RNA viruses cause a variety of common diseases, many of which can be prevented by vaccination.

Diseases: Measles; Mumps; German measles; Polio; Influenza; Hepatitis

Slow viral diseases: Rabies; Leukemia and AIDS; (Mad Cow Disease - Prions)

Measles
Caused by rubeola, which is a single stranded (SS) RNA enveloped virus. The disease is transmitted by the respiratory route and is highly contagious, leading to outbreaks in preschool age children and college students. The disease is initially associated with fever, malaise, coughing, conjunctivis, and photophobia. These symptoms then give way to a skin rash. An attenuated vaccine has been developed (MMR vaccine - mumps, measles and rubella) which is important because acute encephalitis can develope in approximately 1:1000 kids. This can lead to CNS damage where 1 in 10,000 die. Also, measles can kill a fetus in utero.

Mumps
Again an enveloped single stranded RNA virus, transmitted by the respiratory route. Generally a benign childhood disease characterized by swelling of the parotid glands (in the neck). However, can be fatal. The big problem with mumps is for adult males. 20% of adult males acquiring mumps will become sterile due to testicular damage. Again can kill a fetus in utero. A vaccine is available (MMR vaccine).

Rubella
Also an enveloped SS RNA virus, transmitted by the respiratrory route. Again, generally considered to be benign childhood disease. However, severe fetal damage can occur if a pregnant women becomes infected during her first trimester (women are tested for antibody to rubella during early pregnancy and are vaccinated - MMR - if having not been previously exposed). 1964 a German measles pandemic occured in Germany and 30,000 infants were aborted or were born with deformities!

Polio
A non-enveloped SS RNA virus that is transmitted by the fecal-oral route. The virus is an enteric virus and is shed in feces. Well over 90% of cases are subclinical (worst symptoms include mild fever or diarrhea). However, 1% of cases have viremia (i.e. the virus enters the bloodstream) allowing the virus access to motor neurons where it replicates. Eventually, the virus kills the nerve cells and paralysis occurs (polio myelitis). Two vaccines exist - Salk vaccine (killed virus) and the Sabin vaccine (attenuated).

Influenza
An enveloped SS RNA virus that contains spikes and has specific receptors that consist of neuraminidase and hemagglutinin (see Figure 25:1). Neuraminidase degrades mucous whereas hemagglutinin binds the virus to the cell surface. The virus is notable for undergoing rapid antigenic variation, with the new antigenic variants rapidly travelling throughout the population - thus causing Òflu outbreaksÓ. Strains are often named after the city in which it originated (e.g. Hong Kong flu).

Overall, there are three main classes of influenza: Types A, B, and C.

Type A: infects humans, pigs, and horses. Type A pandemics occur approximately every 10 years and tend to be the most severe. Virulence increases with passage through animals.

Types B and C: tend to be less severe, and are restricted to humans. Occur approximately every 2-5 years.

Antigenic variation: Each of the three basic influenza strains, A, B, and C change their surface antigens. Type C less so than A or B. This is the reason why we do not develope resistance to flu infections. Antigenic variation occurs in two ways:

1) antigenic drift: this results from random mutations that accumulate in the genes that encode the hemaglutinin and neuramidase. Thus antibodies generated against one type of protein may not recognise the new protein. This generally leads to flu epidemics.
2) antigenic shifts: this results from gene rearrangements in the neuraminidase and hemagglutinin genes. The changes introduced into the protein structures are more dramatic, and distinctly different flu strains emerge that cause global flu pandemics. Fortunately these types of events are rare (see Figure 25:1).

Once infected, incubation tends to be short, and the symptoms include fever, malaise, coughing sore throat, and prostration. The disease itself is rarely fatal. However, secondary infections (Streptococcus pneumoniae, Hemophilus influenzae) do kill, especially those people with weak immune systems (i.e. the very young and the old). Vaccines of killed virus of the current antigenic variant are available and in the near future a new attentuated vaccine will be available.

Hepatitis
Hepatitis is inflammation of the liver that is caused by several different viral types. The major hepatitis viral infections in the US are caused by a nonenveloped SS RNA virus (hepatitis A - infectious hepatitis) or by an enveloped double-stranded DNA virus (hepatitis B - serum hepatitis). There are also other minor forms (C, D, and E). They are discussed together because symptoms are remarkably similar in both cases (see Figure 25:2).

Hepatitis A - transmitted by the fecal /oral route. Symptoms occur quickly (one week) and include nausea, vomiting, anorexia, and fever. Jaundice may also occur. Symptoms go away and a complete recovery occurs. Death is <1%. An inactivated virus is available.

Hepatitis B - a different story. Long incubation and is transmitted by a variety of routes (serum, fecal/oral, sexually). Same symptoms, but now can last for months, with recurrent cases in up to 20% of people. Fatality is 2 to 5%. Strong association with liver cancer. A vaccine has been available since 1982.

