scholarly journals Effect of synaptic cell-to-cell transmission and recombination on the evolution of double mutants in HIV

2019 ◽  
Author(s):  
Jesse Kreger ◽  
Natalia L. Komarova ◽  
Dominik Wodarz
Keyword(s):  
Synaptic Transmission ◽  
Double Mutant ◽  
Virus Transmission ◽  
Transmission Efficiency ◽  
Free Virus ◽  
Viral Spread ◽  
Cell Transmission ◽  
Virus Versus ◽  
Negative Epistasis

AbstractRecombination in HIV infection can impact virus evolution in vivo in complex ways, as has been shown both experimentally and mathematically. The effect of free virus versus synaptic, cell-to-cell transmission on the evolution of double mutants, however, has not been investigated. Here we do so by using a stochastic agent-based model. Consistent with data, we assume spatial constraints for synaptic but not for free-virus transmission. Two important effects of the viral spread mode are observed: (i) For disadvantageous mutants, synaptic transmission protects against detrimental effects of recombination on double mutant persistence. Under free virus transmission, recombination increases double mutant levels for negative epistasis, but reduces them for positive epistasis. This reduction for positive epistasis is much diminished under pre-dominantly synaptic transmission, and recombination can in fact lead to increased mutant levels. (ii) The mode of virus spread also directly influences the evolutionary fate of double mutants. For disadvantageous mutants, double mutant production is the predominant driving force, and hence synaptic transmission leads to highest double mutant levels due to increased transmission efficiency. For advantageous mutants, double mutant spread is the most important force, and hence free virus transmission leads to fastest invasion due to better mixing. For neutral mutants, both production and spread of double mutants are important, and hence an optimal mixture of free virus and synaptic transmission maximizes double mutant fractions. Therefore, both free virus and synaptic transmission can enhance or delay double mutant evolution. Implications for drug resistance in HIV are discussed.

scholarly journals Effect of synaptic cell-to-cell transmission and recombination on the evolution of double mutants in HIV

2020 ◽  
Vol 17 (164) ◽  
pp. 20190832 ◽  
Author(s):  
Jesse Kreger ◽  
Natalia L. Komarova ◽  
Dominik Wodarz
Keyword(s):  
Synaptic Transmission ◽  
Double Mutant ◽  
Virus Transmission ◽  
Transmission Efficiency ◽  
Free Virus ◽  
Viral Spread ◽  
Cell Transmission ◽  
Virus Versus ◽  
Negative Epistasis

Recombination in HIV infection can impact virus evolution in vivo in complex ways, as has been shown both experimentally and mathematically. The effect of free virus versus synaptic, cell-to-cell transmission on the evolution of double mutants, however, has not been investigated. Here, we do so by using a stochastic agent-based model. Consistent with data, we assume spatial constraints for synaptic but not for free-virus transmission. Two important effects of the viral spread mode are observed: (i) for disadvantageous mutants, synaptic transmission protects against detrimental effects of recombination on double mutant persistence. Under free virus transmission, recombination increases double mutant levels for negative epistasis, but reduces them for positive epistasis. This reduction for positive epistasis is much diminished under predominantly synaptic transmission, and recombination can, in fact, lead to increased mutant levels. (ii) The mode of virus spread also directly influences the evolutionary fate of double mutants. For disadvantageous mutants, double mutant production is the predominant driving force, and hence synaptic transmission leads to highest double mutant levels due to increased transmission efficiency. For advantageous mutants, double mutant spread is the most important force, and hence free virus transmission leads to fastest invasion due to better mixing. For neutral mutants, both production and spread of double mutants are important, and hence an optimal mixture of free virus and synaptic transmission maximizes double mutant fractions. Therefore, both free virus and synaptic transmission can enhance or delay double mutant evolution. Implications for drug resistance in HIV are discussed.

scholarly journals Quantifying the dynamics of viral recombination during free virus and cell-to-cell transmission in HIV-1 infection

2020 ◽  
Author(s):  
Jesse Kreger ◽  
Josephine Garcia ◽  
Natalia L. Komarova ◽  
Dominik Wodarz ◽  
David N. Levy
Keyword(s):  
Synaptic Transmission ◽  
Mathematical Models ◽  
Cell Population ◽  
Evolutionary Dynamics ◽  
Virus Transmission ◽  
Free Virus ◽  
Cell Transmission ◽  
Static Conditions ◽  
Transmission Pathways ◽  
Hiv 1

