Host cell inhibition

Vaccination can prevent the spread of flu, but influenza vaccines are slow to produce and difficult to generalize because of the rate of mutation of the virus. So the first line of defence is a class of antiviral compounds known as neuraminidase inhibitors. Neuraminidase is an enzyme used by the flu virus that targets human cell-surface carbohydrates containing neuraminic acids and allows the virus to release itself from the host cell. Inhibition of this enzyme prevents the new virus particles from spreading. 

The antiviral mechanism of action of acyclovir has been reviewed (72). Acyclovir is converted to the monophosphate in herpes vims-infected cells (but only to a limited extent in uninfected cells) by viral-induced thymidine kinase. It is then further phosphorylated by host cell guanosine monophosphate (GMP) kinase to acyclovir diphosphate [66341 -17-1], which in turn is phosphorylated to the triphosphate by unidentified cellular en2ymes. Acyclovir triphosphate [66341 -18-2] inhibits HSV-1 viral DNA polymerase but not cellular DNA polymerase. As a result, acyclovir is 300 to 3000 times more toxic to herpes vimses in an HSV-infected cell than to the cell itself. Studies have shown that a once-daily dose of acyclovir is effective in prevention of recurrent HSV-2 genital herpes (1). HCMV, on the other hand, is relatively uninhibited by acyclovir. 

A.ntibiotic is an organic chemical substance produced by microorganisms that has the capacity in low concentration to selectively destroy or inhibit the growth of other microorganisms without injuring the host cells. It may be adrninistered systemicaHy and be an antimicrobial chemotherapeutic agent. 

Colicins are pore-forming proteins, produced by certain strains of E. coli, that kill or inhibit the growth of other, competing bacteria and even other strains of E. coli (a process known as allelopathy). Channel-forming colicins are released as soluble monomers. Upon encountering a host cell, the colicin molecule traverses the bacterial outer membrane and periplasm, then inserts itself... 

Abstract The entry of viruses into target cells involves a complex series of sequential steps, with opportunities for inhibition at every stage. Entry inhibitors exert their biological properties by inhibiting protein-protein interactions either within the viral envelope (Env) glycoproteins or between viral Env and host-cell receptors. The nature of resistance to entry inhibitors also differs from compounds inhibiting enzymatic targets due to their different modes of action and the relative variability in... 

Recently, however, there have been a number of encouraging developments in the field of antiviral therapy. For example, acycloguanosine (acyclovir see Chapter 5) has been shown to be non-toxic to host cells while specifically inhibiting the replication of herpes vimses. Successfiil clinical trials have led to the introduction of this dmg for the treatment of a variety of herpetic conditions. 

Acyclovir (acycloguanosine. Fig. 5.221) is a novel type of nucleoside analogue which becomes achvated only in herpes-infected host cells by a herpes-specific enzyme, thymidine kinase. This enzyme inihates conversion of acyclovir initially to a monophosphate and then to the antiviral triphosphate which inhibits viral DNA polymerase. The host cell polymerase is not inhibited to the same extent, and the antiviral triphosphate is not produced in uninfected cells. Ganciclovir (Fig. 5.22J) is up to 100... 

Interferon is a low molecular weight protein, produced by vims-infected cells, that itself induces the formation of a second protein inhibiting the transcriphon of viral mRNA. Interferon is produced by the host cell in response to the vims particle, the viral nucleic and non-viral agents, including synthetic polynucleides such as polyinosinic acid polycytidylic acid (poly I C). There are two types of interferon. 

Finally, during budding, HIV-1 may also incorporate into its membrane envelope a variety of different molecules, including proteins that may subsequently interact with their counterparts on the host cell membrane (reviewed in ref. 192), resulting in intracellular signaling and facilitation of virus fusion (193,194). However, the incorporation of cell membrane-derived molecules does not appear to be an absolute requirement for virus entry (195), indicating the leading role of CD4 and the coreceptor for any such mechanism. However, this phenomenon may account for lower levels of inhibition when the effects of mutant CD4 and/or chemokine receptor are studied. 

The nonnucleoside reverse transcriptase inhibitors (NNRTIs), used in the treatment of AIDS, provide interesting examples of clinically relevant noncompetitive inhibitors. The causative agent of AIDS, HIV, belongs to a virus family that relies on an RNA-based genetic system. Replication of the vims requires reverse transcription of the viral genomic RNA into DNA, which is then incorporated into the genome of the infected host cell. Reverse transcription is catalyzed by a virally encoded nucleic acid polymerase, known as reverse transcriptase (RT). This enzyme is critical for viral replication inhibition of HIV RT is therefore an effective mechanism for abrogating infection in patients. 

Plaque assay When a virus particle initiates an infection upon a layer or lawn of host cells which is growing spread out on a flat surface, a zone of lysis or growth inhibition may occur which results in a clearing of the cpll growth. This clearing is called a plaque, and it is assumed that each plaque has originated from one virus particle. 

Exit of the virus from the cell occurs as a result of cell lysis. The phage codes for a lytic enzyme, the T4 lysozyme, which causes an attack on the peptidoglycan of the host cell. The burst size of the virus (the average number of phage particies per cell) depends upon how rapidly lysis occurs. If lysis occurs early, then a smaller burst size occurs, whereas slower lysis leads to a higher burst size. The wild type phage exhibits the phenomenon of lysis inhibition, and therefore has a large burst size, but rapid lysis mutants, in which lysis occurs early, show smaller burst sizes. 

Associated with NA depletion from host nuclei was the diminution and deformation of these nuclei, significant depletion of host nucleoskeletal protein lamin b, and significant reductions in levels of host cell RNA, protein and acid phosphatase activity. In contrast, host infiltrating cells showed no such changes, supporting an infected cell-specific effect. These observations support the possibility that NA are synthesized by the parasite and modulate host nuclear functions. However, release of other parasite secretory products, not analysed, might have been inhibited in these experiments also. 

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