Envelope, viral fusion with host cell membrane

A FIGURE 17-13 Model for membrane fusion directed by hemagglutinin (HA). A number of low pH-activated HA spikes, possibly in concert with host-cell membrane proteins, form a scaffold that connects a small region of the viral envelope and the endosomal membrane. By unknown mechanisms, the exoplasmic leaflets of the two membranes fuse and then the cytosolic leaflets fuse, forming a pore that widens until the two membranes are completely joined. A similar interaction between membrane bilayers may be brought about during SNARE-mediated vesicle fusion. [Adapted from J. R. Monck and J. M. Fernandez, 1992,... 

Penetration occurs almost instantaneously after attachment between the receptors. It involves energy-dependent mechanisms, the most common of which is receptor-mediated endocytosis, the process by which many hormones and toxins enter cells. The virion is endocytosed and contained within a cellular cytoplasmic vacuole called an endosome. In the case of viruses that penetrate as a consequence of fiision of their envelopes with the plasma membrane, for example, herpesviruses, the envelope remains in the cell membrane and the nudeocapsid enters the cytoplasm. Fusion of viral envelopes with host cell membrane requires the interaction of specific viral proteins in the envelope with proteins in the host cell membrane. 

Budding and release of progeny virus. B. Replicative cycle of an influenza virus, an example of an RNA virus. 1. Attachment. 2. Endocytosis. 3. Influx of H+ through M2 protein. 4. Fusion of the viral envelope with the endosomes membrane, dissociation of the RNP complex, and entry of viral RNA into the nucleus. 5. Synthesis of viral mRNA by viral RNA polymerase. 6. Translation of viral mRNA by host cell s ribosomes. 7. Replication of viral RNA, using viral RNA polymerase, via cRNA replicative form. 8. Assembly of virus particles, and 9. Budding and release of progeny virus. 

In addition to binding to sialic acid residues of the carbohydrate side chains of cellular proteins that the virus exploits as receptors, hemagglutinin has a second function in the infection of host cells. Viruses, bound to the plasma membrane via their membrane receptors, are taken into the cells by endocytosis. Proton pumps in the membrane of endocytic vesicles that now contain the bound viruses cause an accumulation of protons and a consequent lowering of the pH inside the vesicles. The acidic pH (below pH 6) allows hemagglutinin to fulfill its second role, namely, to act as a membrane fusogen by inducing the fusion of the viral envelope membrane with the membrane of the endosome. This expels the viral RNA into the cytoplasm, where it can begin to replicate. 

Docosanol is not directly virucidal instead, it blocks the entry of the virion into the host cell by inhibiting the fusion of the viral envelope with the host plasma membrane. Because it does not affect viral replication or protein production, it may be less susceptible to the development of resistance than other antiviral drugs. 

Viral and cellular lipid membranes must first fuse to allow entry of the viral core into a host cell. The primary receptor required for the entry of primate lentiviruses, HIV-1, HIV-2, and SIV, into cells is the CD4 molecule (1). The interaction of viral envelope protein with CD4 not only attaches virus particles to the cell surface but also induces conformational changes in the envelope protein. These structural alterations allow a secondary interaction with a coreceptor to occur which triggers the fusion process. 

The surface proteins of enveloped viruses perform three m or tasks for the virus shielding of the virus from the immune system, recognition of an appropriate host cell by binding to a cell surface receptor, and the subsequent fusion of the viral and cellular membranes. The first task is somewhat at odds with the last two. Escape from the immune system is aided by rapid evolution of the sequences of the surface proteins, whereas the need to maintain not one but two distinct functions requires that a core structure or structures be maintained. 

In addition to the lipid bilayer, enveloped viruses generally have two or more distinct layers of protein that are organized across the membrane. Thus, most viruses have an outer layer of proteins, usually glycoproteins, which are anchored in the membrane as integral membrane proteins. These proteins function to attach the virion to target host cell receptors and facilitate the entry or fusion of the viral membrane with that of the host cell. In addition, some viruses also contain enzymatic activities associated with this outer layer of protein. For example, influenza virus carries with it a neuraminidase that is responsible for cleaving sialic acid residues on host cells. 

The alphaviruses are a group of 26 icosahedral, positive-sense RNA viruses primarily transmitted by mosquitoes [64]. These 700-A-diameter viruses are some of the simplest of the membrane-enveloped viruses, and members of this group cause serious tropical diseases with characteristic symptoms such as myositis, fever, rash, encephalitis, and polyarthritis [65]. The structures of two different alphavirus-Fab complexes have been determined by cryo-TEM Ross River virus (RR) and Sindbis virus (SIN) [66]. The amino acid sequences of the RR and SIN virus structural and nonstructural proteins are 49 and 64% identical, respectively [67]. The viral RNA genome and 240 copies of the capsid protein form the nucleocapsid core [68-73], and the El and E2 glycoproteins form heterodimers that associate as 80 trimeric spikes on the viral surface. Native SIN and RR lack the E3 glycoprotein because it disassociates from the spike complex after its display on the plasma membrane surface [74, 75]. El has a putative fusion domain that may facilitate host membrane penetration [76, 77]. E2 contains most of the neutralizing epitopes and is also probably involved in host cell recognition [78-80]. 

Viruses (from the Latin virus referring to poison) are nonliving obligate intracellular parasites composed of protein and nucleic acid (DNA or RNA) that manipulate the host cell to produce and manufacture more viruses. Viral infection occurs by tire attachment of virus particles to specific cell receptors within the host cell. After fusion of the host cell plasma membrane with the virus outer envelope, the protein-based viral nucleocapsid (containing the viral DNA) is transported to the host cell nucleus, where components of the viral particle inhibit macromolecular synthesis by tire host cell. Herpes viral DNA and new viral nucleocapsid synthesis occurs within the host nucleus, with the acquisition of new viral envelopes via a budding process through the inner membrane of the host nucleus. The mature newly synthesized viral particles are subsequently... 

Animal V. pass through the cell membrane, either by fusion (e.g. enveloped paramyxoviruses) or by en-dot osis (e.g. Semliki Forest vims). Fusion the vims bin to the cell receptor, the viral envelope and the cell membrane become perforated, the two membranes seal together, and the capsid enters the cell. Endocytosis following adsorption of the vims, a depression forms on the cell surface in the receptor region (adsorption site). Continued invagination forms a coated pit (lined on the cytoplasmic side with cla-thrin), eventually enclosing the vims in a vesicle, which is finally released into the interior of the host cell by abstriction, still surrounded by the vesicle membrane the latter loses its clathrin coat and fuses with other cellular vesicles to form vesicles called en-dosomes viral and endosomal membranes then fuse and the nucleocapsld is released into the host cytoplasm. 

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