Having considered the broad strategy for viral replication in humans, what are the cellular events that underlie the infection in the whole animal? The suggested reasons as to why some viruses are 
pathogenic will be considered by examining the effects of viruses on single cells and the response of the host to the virus. Viral infections do not always result in manufacture of new virus. The terms productive or non productive infections reflect whether manufacture of new infectious virus is achieved or not. Cells that do not permit the immediate manufacture of infectious virus are also described as non-permissive. One key point about arranging the outcomes in such a manner is that cell death in virus-infected cells provides no long-term survival in the host (literally, a ‘dead end’!) whereas non-lethal infections permit the development of alternative strategies for replication and 
spread. Latency is in parentheses because at some point complete virus is produced within the cell. This means that the infected cell is productive. However, latent infections typically occur in cells that are largely non-permissive. 
Perhaps the ideal strategy for a virus is the productive, non-lytic, ‘silent’ infection akin to the carrier state in certain bacterial infections. In this way the virus will be able to multiply and transmit itself without the host developing adverse illness.  Such virus infections of humans probably exist but the problems of such a strategy are twofold: the host will develop immunity to the virus and the virus needs to transmit itself to new hosts. The persistent and latent infections are close in terms of strategy to this silent infection model, but they both have drawbacks. Persistent infections such as chronic hepatitis B infection results in liver damage. Latent infections such as Herpes simplex cold sores have to reactivate occasionally in order to spread to new hosts. The development of the cold sore betrays the presence of the virus to the host as well as risking treatment with antiviral drugs. For many viral infections, only a minority of those people infected develop clinical disease. Alternatively, if as is the case with persistent infections, the virus cannot remain silent indefinitely, then it will at least remain silent for as long as possible in order to produce enough virus for transmission to the next host.

Lysis of virus-infected host cells will occur either as a consequence of massive release of new virus through the host plasma membrane or through the disruption of host metabolism and protein synthesis as a result of the virus diverting the host machinery into virus manufacture.


Here, virus-infected cells are not killed quickly but continue to produce intact virus. For viruses to 
persist it is important that they delay or prevent effective immunity developing against them. Hepatitis B virus infections of the liver become chronic when an effective cell-mediated immunity fails to develop and the virus is not eradicated. The host gains from this apparent failure of immunity in that liver failure through clinical hepatitis is avoided, but the payback is the persistence of the virus and subsequent risk of chronic hepatitis and liver cancer. 

Latent infections (dormant infections) result from virus incorporation into the host genome such that complete virus is not manufactured. Typically they are DNA viruses. A subset of viral genes are expressed so as to produce viral proteins necessary for regulation and maintenance of the viral genome in the cell. Herpes simplex(HSV) and Varicella zoster(VZV) viruses both become latent by ‘hiding’ in the sensory nerve ganglia and, when reactivated, cause cold sores and shingles respectively. Reactivated virus, infected cells are damaged as a result (HSV-infected cells are lysed in vitro) whereas, in the latent stage, the cells are intact. Reactivation from latency risks the host developing immunity, consequently VZV can only occur once. HSV appears to avoid generating protective immunity. It is interesting to note that the HSV is latent in nerve cell type. Nerves are postmitotic, i.e. non-dividing cell type, and therefore the host genome will not replicate and expose the virus.    Epstein Barr virus establishes latency in B lymphocytes, cells which can undergo periodic repeated proliferation, thereby permitting opportunities for the virus to multiply and infect new hosts. 

Viruses do not always gain control of the infected cell so that, in abortive infections, replication of  the virus is not completed and the viral genetic material is destroyed. The host cell may lack suitable enzymes for the complete manufacture of new virion or virus produced is incomplete or defective in some way. This restriction to viral replication has practical implications. Different cell lines are needed for the successful replication of viruses in cell culture systems. Abortive infections may cause cytopathic damage (CPE) because of the viral replication process, but the release of infectious virus is not achieved.