Slow viral diseases
Rabies - an enveloped SS RNA virus that is bullet shaped. Usually transmitted through animal bites, but can be acquired through the inhalation of bat guano (wow!). First disease to have an effective vaccine (Pasteur).

Has a long incubation because the virus moves up the neurons to the CNS. The closer the bite to the head the shorter the incubation period. From the CNS the virus then moves to the salivary glands where it is released into the saliva. If untreated the disease is virtually 100% fatal. Initial symptoms include fever, malaise, and headache, which are followed by neurological changes (mood swings, depression, mania, forgetfulness) and then goes onto hydrophobia (victims are desperately thristy but is scared to drink due to diffculty in swallowing). Terminal symptoms include delirium and coma.

Oddly, vaccination is administered after infection. The antibody prevents the virus from from travelling past the neural synapses and reaching the CNS. Vaccine is inactivated virus grown in human tissue culture cells (previously, the vaccine was inactivated virus grown in duck eggs).

AIDS (and leukemia)
Both are known as lentiviruses. They are SS RNA viruses that replicate their RNA into DNA using the enzyme reverse transcriptase. The DNA that is formed can then integrate into the chromosome (forms a provirus). They are also enveloped and derive their lipid coat following budding from the membrane (see Figure 25:3).

The Human ImmunodefiencyÊVirus (HIV) is a lentivirus that causes Acquired Immunodeficeincy Syndrome (AIDS). There are two subgroups of HIV; HIV-1, and HIV-2. Each has quite distinct genomes. HIV-1 is the main agent for AIDS.

HIV-1 may have arisen from a simian immunodeficiency virus (SIV) in Central Africa. There are also immunodeficiency viruses of sheep, cats, cows, horses and goats (see Figure 25:4).

The first case in the US was in 1981. However, there are now at least 13 million cases worldwide and the number is growing at a prodigious rate. Today there are approxiamtely 1 million cases in the US. Approximately 4 million people have full blown AIDS. Originally AIDS appeared to be restricted to homosexual men and IV drug users, heterosexual transmission is now rapidly increasing (see Figure 25:5).

Transmission: sexual, parenterally (blood to blood) and horizontally from mother to fetus. It is not transmitted by saliva, casual contact nor by biting arthropods. Transmission is elevated (100X) by the presence of other sexually transmitted diseases (gonorrhea, syphilis, Chlamydia).

The time between initial contact and the onset of AIDS averages about 10 years (see Figure 25:6). The initial viremia lasts about one month, and the symptoms mimic mononucleosis. A subset of monocytes that express CD4+ antigens are infected and are implicated in disseminating the virus throughout the body, as well as maintaining the virus during the latency period.

The virus infects CD4+ cells (macrophages and T cells) in the lymph nodes and it may be the shift in predilection for moncytes to T cells that triggers developement of full blown AIDS. Depletion of CD4+ T helper cells results in many immune aberations since these cells up-regulate and control the immune response (e.g hypergammaglobulinemia (excess ÒnonsenseÓ antibody) occurs when B cells are inappropiately activated by mis-functioning T-helpers, as is the production of autoantibodies). Eventually, destruction of the T helper pool causes the normal ratio of 5:1 CD4+ T helper:CD8+ T suppressors to 1:5 CD4+ T helper:CD8+ T suppressors. The virus also attacks neural cells which leads to dementia.

Consequently, the immune system shuts down and the victim becomes susceptible to cancer (e.g. KarposiÕs syndrome and BurkittÕs lymphona), secondary bacterial infections (TB, Salmonella, Strep etc) fungal infections (candidiasis) and other viral infecftion (herpes, hepatitis). The immune destruction insures a 100% fatality rate, although there are a number of patients who have survived for many years following the onset of symptoms.

Treatment consists of poisoning the enzyme reverse transcriptase with nucleic acid analogues (e.g AZT). The reason this works is that the viral polymerase has a higher affinity for the drug than for true nucleotides. These drugs slow the progression of the disease but do not cure it. The newest form of drugs are protease inhitbitors. The provirus is transcribed as one big protein that is then cleaved into three seperate proteins by a protease. Protease inhibitors prevent this cleavage step from happening.

There is no vaccine for AIDS partly due to the rapid antigenic variation resulting from errors inserted into the genome by the error-prone reverse trasncriptase (shaded regions in Figure 25:7 indicate the hypervariable regions in the major surface exposed protein of HIV). While other HIV-like viruses are being tried as vaccine candidates, other novel therapeutic approaches include blocking the CD4+ receptors on cells (i.e. prevent the virus from being taken up into the cell), or, alternatively, flooding the system with CD4+ antigen.

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