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Viruses grow (replicate) only inside living cells. Are viruses alive? Probably not, but the more important issue is their infectivity. Polymerase chain reaction (PCR) methods approach the issue of infectivity in that they measure the presence of viral nucleic acid (DNA or RNA – the viral genome). However, PCR evidence of viral nucleic acid does not necessarily indicate the presence of infectious virus.
Many methods of viral detection exist, including the detection of viral nucleic acid – PCR, Southern (DNA) and northern (RNA) blots; viral protein (antigen) – immunohistochemistry, ELISA (enzyme linked ; electron microscopic visualization of virus; direct measurement of infectious virus particles – the plaque assay.
Viruses may change their proteins (their antigens) and this may have important consequences for their infectivity and for their antibody control.
The issue of the “aliveness” of viruses may be considered along that of atypical agents, including endogenous retroviruses, viroids and prions. Endogenous retroviruses are components of normal cells, viroids consist of a bit of RNA, and prions are “infectious” but contain no DNA or RNA. All are very unusual in considering the concepts of living agents and infectious agents.While viruses may be pathogenic and cause disease, viruses also may be used to attack bacteria (bacteriophage).
Autoimmune illnesses of the nervous system may follow viral infections and viral vaccines, although the frequency is low. The mechanisms of such illnesses remain unclear but are thought to relate to aberrant responses by the immune system, including B and T lymphocyte responses. Such illnesses are frequently the result of demyelination, of peripheral nervous system myelin or central nervous system myelin.
Multiple sclerosis, due to central nervous system demyelination has been considered as having a viral or post-viral component for many years based on epidemiological grounds and abnormal cerebrospinal fluid (CSF). CSF analysis, particularly the analysis of IgG has been important in the evaluation of autoimmune and viral illnesses of the nervous system.
In some instances, such as progressive multifocal leukoencephalopathy, reactivation of a latent infection results in a demyelinating illness of the brain.
Among the “infections” of the nervous system none are probably more unusual than the prion illnesses. Prions, the cause of illnesses such as kuru, Creutzfeldt–Jakob disease and scrapie are caused by abnormal proteins, without DNA or RNA being present. What is strange is that the illnesses can be transmitted, like infections. But some prion illnesses can be genetically transmitted.
Significant advances in the development of antiviral medications has come from efforts towardsthe control of human immunodeficiencyvirus (HIV), with nucleoside analogs and protease inhibitors leading the way. Similar are advances in vaccine development and understanding the immune system, including immune senescence with age. Antibodies will be used to directly treat illnesses and also to deliver medications including oligonucleotides to abnormal cells. Similarly, viruses have been used to deliver genes to human cells, including abnormal neurons to treat hitherto untreatable illnesses.
Development of methods to measure T lymphocyte functions will enhance understanding of human viral infections and autoimmune illnesses – both of which vary with age. Included in this will be the role of epigenetics on immune functions.
Understanding of latent virus infections of the nervous system will develop including the role of viral genes and also neuronal genes. Related will be understanding if neuronal damage and the development of the post-polio syndrome.
Multiple types of viruses may infect the human nervous system and cause meningitis and encephalitis. Some are specific as to cell type, such as poliomyelitis virus infection of motor neurons, and some are less specific, such as HSV encephalitis. Worldwide, infections of the nervous system by some of the many viruses in the Arbovirus group, such as yellow fever virus, dengue virus, Zika virus, and West Nile virus, are important public health concerns.
Slow virus infections such as the neurological infection subacute sclerosing panencephalitis may be contrasted with latent viral infections. Latent virus infections that have reactivated and new virus infections may cause birth defects including microcephaly.
Atypical agents such as endogenous retroviruses are part of human DNA, and one can consider them as infections or not. Illnesses caused by them may be better considered as degenerative or metabolic illnesses. Other atypical agents such as viroids consist of a simple piece of RNA and require another virus for their replication.
The COVID-19 pandemic has emphasized epidemiology. Some of the epidemiology discussion relates to probability and decision making. Some of the discussion relates to comparisons with clinical medicine, particularly in the great utilization of PCR testing in clinically asymptomatic individuals.
Latent herpes simplex virus (HSV) infection of the nervous system is an infection of neurons of sensory ganglia. During latency the viral DNA is present but minimal expression of viral functions is evident – only one viral RNA termed latency associated transcript (LAT).
While the nucleoside analog acyclovir is effective against HSV infections it cannot clear latent HSV infections. To investigate mechanisms of neuronal HSV latency and reactivation, studies were performed with HSV mutants that are resistant to acyclovir. Such mutants grow poorly in non-dividing cells, such as neurons.
