Viruses outside the host cell

Go To Your Study Dashboard. Home School Viruses are inert outside the host cell Post Answer. R Ritika Jonwal. Latest Asked Questions can I give the neet exam where my age is 2 month small to 17 Q. Start Now. Write your question. Create Your Account Name. Mobile No. I am already a member. Your Answer. Thus, the actin cytoskeleton can be exploited in both donor and target cells to promote virus transmission. Cell biology of viral spreading II.

The utilization of inter-cellular membrane bridges. The membrane biology of cell-to-cell transmission can be complex and remains often controversial. For most animal viruses, all surface or endocytic entry events classically discussed during virus egress or virus entry of cell-free virus also apply to transmission at sites of cell-cell contact Figure 3 [ 28 , 50 ]. Thin actin-rich connections can provide bridges for the movement of surface virus from cell to cell [ 36 , 42 , 51 , 52 ].

Direct cell-to-cell connectivity can be used for the transport of viral genomes of plant viruses thereby bypassing the need for an extracellular phase [ 7 ]. Cell-to-cell connectivity has also been proposed for the microtubule-driven exchange of vesicles carrying completely pinched-off viral particles [ 52 , 53 ].

Multiple observations suggest that cell-to-cell transmission contributes to the pathogenesis of many viral infections. The ability of neurotropic viruses such as Herpes viruses to spread along neurons manifests their clinical pathogenesis. Bidirectional transport along neurons allows Herpes viruses to reach ganglions to establish latency. Yet upon activation, viruses travel back to the periphery to cause another round of acute infection [ 44 ][ 54 ].

Viral spread via tight cell-cell contacts also allows many viruses to evade neutralizing antibodies thus contributing to immune evasion [ 13 , 14 , 55 — 59 ]. The high local virus concentration also lowers the effectiveness of antiviral compounds as it requires a considerably higher drug concentration for effective inhibition [ 62 — 65 ].

Higher proviral content could result in higher genetic diversity of the viral population as recombinant variants may appear at faster rates. These considerations reinforce the importance of studying viral spreading directly within a living organism. Recently, the first visualization of the behavior of retrovirus-infected cells has been accomplished in living mice [ 66 , 67 ].

Intravital imaging of HIV-infected T cells in humanized mice confirms a critical role of the viral glycoprotein in adhesive interactions with uninfected cells [ 66 ]. Work in our laboratory revealed that B cells infected with MLV can indeed form virological synapses within the lymph node of living mice.

Thus, both studies verify some of the main concepts of the virological synapses in vivo. These technologies will shed new light on the role of virus cell-to-cell transmission in a living organism. Finally, if virus cell-to-cell transmission is truly central to the pathogenesis of many viral infections, the development of inhibitors that directly interfere with this process may be critical to prevent the spread of viral infections.

Barriers in the cell-free mode of virus transmission can promote virus cell-to-cell transmission. We thank Ari Helenius for discussions. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form.

Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Papers of particular interest, published within the period of review, have been highlighted as:. National Center for Biotechnology Information , U. Curr Opin Virol. Author manuscript; available in PMC Feb 1. Peng Zhong , 1 Luis M.

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See other articles in PMC that cite the published article. Abstract The life cycle of most viruses involves the release of particles into the extra-cellular space. Barriers in the cell-free path can enforce a contact-dependent mode of transmission The question of why a specific virus spreads by cell-free or by cell-to-cell transmission can be better understood if one considers the requirements for spreading by a cell-free mode of transmission.

Donor cell-induced contact dependence Many cell types do not support viral gene expression or promote efficient viral release at levels required for efficient cell-free spread. Target cell-induced contact dependence Inefficient virus binding to and fusion with target cells often severely decreases the infectivity of cell-free viruses [ 23 — 26 ].

The role for surface retention, cell adhesion and polarization in virus cell-to-cell transmission The viability of cell-free viral spread via diffusion in a 3-dimensional space is dependent on the distance between the producer and target cells and the time taken to cross that distance [ 4 ].