AbstractRecombination has been shown to contribute to HIV-1 evolution in vivo, but the underlying dynamics are extremely complex, depending on the nature of the fitness landscapes and of epistatic interactions. A less well-studied determinant of recombinant evolution is the mode of virus transmission in the cell population. HIV-1 can spread by free virus transmission, resulting largely in singly infected cells, and also by direct cell-to-cell transmission, resulting in the simultaneous infection of cells with multiple viruses. We investigate the contribution of these two transmission pathways to recombinant evolution, by applying mathematical models to in vitro experimental data on the growth of fluorescent reporter viruses under static conditions (where both transmission pathways operate), and under gentle shaking conditions, where cell-to-cell transmission is largely inhibited. The parameterized mathematical models are then used to extrapolate the viral evolutionary dynamics beyond the experimental settings. We find that recombinant evolution is fastest if only synaptic transmission operates, and that the addition of free virus transmission reduces the number of recombinants at a given infected cell population size. This is due to synaptic transmission (i) increasing infection multiplicity, (ii) promoting the co-transmission of different virus strains from cell to cell, and (iii) increasing the rate at which point mutations are generated as a result of more reverse transcription events. This work further resulted in the estimation of various parameters that characterize these evolutionary processes. For example, we estimate that during cell-to-cell transmission, an average of 3 viruses successfully integrated into the target cell, which can significantly raise the infection multiplicity compared to free virus transmission. In general, our study points towards the importance of infection multiplicity and cell-to-cell transmission for HIV-evolution within patients.

scholarly journals Antiretroviral Agents Effectively Block HIV Replication after Cell-to-Cell Transfer

2012 ◽  
Vol 86 (16) ◽  
pp. 8773-8780 ◽  
Author(s):  
Marc Permanyer ◽  
Ester Ballana ◽  
Alba Ruiz ◽  
Roger Badia ◽  
Eva Riveira-Munoz ◽  
...  
Keyword(s):  
Virus Replication ◽  
Fluorescent Protein ◽  
Virus Transmission ◽  
Lymphoid Cells ◽  
Target Cells ◽  
Virus Infections ◽  
Free Virus ◽  
Cell Transmission ◽  
Hiv 1

Cell-to-cell transmission of HIV has been proposed as a mechanism contributing to virus escape to the action of antiretrovirals and a mode of HIV persistence during antiretroviral therapy. Here, cocultures of infected HIV-1 cells with primary CD4+T cells or lymphoid cells were used to evaluate virus transmission and the effect of known antiretrovirals. Transfer of HIV antigen from infected to uninfected cells was resistant to the reverse transcriptase inhibitors (RTIs) zidovudine (AZT) and tenofovir, but was blocked by the attachment inhibitor IgGb12. However, quantitative measurement of viral DNA production demonstrated that all anti-HIV agents blocked virus replication with similar potency to cell-free virus infections. Cell-free and cell-associated infections were equally sensitive to inhibition of viral replication when HIV-1 long terminal repeat (LTR)-driven green fluorescent protein (GFP) expression in target cells was measured. However, detection of GFP by flow cytometry may incorrectly estimate the efficacy of antiretrovirals in cell-associated virus transmission, due to replication-independent Tat-mediated LTR transactivation as a consequence of cell-to-cell events that did not occur in short-term (48-h) cell-free virus infections. In conclusion, common markers of virus replication may not accurately correlate and measure infectivity or drug efficacy in cell-to-cell virus transmission. When accurately quantified, active drugs blocked proviral DNA and virus replication in cell-to-cell transmission, recapitulating the efficacy of antiretrovirals in cell-free virus infections andin vivo.

scholarly journals Reverse zoonosis of coronavirus disease-19: Present status and the control by one health approach

2021 ◽  
pp. 2817-2826
Author(s):  
R. Kumar Pramod ◽  
Asha V. Nair ◽  
Padmakar Kamalakar Tambare ◽  
Kanchana Chauhan ◽  
T. Vinay Kumar ◽  
...  
Keyword(s):  
Public Health ◽  
Disease Transmission ◽  
One Health ◽  
Companion Animals ◽  
Virus Transmission ◽  
Careful Study ◽  
History Of Public Health ◽  
Viral Spread ◽  
Global Threat

The recent coronavirus disease (COVID-19) outbreak is one of its kind in the history of public health that has created a major global threat. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a zoonotic source and hence, reverse zoonosis (disease transmission from humans to animals) increases the risk and rate of SARS-CoV-2 infection. Serological and molecular analyses and experimental infection studies have identified SARS-CoV-2 infection in several animal species in various countries. Different domestic and wild animals, including cats, dogs, tigers, lions, puma, snow leopard, minks, and pet ferrets, are infected naturally with SARS-CoV-2, mostly through suspected human to animal transmission. In addition, in vivo experimental inoculation studies have reported the susceptibility of cats, ferrets, hamsters, Egyptian fruit bats, and non-human primates to the virus. These experimentally infected species are found to be capable of virus transmission to co-housed animals of the same species. However, SARS-CoV-2 showed poor replication in livestock species such as pigs, chickens, and ducks with no detection of viral RNA after the animals were deliberately inoculated with the virus or exposed to the infected animals. As the pets/companion animals are more susceptible to COVID-19, the infection in animals needs an in-depth and careful study to avoid any future transmissions. The one health approach is the best inter-disciplinary method to understand the consequences of viral spread and prevention in novel host populations for the betterment of public health. Further in this review, we will explain in detail the different natural and experimentally induced cases of human to animal SARS-CoV-2 infection.

