Hepatitis A Virus- An Overview

Hepatitis A virus (HAV) is a member of the picornavirus family, which are small, non-enveloped, single-stranded RNA viruses that cause various human and animal diseases. HAV is the causative agent of hepatitis A, an acute and self-limiting infection of the liver that is transmitted by the fecal-oral route. Hepatitis A is a global public health problem, especially in regions with poor sanitation and hygiene.

The structure of HAV is similar to other picornaviruses, but with some distinctive features. The virus has a spherical particle with icosahedral symmetry, measuring about 27 to 32 nm in diameter . The capsid consists of 60 copies of each of the three main proteins: VP1 (also known as 1D), VP2 (1B), and VP3 (1C) . These proteins form a stable shell that protects the viral RNA genome from degradation.

The genome of HAV is a linear single-stranded RNA molecule with positive polarity, meaning that it can act as a messenger RNA for protein synthesis . The genome is about 7.5 kb long and has a low G+C content compared to other picornaviruses. The genome has three main parts: a 5` noncoding region (NCR) that comprises about 10% of the genome and is covalently linked to a viral protein VPg; a single open reading frame (ORF) that encodes all of the viral proteins, with regions designated as P1 for capsid proteins and P2 and P3 for nonstructural proteins; and a short 3` NCR that terminates in a poly(A) tail .

The P1 region contains four segments for structural proteins that make up the capsid: 1A-VP4, 1B-VP2, 1C-VP3, and 1D-VP1 . The P2 and P3 regions comprise seven nonstructural proteins that are involved in viral replication and processing: 2A, 2B, 2C, 3A, 3B (VPg), 3C (a cysteine protease), and 3D (an RNA-dependent RNA polymerase) .

The structure of HAV is important for understanding its replication cycle, pathogenesis, and immune response. The capsid proteins mediate the attachment and entry of the virus into host cells, as well as the assembly and release of new virions . The nonstructural proteins orchestrate the synthesis and processing of viral RNA and proteins, as well as the modulation of host cell functions. The genome structure and sequence determine the antigenicity and variability of the virus, as well as its interaction with cellular factors.

In summary, HAV is a small RNA virus with a simple but stable structure that enables it to infect human liver cells and cause hepatitis A. The virus has a single-stranded RNA genome with three main parts: a 5` NCR linked to VPg, an ORF encoding capsid and nonstructural proteins, and a 3` NCR with a poly(A) tail. The capsid consists of three main proteins: VP1, VP2, and VP3. The nonstructural proteins include seven proteins: 2A, 2B, 2C, 3A, 3B (VPg), 3C (a protease), and 3D (a polymerase).

HAV is a positive-strand RNA virus classified in the genus Hepatovirus of the family Picornaviridae . It has a linear, uncapped, single-stranded RNA genome with a size of 7.5 kb and a poly (A) tail at the 3′ end . The genome of HAV can be divided into three parts:

• A 5′ noncoding region (NCR) that comprises approximately 10% of the genome, is covalently linked at the 5′ terminus to viral protein VPg, and contains an internal ribosome entry site (IRES) that mediates cap-independent translation of the viral proteins .
• A single open reading frame (ORF) that encodes a large polyprotein of about 2200 amino acids, which is cleaved by viral and host proteases into structural and nonstructural proteins . The ORF can be divided into three regions: P1 for capsid proteins (VP1-VP4), P2 and P3 for nonstructural proteins (2A-2C and 3A-3D) .
• A short 3′ NCR that contains cis-acting elements for viral replication and polyadenylation .

The P1 region contains four segments for structural proteins that make up the capsid: 1A-VP4, 1B-VP2, 1C-VP3, and 1D-VP1. These proteins are responsible for virus attachment, entry, and assembly.

The P2 region comprises three nonstructural proteins: 2A, 2B, and 2C. These proteins play a role in viral replication, such as membrane alteration, RNA synthesis, and polyprotein processing.

The P3 region makes up four nonstructural proteins: 3A, 3B, 3C, and 3D. These proteins are involved in various aspects of viral replication, such as:

• 3A: anchors the replication complex to cell membrane
• 3B: it is VPg protein that serves as a primer for RNA synthesis
• 3C: it is a cysteine protease that cleaves the polyprotein into individual products
• 3D: it is an RNA-dependent RNA polymerase that catalyzes the synthesis of new RNA strands

The genome of HAV is highly conserved among different strains, with less than 10% nucleotide divergence. However, some genetic variations have been observed in different regions of the genome, such as the VP1/2A junction and the VP1 capsid protein. These variations may affect the antigenicity, virulence, and epidemiology of HAV.