Open in a separate window. Figure 1. Cell biology of virus cell-to-cell transmission Biological models that aim to explain efficient virus cell-to-cell transmission should address aspects such as cell-cell adhesion, polarity and driving forces [ 3 , 18 ]. Figure 2. Figure 3. Figure 4. Cell-to-cell transmission and viral pathogenesis Multiple observations suggest that cell-to-cell transmission contributes to the pathogenesis of many viral infections.

Intravital imaging of viral spreading These considerations reinforce the importance of studying viral spreading directly within a living organism. Acknowledgments We thank Ari Helenius for discussions. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.

Marsh M, Helenius A. Virus entry: open sesame. Sattentau QJ. The direct passage of animal viruses between cells. Current opinion in virology. Virus cell-to-cell transmission. J Virol. Cell-free transmission of human adenovirus by passive mass transfer in cell culture simulated in a computer model. Journal of virology. Vaccinia virus motility. Annu Rev Microbiol.

Frischknecht F, Way M. Surfing pathogens and the lessons learned for actin polymerization. Trends Cell Biol. Lucas WJ. Plant viral movement proteins: agents for cell-to-cell trafficking of viral genomes. Formation of syncytia is repressed by tetraspanins in human immunodeficiency virus type 1-producing cells. Journal of immunology. Cell-to-cell spread of HIV-1 occurs within minutes and may not involve the participation of virus particles. HIV-1 neutralization: the consequences of viral adaptation to growth on transformed T cells.

Cell-to-cell transmission can overcome multiple donor and target cell barriers imposed on cell-free HIV. PLoS pathogens. Most comprehensive study on the differential susceptibility of HIV cell-to-cell transmission to neutralizing antibodies. Tetherin restricts productive HIV-1 cell-to-cell transmission. PLoS Pathog. Mode of transmission affects the sensitivity of human immunodeficiency virus type 1 to restriction by rhesus TRIM5alpha.

Energy is also needed because of another fundamental property of bilayer membranes. Biological membranes have shapes that are determined by their precise lipids and the proteins associated with them 7. Work is required to force membranes out of their spontaneous shape, which is the shape of lowest energy. The fusion pore that connects the virus and cell is roughly an hourglass shape 8. The wall of a fusion pore is a membrane with components that are a mixture of the two original membranes.

An hourglass shape deviates significantly from the spontaneous shape of the initial membranes that constitute the pore.

The greater the diameter of the pore, the greater is the area of the lining membrane, and so pore expansion is a highly energy consuming process. In fact, it appears that more energy is required for pore expansion than for hemifusion or pore formation. All viral fusion proteins contain a greasy segment of amino acids, referred to as a fusion peptide or fusion loop. Soon after activation of the fusion protein, the fusion peptide inserts into the target membrane either plasma or endosomal.

At this point, two extended segments of amino acids are anchored to the membranes: the fusion peptides in the target membrane and the membrane-spanning domains of the fusion proteins in the viral envelope Fig.

The fusion proteins continue to reconfigure, causing the two membrane-anchored domains to come toward each other. This pulls the viral envelope and cellular membrane closely together 9. The fusion proteins exert additional forces, but exactly what these forces are and how they promote fusion remains unknown.

A virion engulfed into an endosome is like a Trojan horse, because the cell perceives the virus particle as food. Fusion of viruses within endosomes depends critically on the acidic environment.

By breaking molecular bonds, acid triggers the conformational changes in the fusion protein that lead to the sequential steps of membrane fusion. The hemifusion diaphragm is a bilayer membrane that is unusual in that each of its lipid monolayers is derived from different membranes, and it does not contain any membrane-spanning proteins Several copies of the fusion protein within a virus are required to induce both hemifusion and pore formation.

During hemifusion, the proteins form a ring just outside the diaphragm and act cooperatively to create stresses that lead to a local rupture in the diaphragm, thereby creating the initial fusion pore. The universality of this mechanism is remarkable when one considers that the primary amino acid sequences and structures of fusion proteins are quite diverse.

Influenza, HIV, and Ebola are enveloped viruses of significant public health concern. The flu pandemic of resulted in the deaths of some 20 million people and arguably accelerated the end of World War I Flu pandemics have continued to occur periodically, as they did in , , , and , but were far less deadly.

