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 The pentameric complex drives immunologically covert cell–cell transmission of wild-type human cytomegalovirus

2017 ◽  
Vol 114 (23) ◽  
pp. 6104-6109 ◽  
Author(s):  
Isa Murrell ◽  
Carmen Bedford ◽  
Kristin Ladell ◽  
Kelly L. Miners ◽  
David A. Price ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Neutralizing Antibodies ◽  
Artificial Chromosome ◽  
Wild Type ◽  
Free Virus ◽  
Conditional Expression ◽  
Intact Virus ◽  
Cell Transmission ◽  
Cell Cell

Human cytomegalovirus (HCMV) strains that have been passaged in vitro rapidly acquire mutations that impact viral growth. These laboratory-adapted strains of HCMV generally exhibit restricted tropism, produce high levels of cell-free virus, and develop susceptibility to natural killer cells. To permit experimentation with a virus that retained a clinically relevant phenotype, we reconstructed a wild-type (WT) HCMV genome using bacterial artificial chromosome technology. Like clinical virus, this genome proved to be unstable in cell culture; however, propagation of intact virus was achieved by placing the RL13 and UL128 genes under conditional expression. In this study, we show that WT-HCMV produces extremely low titers of cell-free virus but can efficiently infect fibroblasts, epithelial, monocyte-derived dendritic, and Langerhans cells via direct cell–cell transmission. This process of cell–cell transfer required the UL128 locus, but not the RL13 gene, and was significantly less vulnerable to the disruptive effects of IFN, cellular restriction factors, and neutralizing antibodies compared with cell-free entry. Resistance to neutralizing antibodies was dependent on high-level expression of the pentameric gH/gL/gpUL128–131A complex, a feature of WT but not passaged strains of HCMV.

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 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.

Single-chain variable fragments of broadly neutralizing antibodies prevent HIV cell-cell transmission

2021 ◽  
Author(s):  
Rebecca T van Dorsten ◽  
Lucia Reh ◽  
Alexandra Trkola ◽  
Lynn Morris ◽  
Penny L Moore
Keyword(s):  
Hiv Prevention ◽  
Neutralizing Antibodies ◽  
Geometric Mean ◽  
Single Chain ◽  
Broadly Neutralizing Antibodies ◽  
Free Virus ◽  
Fold Reduction ◽  
Cell Transmission ◽  
Single Chain Variable Fragments ◽  
Cell Cell

Broadly neutralizing antibodies (bNAbs) are able to prevent HIV infection following passive administration. Single-chain variable fragments (scFv) may have advantages over IgG as their smaller size permits improved diffusion into mucosal tissues. We have previously shown that scFv of bNAbs retain significant breadth and potency against cell-free viral transmission in a TZM-bl assay. However, scFv have not been tested for their ability to block cell-cell transmission, a model in which full-sized bNAbs lose potency. We tested 4 scFv (CAP256.25, PGT121, 3BNC117 and 10E8v4) compared to IgG, in free-virus and cell-cell neutralization assays in A3.01 cells, against a panel of seven heterologous viruses. We show that free-virus neutralization titers in the TZM-bl and A3.01 assays were not significantly different, and confirm that scFv show a 1 to 32-fold reduction in activity in the cell-free model, compared to IgG. However, whereas IgG show 3.4 to 19-fold geometric mean potency loss in cell-cell neutralization compared to free-virus transmission, scFv had more comparable activity in the two assays, with only a 1.3 to 2.3-fold reduction. Geometric mean IC 50 of scFv for cell-cell transmission ranged from 0.65 μg/ml (10E8v4) to 2.3 μg/ml (3BNC117) with IgG and scFv neutralization showing similar potency against cell-associated transmission. Therefore, despite the reduced activity of scFv in cell-free assays, their retention of activity in the cell-cell format may make scFv useful for the prevention of both modes of transmission in HIV prevention studies. Importance Broadly neutralizing antibodies (bNAbs) are a major focus for passive immunization against HIV, with the recently concluded HVTN AMP (Antibody Mediated Protection) trial providing proof of concept. Most studies focus on cell-free HIV, however cell-associated virus may play a significant role in HIV infection, pathogenesis and latency. Single-chain variable fragments (scFv) of antibodies may have increased tissue penetration, and reduced immunogenicity. We previously demonstrated that scFv of four HIV-directed bNAbs (CAP256-VRC26.25, PGT121, 3BNC117 and 10E8v4) retain significant potency and breadth against cell-free HIV. As some bNAbs have been shown to lose potency against cell-associated virus, we investigated the ability of bNAb scFv to neutralize this mode of transmission. We demonstrate that unlike IgG, scFv of bNAbs are able to neutralize cell-free and cell-associated virus with similar potency. These scFv, which show functional activity in the therapeutic range, may therefore be suitable for further development as passive immunity for HIV prevention.

scholarly journals Bone marrow mesenchymal stem cells promote prostate cancer cell stemness via cell–cell contact to activate the Jagged1/Notch1 pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ji-wen Cheng ◽  
Li-xia Duan ◽  
Yang Yu ◽  
Pu Wang ◽  
Jia-le Feng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Western Blot ◽  
Cell Contact ◽  
Activity Levels ◽  
Tumor Resistance ◽  
Cell Cell

Abstract Background Mesenchymal stem cells (MSCs) play a crucial role in cancer development and tumor resistance to therapy in prostate cancer, but the influence of MSCs on the stemness potential of PCa cells by cell–cell contact remains unclear. In this study, we investigated the effect of direct contact of PCa cells with MSCs on the stemness of PCa and its mechanisms. Methods First, the flow cytometry, colony formation, and sphere formation were performed to determine the stemness of PCaMSCs, and the expression of stemness-related molecules (Sox2, Oct4, and Nanog) was investigated by western blot analysis. Then, we used western blot and qPCR to determine the activity levels of two candidate pathways and their downstream stemness-associated pathway. Finally, we verified the role of the significantly changed pathway by assessing the key factors in this pathway via in vitro and in vivo experiments. Results We established that MSCs promoted the stemness of PCa cells by cell–cell contact. We here established that the enhanced stemness of PCaMSCs was independent of the CCL5/CCR5 pathway. We also found that PCaMSCs up-regulated the expression of Notch signaling-related genes, and inhibition of Jagged1-Notch1 signaling in PCaMSCs cells significantly inhibited MSCs-induced stemness and tumorigenesis in vitro and in vivo. Conclusions Our results reveal a novel interaction between MSCs and PCa cells in promoting tumorigenesis through activation of the Jagged1/Notch1 pathway, providing a new therapeutic target for the treatment of PCa.

scholarly journals Cell- Cell Transmission of VSV-G Pseudotyped Lentivector Particles

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e74925 ◽  
Author(s):  
Amy M. Skinner ◽  
Santhosh Chakkaramakkil Verghese ◽  
Peter Kurre
Keyword(s):  
Cell Transmission ◽  
Cell Cell
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