Occasionally, cells that have been infected with certain viruses exhibit a number of characteristics that are not seen in ‘normal’ uninfected cells. These newly acquired features are related to the regulation of the growth and multiplication of the cells. Essentially the virus causes the cell to extend its normal replicative lifespan.  The normal limited number of times the cell would replicate before senescing (i.e. stop proliferating but still remain metabolically active) is extended in transformed cells. In other words, the cells keep multiplying.As intracellular parasites, viruses can only benefit from the cell up regulating biosynthetic machinery (and make more virus components) and prolong the number of times it divides (thereby increasing the virus yield, for longer). 
Viral transformation occurs following infection with viruses that are able to incorporate viral DNA into the host cell chromosome. Once inserted into the host genome, the virus is called a provirus. This ability is limited to DNA viruses (the viral DNA incorporates directly)  and retroviruses (the DNA is synthesised from the viral RNA using reverse transcriptase and subsequently incorporated into the host genome). It is important to place these events in perspective. Finally, cells that are transformed are not necessarily neoplastic (tumour forming) because transformation is only one stage of many in the process where a eukaryotic cell becomes neoplastic and it does not follow that a transformed cell will become malignant. 

An immune response is necessary for the prevention of uncontrolled proliferation of virus. Viruses will need to suppress the immune response sufficient to permit adequate replication and 
transmission. Complete suppression is unnecessary and would be costly in terms of viral resources and would allow the proliferation of other micro-organisms. The balance that exists between mounting a vigorous immune response that is damaging to the host tissues and not being able to contain the virus can be illustrated in experiments in people suffering from the common cold. The general miserable symptoms were reduced by patients who took anti-inflammatory pain killers but the group who took nothing had a shorter period of illness at the expense of feeling worse. It is said that viruses do not produce typical toxins as seen in toxigenic bacteria. This might reflect the 
overall limits in our knowledge of viral genomes. Certainly it has become clear that viruses do code for proteins that are potentially harmful. Several of the viruses that are linked with human cancers produce proteins that act to prevent the host cell from undergoing apoptosis(programmed cell suicide). Apoptosis should be contrasted with necrosis. It is not possible to summarise the toxicity of viruses into one dominant effect because of the diverse strategies employed by the viruses to successfully replicate and be transmitted.The mammalian cell has developed several mechanisms to try to limit the virus from overwhelming the host. Whilst we all recognise the symptoms of a developing cold or other viral infection, the extent to which this directly represents the toxicity of the viral infection or our reaction to an invader is not clear. The host response to infection at the cellular level is an appropriate place to examine the fight back. The human host responds to all infectious agents with cell-mediated and humoral responses.  Against 
intracellular pathogens, cell-mediated responses are generally more important since, although antibodies can mop up free virus in body fluids such as the bloodstream, they cannot penetrate cells. For antiviral immunity, one important group of polypeptides are the chemokines and cytokines. These small molecular weight proteins regulate the interaction between immediate immune response (the innate immunity) and the adaptive immune response that confers specific immunity. Chemokines and cytokines have homeostatic and proinflammatory functions. The former concerns the maintenance of  haematopoietic system (lymphoid cell lineages from the bone marrow) and the latter is involved in the recruitment of leukocytes from the circulation to the sites of infection. Chemokines/cytokines act on cells through binding to appropriate cell surface receptors triggering the synthesis of antiviral proteins. Chemokines receptors have proved to be important in viral infections through the discovery that the HIV binds to a particular chemokine receptor on lymphocytes. The people with the rare congenital deficiency in this receptor are resistant to infection with HIV. Cytokines are released from activated immune cells in response to infection and they exert antiviral activity. There are increasing numbers of cytokines being identified but the key antiviral cytokines are interferon-alpha, -beta, -gamma and tumour necrosis factor.Cytokines bind to specific receptors on the appropriate host cells (typically macrophages and lymphocytes) which activate signalling pathways that, in turn, activate various intracellular antiviral events.  Many of the mechanisms are as yet unknown but the inhibition of the replication of the virus is the net effect. The antiviral mechanisms activated by cytokines can result in the lysis of the infected cell or more subtle interference of viral replication without killing the infected host cell. Destroying infected cells may be too damaging when dealing with cells that cannot regenerate, for example nerves or in massive infections of a vital organ (e.g. extensive liver damage by hepatitis viruses) and a non-cytolytic, non-cytopathic mechanism is required.

Cited By Kamal Singh Khadka
Msc Microbiology, TU.
Assistant Professor in PU, PBPC, PNC, LA, NA.
Pokhara, Nepal.

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