The HAV genome is a single-stranded RNA molecule of about 7.5 kilobases (kb) in length. It has a 5` noncoding region (NCR), a single open reading frame (ORF), and a 3` NCR. The ORF encodes a large polyprotein that is cleaved by viral proteases into structural and nonstructural proteins. The ORF can be divided into three functional regions: P1, P2, and P3 .

The P1 region contains four segments that encode the capsid proteins: VP4 (1A), VP2 (1B), VP3 (1C), and VP1 (1D). These proteins form the icosahedral shell of the virus particle and are responsible for binding to the host cell receptor and mediating uncoating .

The P2 region comprises three segments that encode nonstructural proteins: 2A, 2B, and 2C. These proteins are involved in viral replication and modulating host cell functions. 2A is a small protein that may facilitate the release of viral RNA from the capsid. 2B is a membrane-associated protein that may induce membrane alterations and vesicle formation. 2C is an ATPase that may participate in RNA synthesis and polyprotein processing .

The P3 region consists of four segments that encode nonstructural proteins: 3A, 3B, 3C, and 3D. These proteins form the viral replication complex and catalyze the synthesis of new viral RNA. 3A is a membrane-associated protein that anchors the replication complex to the cell membrane. 3B is a small protein that is covalently linked to the 5` end of the viral RNA and serves as a primer for RNA synthesis. 3C is a cysteine protease that cleaves the polyprotein into mature viral proteins. 3D is an RNA-dependent RNA polymerase that copies the viral RNA template .

The processing of the HAV polyprotein is regulated by the amino acid sequence at the cleavage sites and by cofactors that interact with the viral proteases. The processing intermediates, such as 3AB and 3ABC, may also have important functions in viral replication and assembly.

Hepatitis A virus (HAV) is a global public health problem that affects millions of people every year. According to the World Health Organization (WHO), there were an estimated 1.4 million cases of hepatitis A worldwide in 2016. The disease is highly endemic in some regions, especially in Central and South America, Africa, the Middle East, Asia, and the Western Pacific. The incidence and severity of hepatitis A vary depending on the level of socioeconomic development, sanitation, and hygiene of the population.

In areas with low socioeconomic development and poor sanitation, hepatitis A is usually acquired in early childhood and is often asymptomatic or mild. As a result, most people develop immunity to the virus and the disease becomes rare in adults. However, in areas with intermediate socioeconomic development and improved sanitation, hepatitis A may occur in older children and adults who have not been exposed to the virus in early life. These groups are more likely to develop symptomatic and severe disease, which can lead to outbreaks and epidemics.

In areas with high socioeconomic development and good sanitation, hepatitis A is uncommon and most people are susceptible to the virus. The disease may occur sporadically or as a result of exposure to contaminated food or water, or through person-to-person contact with travelers or immigrants from endemic areas. Hepatitis A can also affect specific populations at higher risk, such as men who have sex with men (MSM), people who use drugs (PWUD), people who are homeless, people who are incarcerated, or people who have chronic liver disease.

The transmission of hepatitis A is mainly through the fecal-oral route, either by direct contact with an infected person or by ingestion of contaminated food or water. The virus can survive for long periods in the environment and can resist freezing, drying, and heating up to 60°C. The incubation period of hepatitis A ranges from 15 to 50 days, with an average of 28 days. The virus can be detected in blood and stool within a few days of exposure and can be shed for up to several weeks after infection.

Hepatitis A is a self-limited disease that does not cause chronic infection or liver cancer. However, it can cause acute liver failure in rare cases, especially in older adults or people with underlying liver disease. The case-fatality rate of hepatitis A is estimated at 0.3% for the general population and up to 1.8% for people aged 50 years or older. The best way to prevent hepatitis A is by vaccination, which is safe and effective for all age groups.

Hepatitis A virus (HAV) is a highly contagious infection that can spread easily through contact with contaminated feces, food, water, or objects. The fecal-oral route of transmission means that the virus is present in the stool of an infected person and can enter the mouth of another person through:

• Eating food or drinking water that has been contaminated by feces from an infected person or animal. This can happen when food or water is not properly washed, cooked, or treated before consumption. Some examples of foods that can carry HAV are raw or undercooked shellfish, fruits, vegetables, and salads.
• Sharing utensils, cups, plates, or other items with an infected person or touching them after they have been used by an infected person.
• Having close personal contact with an infected person, such as shaking hands, hugging, kissing, or having sexual intercourse. The virus can also be transmitted through oral-anal contact during sexual activity.
• Using needles or syringes that have been used by an infected person or coming into contact with their blood or body fluids.