scholarly journals Synaptic transmission may provide an evolutionary benefit to HIV through modulation of latency

2018 ◽  
Author(s):  
Cesar Vargas-Garcia ◽  
Ryan Zurakowski ◽  
Abhyudai Singh
Keyword(s):  
Infected Cell ◽  
Close Contact ◽  
Uninfected Cell ◽  
Viral Fitness ◽  
Free Virus ◽  
Hiv Replication ◽  
Cell Transmission ◽  
Virological Synapses ◽  
Cell Cell

AbstractTransmission of HIV is known to occur by two mechanisms in vivo: the free virus pathway, where viral particles bud off an infected cell before attaching to an uninfected cell, and the cell-cell pathway, where infected cells form virological synapses through close contact with an uninfected cell. It has also been shown that HIV replication includes a positive feedback loop controlled by the viral protein Tat, which may act as a stochastic switch in determining whether an infected cell enters latency. In this paper, we introduce a simple mathematical model of HIV replication containing both the free virus and cell-cell pathways. Using this model, we demonstrate that the high multiplicity of infection in cell-cell transmission results in a suppression of latent infection, and that this modulation of latency through balancing the two transmission mechanisms can provide an evolutionary benefit to the virus. This benefit increases with decreasing overall viral fitness, which may provide a within-host evolutionary pressure toward more cell-cell transmission in late-stage HIV infection.

scholarly journals Examining the interplay between face mask usage, asymptomatic transmission, and social distancing on the spread of COVID-19

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adam Catching ◽  
Sara Capponi ◽  
Ming Te Yeh ◽  
Simone Bianco ◽  
Raul Andino
Keyword(s):  
Social Distance ◽  
Large Fraction ◽  
Real Life ◽  
Virus Transmission ◽  
Face Mask ◽  
Social Distancing ◽  
Viral Spread ◽  
The Face ◽  
Asymptomatic Individuals ◽  
High Virus

AbstractCOVID-19’s high virus transmission rates have caused a pandemic that is exacerbated by the high rates of asymptomatic and presymptomatic infections. These factors suggest that face masks and social distance could be paramount in containing the pandemic. We examined the efficacy of each measure and the combination of both measures using an agent-based model within a closed space that approximated real-life interactions. By explicitly considering different fractions of asymptomatic individuals, as well as a realistic hypothesis of face masks protection during inhaling and exhaling, our simulations demonstrate that a synergistic use of face masks and social distancing is the most effective intervention to curb the infection spread. To control the pandemic, our models suggest that high adherence to social distance is necessary to curb the spread of the disease, and that wearing face masks provides optimal protection even if only a small portion of the population comply with social distance. Finally, the face mask effectiveness in curbing the viral spread is not reduced if a large fraction of population is asymptomatic. Our findings have important implications for policies that dictate the reopening of social gatherings.

scholarly journals Early Spatial and Temporal Events of Human T-Lymphotropic Virus Type 1 Spread following Blood-Borne Transmission in a Rabbit Model of Infection

2010 ◽  
Vol 84 (10) ◽  
pp. 5124-5130 ◽  
Author(s):  
Rashade A. H. Haynes ◽  
Bevin Zimmerman ◽  
Laurie Millward ◽  
Evan Ware ◽  
Christopher Premanandan ◽  
...  
Keyword(s):  
Virus Type ◽  
Ex Vivo ◽  
Rabbit Model ◽  
Virus Detection ◽  
Mononuclear Leukocytes ◽  
T Lymphotropic Virus ◽  
Viral Spread ◽  
Temporal Events

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell leukemia/lymphoma (ATL) and is associated with a variety of lymphocyte-mediated disorders. HTLV-1 transmission occurs by transmission of infected cells via breast-feeding by infected mothers, sexual intercourse, and contaminated blood products. The route of exposure and early virus replication events are believed to be key determinants of virus-associated spread, antiviral immune responses, and ultimately disease outcomes. The lack of knowledge of early events of HTLV-1 spread following blood-borne transmission of the virus in vivo hinders a more complete understanding of the immunopathogenesis of HTLV-1 infections. Herein, we have used an established animal model of HTLV-1 infection to study early spatial and temporal events of the viral infection. Twelve-week-old rabbits were injected intravenously with cell-associated HTLV-1 (ACH-transformed R49). Blood and tissues were collected at defined intervals throughout the study to test the early spread of the infection. Antibody and hematologic responses were monitored throughout the infection. HTLV-1 intracellular Tax and soluble p19 matrix were tested from ex vivo cultured lymphocytes. Proviral copy numbers were measured by real-time PCR from blood and tissue mononuclear leukocytes. Our data indicate that intravenous infection with cell-associated HTLV-1 targets lymphocytes located in both primary lymphoid and gut-associated lymphoid compartments. A transient lymphocytosis that correlated with peak virus detection parameters was observed by 1 week postinfection before returning to baseline levels. Our data support emerging evidence that HTLV-1 promotes lymphocyte proliferation preceding early viral spread in lymphoid compartments to establish and maintain persistent infection.

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