Influenza virus is not free to infect other cells upon budding because HA binding to specific sugars, sialic acids, that protrude from cell surfaces prevents a virus from freeing itself from the cell. Another envelope protein, neuraminidase NA , cleaves sialic acids off the cell, setting the influenza free. Drugs that are NA inhibitors, such as the well-known Tamiflu oseltamivir , stop further infection within an individual by eliminating the cleavage of sialic acids Research efforts for influenza, HIV, and Ebola virus have focused on targeting their fusion proteins.

But particular properties of the viruses and their proteins have hindered the successful development of vaccines that protect against infection. Standard vaccines against envelope viruses prime the immune system to generate antibodies Abs against the envelope proteins.

Abs bind to exposed outer portions of envelope proteins and are large, thereby hindering close engagement of the virus with a cell membrane. Some antigenic sites surround an indented pocket within the surface of HA that is responsible for binding sialic acids on cell surfaces. Abs thus block the binding of HA to plasma membranes, eliminating the membrane fusion that leads to infection.

HA readily mutates, and although the accumulated individual mutations lead to only small changes in the conformation of HA, these mutations greatly reduce binding of Abs to HA.

Hence, a new vaccine must be developed each year Influenza presents another problem: its genome is not one continuous strand of RNA, like most viruses, but is segmented into multiple strands. Segmentation allows the genes for HA and NA to reassort: the RNA strands of different flu viruses—such as genes from an avian flu virus and a mammalian flu virus—combine to make what is essentially a new virus.

Some reassortments cause periodic influenza pandemics that are characterized by an unusually large number of severe, and sometimes fatal, infections HIV-1 is clinically, to date, the most important retrovirus.

HIV is a relatively recent emerging virus, appearing in the last 70 years or so. It has independently jumped to humans at least four times, probably due to the bush meat trade of gorillas and chimpanzees, and from chimps kept as pets Viruses not only cause diseases, but have also been important in evolution.

The traditional approach of using attenuated or inactivated virus, and by extension, envelope proteins, as vaccines has been ineffective against HIV-1 for a number of reasons.

The fidelity of the reverse transcriptase of HIV-1 is low and therefore mutations in the viral protein occur frequently. As a result, HIV-1 Env mutates so rapidly that it quickly evades a static vaccine. Furthermore, Env is highly glycosylated, effectively sugarcoating the exposed portion of the protein, and Abs do not bind well to sugars. There is a small unglycosylated region on the surface of Env, and efforts were directed against this bald spot but did not lead to clinically effective approaches.

Many nontraditional vaccine approaches have been developed and tested and these efforts continue, but none have yet been sufficiently successful. Modern biology and public health measures have combined to develop positive methods to prevent and treat the acquired immunodeficiency syndrome. Antiretroviral therapies have largely eliminated the progression of viral infection to AIDS in individuals for whom these therapies have been available.

This was achieved only because prior advancements in the biological sciences allowed the development of new diagnostic methods that were sensitive enough to detect HIV. More recently it has been shown that HIV infection can be eliminated from the body: the Berlin Patient infected with HIV and suffering from leukemia received a stem cell transplant and was thereafter free of the virus It appears that with Ebola, unlike influenza, infected individuals do not become contagious until they exhibit symptoms.

Trial vaccines using virus inactivated by traditional methods have proven unsuccessful, but viruses using recombinant technologies are showing considerable promise. Several other approaches may also be effective, including a cocktail of humanized murine monoclonal Abs, which have been shown to be statistically effective in protecting nonhuman primates.

Acidification of endosomes causes Ebola fusion in an unusual manner. This cleavage confers to HA and Env the full ability to induce fusion. In contrast, Ebola GP must be cleaved at an additional site to cause fusion.

This cleavage occurs within endosomes by a protease cathepsin that is effective at low pH Binding activates GP, and a merger between the viral and endosomal membranes then proceeds. The identification of Niemann-Pick type C1 as a receptor opens up a new potential target for a small molecule drug to block binding and prevent infection The most reliable way to prevent infection caused by any virus is to eliminate entry in the first place.

Intellectual and technological progress has been great, but recurrent viral outbreaks highlight the need for more innovative approaches.

In addition to the proteins responsible for viral entry, many other targets are being explored, including genetic variations that increase susceptibility to infection, proteins that bind to viral proteins, and host immunity proteins.