The risk of getting HAV from these sources depends on the hygiene and sanitation practices of the people and places involved. People who live in or travel to areas where HAV is common, such as Central and South America, Africa, the Middle East, Asia, and the Western Pacific, are more likely to be exposed to the virus. People who use drugs, people who are homeless, and men who have sex with men are also at higher risk of getting HAV in the United States.

The incubation period of HAV is usually 15 to 45 days, which means that symptoms may not appear until several weeks after exposure to the virus. During this time, an infected person can still spread the virus to others through their feces. The virus can be detected in the stool up to two weeks before symptoms appear and up to two weeks after symptoms resolve. Therefore, it is important to practice good hygiene and avoid contact with potentially contaminated sources to prevent HAV transmission.

Some possible additional sentences to conclude the point are:

• To prevent HAV infection, the best protection is to get vaccinated against the virus. The hepatitis A vaccine is safe and effective and can provide long-term immunity.
• If you think you have been exposed to HAV, you should contact your health care provider as soon as possible. You may be given a shot of immune globulin (IG), which can provide short-term protection against the virus if given within two weeks of exposure.
• If you have symptoms of HAV infection, such as fever, nausea, vomiting, abdominal pain, dark urine, clay-colored stool, or jaundice (yellowing of the skin and eyes), you should seek medical attention and get tested for the virus. You should also inform your close contacts and follow your health care provider`s advice on how to prevent spreading the virus to others.

Hepatitis A virus (HAV) is a positive-strand RNA virus that replicates mainly in the cytoplasm of hepatocytes. The replication cycle of HAV involves several steps:

• Attachment and entry: HAV binds to a specific receptor on the surface of hepatocytes, called HAV cellular receptor 1 (HAVcr-1), which mediates endocytosis of the virus into the host cell. The endosome containing the virus becomes acidic, which triggers a conformational change in the viral capsid and the release of a small protein called VP4. VP4 forms a pore in the endosomal membrane and allows the viral RNA to escape into the cytoplasm.
• Translation and processing: The viral RNA is uncapped and covalently linked to another protein called VPg at its 5` end. The RNA is translated by host ribosomes into a single polyprotein that contains all the viral proteins. The translation is initiated by an internal ribosome entry site (IRES) located in the 5` noncoding region of the RNA. The polyprotein is then cleaved by viral and host proteases into four structural proteins (VP1, VP2, VP3, and VP4) and seven nonstructural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D). The structural proteins form the viral capsid, while the nonstructural proteins are involved in viral replication and assembly.
• Replication: The viral RNA serves as a template for the synthesis of a complementary negative-strand RNA by the viral RNA-dependent RNA polymerase (RdRp), also known as 3D. The negative-strand RNA then serves as a template for the synthesis of multiple positive-strand RNAs by the same enzyme. The replication process requires several other viral and host factors, such as VPg, 3C, 3B, 3A, 2C, and TENT4 poly(A) polymerases . TENT4 poly(A) polymerases are a group of enzymes that add poly(A) tails to the 3` end of RNAs. They interact with a human protein called ZCCHC14, which binds to a specific sequence in the 3` noncoding region of HAV RNA. This interaction is essential for HAV replication and can be targeted by an antiviral drug called RG7834.
• Assembly and release: The newly synthesized positive-strand RNAs are packaged into preformed capsids in the cytoplasm. The capsids acquire a lipid envelope derived from host cell membranes by interacting with components of the endosomal sorting complexes required for transport (ESCRT) system. These enveloped virions, also known as eHAV, are released from the cell by exocytosis or budding without causing cell lysis. Some eHAV may lose their envelope during transit and become nonenveloped virions, also known as nHAV. Both eHAV and nHAV are infectious and can spread to other cells or be shed in feces.

Viral replication occurs primarily within hepatocytes and the secretion of virus into bile results in large quantities of virus being shed in the feces . During the incubation period, viremia is observed at about the same time that fecal shedding of HAV is occurring. Viremia terminates shortly after hepatitis develops, whereas feces may remain infectious for another 1 to 2 weeks.

Acute hepatitis includes features like inflammatory cell infiltration, hepatocellular necrosis and liver cell regeneration. Portal infiltration by lymphocytes, plasma cells and periodic acid Schiff (PAS)-positive macrophages are prominent features in early biopsies. Parenchymal cells undergo ballooning degeneration. These hepatocytes are swollen and have indistinct plasma membranes, enlarged nuclei, and a featureless cytoplasm, except for some cytoplasmic remnants condensed around the nuclei. Disruption of bile canaliculi may lead to bile retention after liver cell enlargement or necrosis. In some cases, extension of the inflammatory infiltrate from the periportal region into the hepatic parenchyma with significant erosion of the limiting plate is seen.

