Replication cycle

Viral Proteases. Figure 1 Role of virally encoded proteases in the replication cycle of a retrovirus (HIV, part a) and of a (+)-strand RNA virus (HCV, part b). The numbers correspond to the following steps in the infectious cycle ... 

In contrast to retroviruses, proteolysis is an early event in the replication cycle of (+)-strand RNA viruses and both protease and polymerase inhibitors can be expected to halt the propagation of infectious viral particles from already infected cells. 

Short replication cycles that may be completed within a few hours, a large amount of viral progeny from one infected host-cell, as well as the general inaccuracy of viral nucleic acid polymerases result in an evolution occurring in fast motion, allowing rapid adaptation of viruses to selective pressures (see chapter by Boucher and Nijhius, this volume). Generalizing, it can be stated that any effective antiviral therapy will lead to the occurrence of resistance mutations. A well studied example... 

Fig. 8 HBV replication cycle and site of action of several anti-HBV agents...

Fig. 3 Representation of the replication cycle of cytomegalovirus showing the site of action of terminase inhibitors...

To summarize, terminase inhibitors point the way toward a switch in strategy for developing HCMV inhibitors, with the aim of achieving a quality different from that of established DNA polymerase inhibitors. Intervention with viral DNA maturation arrests the replicative cycle at the DNA cleavage and packaging step, leading to an accumulation of empty procapsids and unprocessed concatemeric DNA. 

The results of IFN-a-based therapy can theoretically be improved by using better-tolerated drugs that mimic the action of ribavirin and/or by using HCV inhibitors that, when combined, substantially reduce HCV replication. Since the mechanism of action of ribavirin is still unknown, no credible alternative approach is currently available. In contrast, many specific inhibitors of the HCV replication cycle are in preclinical development and several have reached chnical development (Pawlotsky et al. 2007). A number of them are being tested in combination with pegylated IFN-a, with or without ribavirin. 

Pyre K, Bosch BJ, Berkhout B, Jebbink ME, Dijkman R, Rottier P, van der Hoek L (2006) Inhibition of HCoV-NL63 infection at early stages of the replication cycle, Antim Ag Chemoth 50 2000-2008... 

Phosphorylation of histone HI is associated with the condensation of chromosomes during the replication cycle. 

The long incubation times of many human virus diseases indicate that they replicate slowly in host cells. In tissue culture systems it has been shown that most human viruses take from 4 to 24 hours to complete a single replication cycle, contrasting with the 30 or so minutes for many bacterial viruses. 

Reverse transcriptase inhibitors prevent DNA from being produced in newly infected cells. They do not, however, prevent the reactivation of HIV from previously infected cells, the reason being that the enzyme is not involved in this process. Thus, agents that act at a later point in the replication cycle, possibly preventing reactivation, would be a major advance in the treatment of AIDs sufferers. The HIV protease inhibitors, which are currently receiving considerable attention, are believed to act in the manner depicted in Fig. 5.24. 

De Clercq E. Anti-HIV agents interfering with the initial stages of the HIV replicative cycle. In Morrow WJW, Haigwood NL, eds. HIV Molecular Organization, Pathogenicity and Treatment. Amsterdam Elsevier Science Publishers, 1993 267-292. 

Edgar I can address the first question concerning the relationship between cell growth and the cell cycle. In all the experiments we have done, we have found that cell cycle progression—especially the DNA replication cycle—is required for growth. This is fairly trivial. 

Figure 5.9 The replication cycle of a bacterial virus. The general stages of virus replication are indicated.

The eclipse is the period during which the stages of virus multiplication occur. This is called the latent period, because no infectious virus particles are evident. Finally, maturation begins as the newly synthesized nucleic acid molecules become assembled inside protein coats. During the maturation phase, the titer of active virus particles inside the cell rises dramatically. At the end of maturation, release of mature virus particles occurs, either as a result of cell lysis or because of some budding or excretion process. The number of virus particles released, called the burst size, will vary with the particular virus and the particular host cell, and can range from a few to a few thousand. The timing of this overall virus replication cycle varies from 20-30 minutes in many bacterial viruses to 8-40 hours in most animal viruses. We now consider each of the steps of the virus multiplication cycle in more detail. 

Cycle 2 the matrix replication cycle. The matrix molecule can multiply by polymerisation in the presence of a component from cycle 1 it contains all the genetic information required by the whole system. 

For example, with the crystal structure of the aspartyl protease from human immundeficiency virus (HIV-1) in 1989 came the opportunity to design molecules to block this important enzyme that acts as a molecular scissors. HIV is the virus responsible for AIDS. Essential to viral replication, the HIV protease cuts long strands composed of many proteins into the functional proteins found in mature virus particles. This proteolysis occurs at the very end of the HIV replication cycle (Figure 7-1). The three-dimensional structural information derived from the x-ray crystal structure, combined with computer modeling techniques, allowed chemists to design potent, selective inhibitors of the protease enzyme (Figure... 

Figure 1. Replication cycle of human immunodeficiency virus (HIV).

Recently, it has been found that NO donors inhibit HIV-1 replication in acutely infected human peripheral blood mononuclear cells (PBMCs), and have an additive inhibitory effect on HIV-1 replication in combination with 3 -azido-3 -deoxythymisylate (AZT) [139, 140]. S-nitrosothiols (RSNOs) inhibit HIV-1 replication at a step in the viral replicative cycle after reverse transcription, but before or during viral protein expression through a cGMP-independent mechanism. In the latently infected U1 cell line, NO donors and intracellular NO production stimulate HIV-1 reactivation. These studies suggest that NO both inhibits HIV-1 replication in acutely infected cells and stimulates HIV-1 reactivation in chronically infected cells. Thus, NO donors may be useful in the treatment of HIV-1 disease by inhibiting acute infection, or reactivating a latent virus. 

There is a need for more effective anti-HIV agents, especially since resistance to all the currently used agents is beginning to develop a combination of different agents targeting different stages of the virus replicative cycle could provide a more effective therapy (348). 

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