Latent infections by such mutants expressed LAT but did not reactivate. However, reactivation was markedly enhanced by supplemental thymidine nucleoside, consistent with low levels of some nucleosides and related enzymes in non-ividing neurons. Results were supported when medication which clinically blocks the transport of nucleosides reversed the enhanced reactivation.
Lastly, growth of mutant virus in mice was enhanced by thymidine nucleoside, suggesting that the thymidine nucleoside effect may have applicability outside the laboratory.
The “Central Dogma” describes DNA being transcribed into RNA and RNA being translated into protein. In all instances,a biochemical template is used.
The template concept is based on the complementation of specific nucleotides for other specific nucleotides. For example, the deoxynucleotide thymidine complements (hybridizes – binds to) the deoxynucleotide adenine.
The concepts of complementation and hybridization are used in PCR and nucleic acid hybridization – including Southern blot, northern blot, and in situ hybridization – to detect viral DNA and RNA.
The concept of the synthesis of DNA from nucleotides is utilized in the development of some antiviral medications. In these, nucleoside analogs are used, which when converted to nucleotides in cells and then incorporated into viral DNA or RNA damage the viral DNA or RNA. This blocks further synthesis of the viral nucleic acid genome. Nucleoside analogs have been of great value in treating people with HIV (human immunodeficiency disease virus) infection.
Abnormalities in human DNA may lead to significant mutations such as the clinically important sickle cells disease. With modern technology this can be treated by using a virus to bring the normal gene for hemoglobin into human cells.
Viral pathogenesis depends on viral and host factors. Viral infections may be lytic, where the virus replicates an destroys cells of the host. Alternatively, the infection may be latent, at which time the viral genome (the viral nucleic acid) is maintained in the infected cell, but new virus is not made. Such latent infections may be maintained for long periods of time, in part because there is no clear target for the host immune system or for antiviral medications. Human immunodeficiency virus (HIV) infection and the herpes virus infections herpes simplex virus (HSV) and varicella-zoster virus (VZV) establish well-described latent infections.
HSV and VZV latent infections are infections of neurons. With reactivation infectious virus is produced and clinical infections, cold sores and genital infection by the former, and shingles by the latter. Latent infections are not low-level infections but are qualitatively different, with very limited expression of viral functions.
Latent infection by HSV and VZV are infections of neurons of the peripheral nervous system. There is some evidence that HSV may establish latent infection of the brain. If so, a possible relationship to many types of human illnesses may need be considered.
While there are many methods to measure viruses, there are few to measure infectious virus. One of the best is the viral plaque assay, performed on living cells in cell culture plates. The premise of the assay is that each infectious virus particle (not all virus particles are infectious) will infect one cell, will replicate in that cell and will spread to other adjacent cells. The read-out of the assay is plaque-forming units (PFUs), where each indicates an infectious virus particle.
Modification of the plaque assay may be performed to measure neutralizing antibody. There are many methods to measure antibody to viruses, but few to measure neutralizing antibody. In this assay, a known amount of virus (a known number of PFUs) is incubated with the specimen (for example, human serum) to be tested for neutralizing antibody. Decrease in the PFUs seen indicates the degree to which the serum blocked (neutralized) the virus from infecting cells.
The innate and the acquired immune systems combat viral infections. The former is infection type independent. The latter is infection type dependent and takes several days to be “educated” as to the, for example, specific viral infection. With that, B and T lymphocytes are activated. B lymphocytes make specific antibody, which is readily measured, while T lymphocyte functions are not so easily measured.
Specific antibody is measured to indicate that a specific infection has occurred. Antibody (monoclonal or polyclonal) may also be used to treat individuals. Such antibody-treated individuals are passively immunized, which is short lasting as compared with more long-lasting active immunity. The latter is achieved by recovery from infection or vaccine immunization.
Immunization with vaccines has been very important in public health. New types of vaccines have been developed, with recent emphasis particularly on mRNA vaccines. These can be made much more quickly than prior types of vaccines. They target a specific viral protein (antigen) and may find use in other types of illnesses where a specific abnormal protein is identified.
While side effects may occur with vaccines, as is the case with all medications, they are very safe.
The plethora of miscommunication and disinformation about how SARS-CoV-2 (COVID-19) spreads suggests a widespread misunderstanding of how viruses work. This book will focus on the interpretation of scientific and medical results, giving the reader guidance on interpreting virological data, including the concepts of 'live' versus infectious virus. The first section covers the background of virology and immunology, introducing the reader to the science of virology (using COVID-19 as an illustration) and considers the measurement of infectious disease, using polymerase chain reaction (PCR), molecular biology and the immune system. The second section looks at clinical virology and neurovirology. Taking a novel perspective on how viruses may play a role in evolution, this book discusses antivirals and how autoimmune disorders may be caused or triggered by viruses. Concise and practical, this is a key resource for those working in neurology, infectious disease and virology.
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