ASSEMBLY OF THE VIRION

Gibson W (1996) Structure and assembly of the virion. Intervirology 39 389 00 Goldman ME, Nunberg JH, O Brien JA, Quintero JC, Schleif WA, Freund KF, Gaul SL, Saari WS, Wai IS, Hoffman JM et al. (1991) Pyridinone derivatives specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc Natl Acad Sci USA... 

This protein may play important roles in the replication of the genome and/or assembly of the virion (I4). 

The shell of all picomaviruses is built up from 60 copies each of four polypeptide chains, called VPl to VP4. These are translated from the viral RNA into a single polypeptide, which is posttranslationally processed by stepwise proteolysis involving viraily encoded enzymes. First, the polypeptide chain is cleaved into three proteins VPO (which is the precursor for VP2 and VP4), VPl and VP3. These proteins begin the assembly process. The last step of the processing cascade occurs during completion of the virion assembly the precursor protein VPO is cleaved into VP2 and VP4 by a mechanism that is probably autocatalytic but may also involve the viral RNA. VPl, VP2, and VP3 have molecular masses of around 30,000 daltons, whereas VP4 is small, being 7000 daltons, and is completely buried inside the virion. 

The asymmetric unit contains one copy each of the subunits VPl, VP2, VP3, and VP4. VP4 is buried inside the shell and does not reach the surface. The arrangement of VPl, VP2, and VP3 on the surface of the capsid is shown in Figure 16.12a. These three different polypeptide chains build up the virus shell in a way that is analogous to that of the three different conformations A, C, and B of the same polypeptide chain in tomato bushy stunt virus. The viral coat assembles from 12 compact aggregates, or pen tamers, which contain five of each of the coat proteins. The contours of the outward-facing surfaces of the subunits give to each pentamer the shape of a molecular mountain the VPl subunits, which correspond to the A subunits in T = 3 plant viruses, cluster at the peak of the mountain VP2 and VP3 alternate around the foot and VP4 provides the foundation. The amino termini of the five VP3 subunits of the pentamer intertwine around the fivefold axis in the interior of the virion to form a p stmcture that stabilizes the pentamer and in addition interacts with VP4. 

Figure 5.4 Structure and manner of assembly of a simple virus, tobacco mosaic virus, (a) Electron micrograph at high resolution of a portion of the virus particle, (b) Assembly of the tobacco mosaic virion. The RNA assumes a helical configuration surrounded by the protein capsomeres. The center of the particle is hollow.

Mechanism of Action A dopaminergic agonist that blocks the uncoating of influenza A virus, preventing penetration into the host and inhibiting M2 protein in the assembly of progeny virions. Amantadine also blocks the reuptake of dopamine into presyn-aptic neurons and causes direct stimulation of postsynaptic receptors. Therapeutic Effect Antiviral and antiparkinsonian activity. 

As a close relative to the brome mosaic virus the cowpea chlorotic mottle vims (CCMV) possesses an outer diameter of 28 nm, is assembled from 180 subunits that create an icosahedral type structure, and contains an RNA core. " Another similarity is the cationic interior surface of the viral capsid which is formed from subunits with highly basic N-termini (6 positively charged arginine and 3 lysine residues) that project into the cavity and stabilize the RNA core. However as a potential biomineralization template, the electrostatic environment of the virion cavity precludes any cationic metal precursors and thus limits its applicability for nanoparticle synthesis. 

Host cell transcription factors initiate transcription from the LTR, and new viral particles are formed at the plasma membrane. Gag-pol and gag precursors assemble together with two copies of viral RNA, and during the budding process env glycoproteins are incorporated into the viral membrane. In the newly formed virion, gag and gag-pol precursors are subjected to processing by the viral enzyme protease, which results in maturation of the virion. [For more details see (30).]... 

Despite the diversity in the structures of viruses and the types of host cell that are infected, there are several basic steps in the life cycle of all viruses infection (penetration of the virion or its nucleic acid into the host cell), replication (expression of the viral genome), maturation (assembly of viral components into virions), and release (the emission of new virions from the host cell). Because viruses usually possess only enough genetic information to specify the synthesis of their own components, each type must exploit some of the normal metabolic reactions of its host cell to complete the life cycle. For this reason there are numerous variations on these basic steps. This point can be illustrated by comparing the life cycles of two well-researched viruses the T4 bacteriophage and the human immunodeficiency virus (HIV). 

There is no cure for AIDS. Treatment seeks to suppress symptoms (e.g., antibiotics for the infections) and slow viral reproduction. Mortality rates have decreased since 1995 because of the introduction of a treatment protocol called highly active antiretroviral therapy (HAART) that consists of combinations of drugs from the following categories (1) nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., azidothymidine, also called zidovudine or AZT), (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz) and protease inhibitors (e.g., indinavir). Both NRTIs and NNRTIs inhibit vDNA synthesis catalyzed by reverse transcriptase. Protease inhibitors are a class of drugs that prevent the processing of viral protein that is required for the assembly of new virions. 

The F protein is synthesized as a single polyprotein (Fo) comprising 574 amino acids that is activated to the fusion-competent form by a host cell endoprotease, which produces a disulfide-linked heterodimer designated Fi and F2. The carboxy terminus of F2 is the site of cleavage, a process that reveals the hydrophobic amino acids at the amino terminus of Fi as the fusion peptide (Fig. 3) [65, 66]. The processed peptide assembles on the surface of the virion in an oligomeric form, most probably as a trimeric species, and mediates virus-host cell membrane fusion in a fashion that is not dependent on endocytosis. The F protein has also been shown to interact with the cell surface proteins intercellular adhesion molecule-1 (ICAM-1) and nucleolin, which provide potential avenues for vims entry in the absence of the G or SH proteins [67, 68]. 

The lytic cycle Is somewhat more complicated for DNA viruses that Infect eukaryotic cells. In most such viruses, the DNA genome Is transported (with some associated proteins) Into the cell nucleus. Once Inside the nucleus, the viral DNA Is transcribed Into RNA by the host s transcription machinery. Processing of the viral RNA primary transcript by hostcell enzymes 3delds viral mRNA, which Is transported to the cytoplasm and translated Into viral proteins by host-cell ribosomes, tRNA, and translation factors. The viral proteins are then transported back Into the nucleus, where some of them either replicate the viral DNA directly or direct cellular proteins to replicate the viral DNA, as In the case of SV40 discussed In the last section. Assembly of the capsid proteins with the newly replicated viral DNA occurs in the nucleus, 3deldlng hundreds to thousands of progeny virions. 

This drug interferes at virtually all stages of viral replication—viral uncoating. RNA transcription, protein synthesis, and the assembly of new virions. 

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