results to Leronlimab-treated humans and found that weekly 700 mg Leronlimab led to complete CCR5 RO on peripheral blood CD4+ T cells and a statistically significant increase in CCR5+CD4+ T cells in peripheral blood. Collectively, these results establish two RO calculation methods for longitudinal monitoring of anti-CCR5 therapeutic antibody blockade efficacy in both macaques and humans, demonstrate that CCR5+CD4+ T cell levels temporarily increase with Leronlimab treatment, and facilitate future detailed investigations into the immunological impacts of CCR5 inhibition in multiple pathophysiological processes.

scholarly journals SARS-CoV-2 and Obesity: “CoVesity”—a Pandemic Within a Pandemic

2021 ◽  
Author(s):  
Kimberley Zakka ◽  
◽  
Swathikan Chidambaram ◽  
Sami Mansour ◽  
Kamal Mahawar ◽  
...  
Keyword(s):  
Systematic Review ◽  
Risk Factor ◽  
Viral Load ◽  
Respiratory Failure ◽  
Health Outcomes ◽  
Severe Disease ◽  
Vulnerable Population ◽  
Low Grade ◽  
Obesity Management ◽  
Low Grade Inflammation

AbstractIndividuals who are overweight or suffering from obesity are in a chronic state of low-grade inflammation, making them particularly susceptible to developing severe forms of respiratory failure. Studies conducted in past pandemics link obesity with worse health outcomes. This population is thus of particular concern within the context of the COVID-19 pandemic, considering the cessation of obesity management services. This systematic review highlights [1] the reciprocal link between the obesity and COVID-19 pandemics, [2] obesity as a risk factor for more severe disease in past pandemics, [3] potential mechanisms that make individual’s suffering from obesity more susceptible to severe disease and higher viral load, and [4] the need to safely resume bariatric services as recommended by expert guidelines, in order to mitigate the health outcomes of an already vulnerable population.

scholarly journals Rates and Correlates of Short Term Virologic Response among Treatment-Naïve HIV-Infected Children Initiating Antiretroviral Therapy in Ethiopia: A Multi-Center Prospective Cohort Study

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 161
Author(s):  
Birkneh Tilahun Tadesse ◽  
Adugna Chala ◽  
Jackson Mukonzo ◽  
Tolosssa Eticha Chaka ◽  
Sintayehu Tadesse ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Viral Load ◽  
Plasma Viral Load ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Virological Suppression ◽  
Virologic Suppression ◽  
Hiv Drug Resistance ◽  
Treatment Naïve ◽  
The Impact

There is limited data on virologic outcome and its correlates among HIV-infected children in resource-limited settings. We investigated rate and correlates of virologic outcome among treatment naïve HIV-infected Ethiopian children initiating cART, and were followed prospectively at baseline, 8, 12, 24 and 48 weeks using plasma viral load, clinical examination, laboratory tests and pretreatment HIV drug resistance (PDR) screening. Virologic outcome was assessed using two endpoints–virological suppression defined as having “undetectable” plasma viral load < 150 RNA copies/mL, and rebound defined as viral load ≥150 copies/mL after achieving suppression. Cox Proportional Hazards Regression was employed to assess correlates of outcome. At the end of follow up, virologic outcome was measured for 110 participants. Overall, 94(85.5%) achieved virological suppression, of which 36(38.3%) experienced virologic rebound. At 48 weeks, 9(8.2%) children developed WHO-defined virological treatment failure. Taking tenofovir-containing regimen (Hazard Ratio (HR) 3.1-[95% confidence interval (95%CI) 1.0–9.6], p = 0.049) and absence of pretreatment HIV drug resistance (HR 11.7-[95%CI 1.3–104.2], p = 0.028) were independently associated with earlier virologic suppression. In conclusion, PDR and cART regimen type correlate with rate of virologic suppression which was prominent during the first year of cART initiation. However, the impact of viral rebound in 38.3% of the children needs evaluation.

Proviral HIV-1 DNA in subjects followed since primary HIV-1 infection who suppress plasma viral load after one year of highly active antiretroviral therapy

AIDS ◽  
2001 ◽  
Vol 15 (6) ◽  
pp. 665-673 ◽  
Author(s):  
Nicole Ngo-Giang-Huong ◽  
Christiane Deveau ◽  
Isabelle Da Silva ◽  
Isabelle Pellegrin ◽  
Alain Venet ◽  
...  
Keyword(s):  
Viral Load ◽  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Plasma Viral Load ◽  
Highly Active ◽  
One Year ◽  
Hiv 1

Spontaneous HIV-1 replication in a B-lymphoblastoid cell line obtained from an HIV-1-positive patient with undetectable plasma viral load

