Biology subjects

Duke, E. R.

Publications and source records attributed to Duke, E. R..

3 recordsLinked to original sources

bioRxiv2020

Mathematical modeling explains differential SARS CoV-2 kinetics in lung and nasal passages in remdesivir treated rhesus macaques

Remdesivir was recently demonstrated to decrease recovery time in hospitalized patients with SARS-CoV-2 infection. In rhesus macaques, early initiation of remdesivir therapy prevented pneumonia and lowered viral loads in the lung, but viral loads increased in the nasal passages five days after therapy. We developed mathematical models to explain these results. We identified that 1) drug potency is slightly higher in nasal passages than in lungs, 2) viral load decrease in lungs relative to nasal passages during therapy because of infection-dependent generation of refractory cells in the lung, 3) incomplete drug potency in the lung that decreases viral loads even slightly may allow substantially less lung damage, and 4) increases in nasal viral load may occur due to a slight blunting of peak viral load and subsequent decrease of the intensity of the innate immune response, as well as a lack of refractory cells. We also hypothesize that direct inoculation of the trachea in rhesus macaques may not recapitulate natural infection as lung damage occurs more abruptly in this model than in human infection. We demonstrate with sensitivity analysis that a drug with higher potency could completely suppress viral replication and lower viral loads abruptly in the nasal passages as well as the lung. One Sentence SummaryWe developed a mathematical model to explain why remdesivir has a greater antiviral effect on SARS CoV-2 in lung versus nasal passages in rhesus macaques.

microbiology↗

bioRxiv2019

Thresholds for post-rebound viral control after CCR5 gene-edited autologous hematopoietic cell transplantation

Autologous, CCR5 gene-edited hematopoietic stem and progenitor cell (HSPC) transplantation is a promising strategy for achieving HIV remission. However, only a fraction of HSPCs can be edited ex vivo to provide protection against infection prior to autologous transplantation. The optimal transplantation conditions for achieving viral control in the absence of suppressive antiretroviral therapy (ART) are still unknown. We analyzed data from SHIV-1157ipd3N4-infected juvenile pig-tailed macaques that underwent autologous HSPC transplantation with and without CCR5 gene editing. We developed a mathematical model that recapitulates reconstitution of T cell subset counts and SHIV plasma viral loads in control and transplanted macaques. The model predicts that viral control can be obtained following ART treatment interruption (ATI) when: 1) levels of transplanted HSPCs are at least 10-fold higher than residual endogenous HSPCs after total body irradiation and 2) the fraction of protected HSPCs in the transplant achieves a threshold (73%-90%) sufficient to overcome transplantation-dependent loss of SHIV immunity. Under these conditions, if ATI is withheld until transplanted gene-modified cells engraft and reconstitute to a steady state, then spontaneous viral control is projected to occur immediately. Our results support strategies that 1) increase stem cell dose, 2) enhance potency of conditioning regimen, 3) elevate fraction of gene modified SHIV-resistant cells, 4) extend periods between HSPC transplantation and ATI with tracking of CD4+CCR5- cell recovery and / or 5) augment anti-SHIV immunity to achieve sustained SHIV remission. One Sentence SummaryAutologous transplantation of {Delta}CCR5 HSPCs may induce post-ATI SHIV control when the gene-edited cell dose is sufficient to overcome SHIV immunity loss.

microbiology↗

bioRxiv2017

HIV persistence during antiviral therapy occurs due to cellular proliferation

Antiretroviral therapy (ART) suppresses viral replication in people living with HIV. Yet, infected cells persist for decades on ART and viremia returns if ART is stopped. Persistence has been attributed to viral replication in an ART sanctuary and long-lived and1or proliferating latently infected cells. Using ecological methods and existing data, we infer that >99% of infected cells are members of clonal populations after one year of ART. We reconcile our results with observations from the first months of ART, demonstrating mathematically how a \"fossil record\" of historic HIV replication permits observed viral evolution even while most new infected cells arise from proliferation. Together, our results imply cellular proliferation generates a majority of infected cells during ART. Therefore, reducing proliferation could decrease the size of the HIV reservoir and help achieve a functional cure.

immunology↗