AIDS ◽  
2006 ◽  
Vol 20 (9) ◽  
pp. 1340-1342
Author(s):  
Liliana Belmonte ◽  
Cecilia Parodi ◽  
Patricia Bare ◽  
Marcelo Corti ◽  
Norberto Sanjuan ◽  
...  
Keyword(s):  
Viral Load ◽  
Cell Line ◽  
Plasma Viral Load ◽  
Lymphoblastoid Cell Line ◽  
Positive Patient ◽  
Undetectable Plasma ◽  
Undetectable Plasma Viral Load ◽  
Hiv 1

scholarly journals H5N1 Influenza Virus Pathogenesis in Genetically Diverse Mice Is Mediated at the Level of Viral Load

mBio ◽  
2011 ◽  
Vol 2 (5) ◽  
Author(s):  
Adrianus C. M. Boon ◽  
David Finkelstein ◽  
Ming Zheng ◽  
Guochun Liao ◽  
John Allard ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Load ◽  
H5n1 Virus ◽  
Inbred Mouse ◽  
Severe Disease ◽  
Mouse Strains ◽  
H5n1 Influenza Virus ◽  
Resistant Mouse ◽  
H5n1 Influenza ◽  
Host Genetic

ABSTRACTThe genotype of the host is one of several factors involved in the pathogenesis of an infectious disease and may be a key parameter in the epidemiology of highly pathogenic H5N1 influenza virus infection in humans. Gene polymorphisms may affect the viral replication rate or alter the host’s immune response to the virus. In humans, it is unclear which aspect dictates the severity of H5N1 virus disease. To identify the mechanism underlying differential responses to H5N1 virus infection in a genetically diverse population, we assessed the host responses and lung viral loads in 21 inbred mouse strains upon intranasal inoculation with A/Hong Kong/213/03 (H5N1). Resistant mouse strains survived large inocula while susceptible strains succumbed to infection with 1,000- to 10,000-fold-lower doses. Quantitative analysis of the viral load after inoculation with an intermediate dose found significant associations with lethality as early as 2 days postinoculation, earlier than any other disease indicator. The increased viral titers in the highly susceptible strains mediated a hyperinflamed environment, indicated by the distinct expression profiles and increased production of inflammatory mediators on day 3. Supporting the hypothesis that viral load rather than an inappropriate response to the virus was the key severity-determining factor, we performed quantitative real-time PCR measuring the cytokine/viral RNA ratio. No significant differences between susceptible and resistant mouse strains were detected, confirming that it is the host genetic component controlling viral load, and therefore replication dynamics, that is primarily responsible for a host’s susceptibility to a given H5N1 virus.IMPORTANCEHighly pathogenic H5N1 influenza virus has circulated in Southeast Asia since 2003 but has been confirmed in relatively few individuals. It has been postulated that host genetic polymorphisms increase the susceptibility to infection and severe disease. The mechanisms and host proteins affected during severe disease are unknown. Inbred mouse strains vary considerably in their ability to resist H5N1 virus and were used to identify the primary mechanism determining disease severity. After inoculation with H5N1, resistant mouse strains had reduced amounts of virus in their lungs, which subsequently resulted in lower production of proinflammatory mediators and less pathology. We therefore conclude that the host genetic component controlling disease severity is primarily influencing viral replication. This is an important concept, as it emphasizes the need to limit virus replication through antiviral therapies and it shows that the hyperinflammatory environment is simply a reflection of more viral genetic material inducing a response.

scholarly journals Mechanistic Inferences from Clinical Reports of SARS-CoV-2

2020 ◽  
Author(s):  
Meagan M Jenkins ◽  
Tyler R McCaw ◽  
Paul A Goepfert
Keyword(s):  
Randomized Clinical Trials ◽  
Severe Disease ◽  
Treatment Options ◽  
Management Strategies ◽  
Type I ◽  
Interferon Signaling ◽  
Adaptive Responses ◽  
Initial Clinical Trial ◽  
Inflammatory State ◽  
Clinical Trial Results

SARS-CoV-2 was identified as the causative pathogen in an outbreak of viral pneumonia cases originating in Wuhan, China, with an ensuing rapid global spread that led it to be declared a pandemic by the WHO on March 11, 2020. Given the threat to public health posed by sequelae of SARS-CoV-2 infection, the literature surrounding patient presentation in severe and non-severe cases, transmission rates and routes, management strategies, and initial clinical trial results have become available at an unprecedented pace. In this review we collate current clinical and immunologic reports, comparing these to reports of previous coronaviruses to identify mechanisms driving progression to severe disease in some patients. In brief, we propose a model wherein dysregulated type I interferon signaling leads to aberrant recruitment and accumulation of innate immune lineages in the lung, impairing establishment of productive adaptive responses, and permitting a pathologic pro-inflammatory state. Finally, we extend these findings to suggest possible treatment options that may merit investigation in randomized clinical trials.

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