HAV replication in the liver triggers a substantial immune response, both humoral and cell mediated . CD8 +, cytotoxic T cells that are capable of lysing autologous HAV infected cells , but not of controlling uninfected cells, are present both in circulation and in the liver at the site of disease. These virus specific T cells also produce interferon gamma and other cytokines at the site of infection that may be responsible for much of liver injury. In addition to cell mediated immune response, there is vigorous antibody response to the virus during later stages of infection which are directed against conformational epitopes . Neutralizing antiviral antibodies play an important role in clearance of the virus . Serum antibody responses are first noted at onset of symptoms and include virus specific IgM as well as IgG and IgA .

HAV infection causes an acute, self-limiting hepatitis that does not progress to chronic liver disease. However, the severity and duration of symptoms vary widely, depending on the age and immune status of the infected person. Most children younger than 6 years of age are asymptomatic or have mild symptoms, whereas older children and adults typically develop symptomatic hepatitis .

The incubation period of HAV infection ranges from 15 to 50 days, with an average of 28 days . The onset of symptoms is usually abrupt, but may be preceded by a prodromal phase of nonspecific symptoms such as fever, malaise, fatigue, anorexia, nausea, vomiting, headache, myalgia and arthralgia . These symptoms may last for a few days to several weeks.

The most characteristic symptom of HAV infection is jaundice, which is the yellowing of the skin and sclerae due to elevated levels of bilirubin in the blood. Jaundice occurs in 40% to 80% of symptomatic cases, usually within a week of the onset of prodromal symptoms . Jaundice is often accompanied by dark urine, pale stools and pruritus (itching) due to bile salt deposition in the skin .

Another common symptom of HAV infection is abdominal pain or discomfort, especially in the right upper quadrant where the liver is located. The pain may be dull or colicky and may radiate to the back or shoulder. The pain is caused by inflammation and swelling of the liver and bile ducts .

The severity and duration of symptoms vary among individuals. Most cases recover within 4 to 8 weeks, but some may have prolonged or relapsing symptoms for up to 6 months. In rare cases, HAV infection may cause fulminant hepatitis, which is a life-threatening condition characterized by rapid and severe liver failure, coagulopathy (bleeding disorder), hepatic encephalopathy (brain dysfunction) and multiorgan failure. Fulminant hepatitis occurs in less than 1% of cases and has a high mortality rate of 50% to 80% .

The diagnosis of HAV infection is based on clinical presentation, epidemiological history and laboratory tests. The most specific and sensitive laboratory test for HAV infection is the detection of IgM antibodies to HAV (anti-HAV IgM) in serum. Anti-HAV IgM appears at the onset of symptoms and persists for up to 6 months after infection. The presence of anti-HAV IgM confirms acute or recent HAV infection. Other laboratory tests that may be helpful in diagnosing HAV infection include liver function tests (LFTs), such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and bilirubin. These tests may show elevated levels of liver enzymes and bilirubin due to liver injury caused by HAV infection. However, these tests are nonspecific and may be abnormal in other causes of hepatitis or liver disease.

The laboratory diagnosis of hepatitis A virus (HAV) infection involves the detection of specific antibodies and antigens, as well as the identification of viral RNA in clinical specimens. The following methods are commonly used for the diagnosis of HAV infection:

• Blood test: A blood sample is taken from a vein in the arm and sent to a laboratory for testing. The blood test can detect the presence of anti-HAV IgM antibodies, which are produced by the immune system in response to HAV infection. Anti-HAV IgM antibodies are usually present at the onset of symptoms and persist for up to 6 months after infection. The blood test can also detect the presence of anti-HAV IgG antibodies, which indicate past or current infection and immunity to HAV. Anti-HAV IgG antibodies usually appear within 2 weeks of infection and persist for many years. The blood test can also measure the levels of liver enzymes, such as alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGTP), which may be elevated in HAV infection due to liver damage.

• Stool test: A stool sample is collected and sent to a laboratory for testing. The stool test can detect the presence of HAV antigens, which are proteins on the surface of the virus. HAV antigens can be detected by enzyme immunoassay (EIA) or immunochromatographic assay (ICA). HAV antigens are shed in the feces during the incubation period and for up to 2 weeks after the onset of symptoms. The stool test can also detect the presence of HAV RNA, which is the genetic material of the virus. HAV RNA can be detected by polymerase chain reaction (PCR) or nucleic acid hybridization assay. HAV RNA is present in the feces from a few days after exposure until the clearance of the virus.

• Bile test: A bile sample is obtained by inserting a thin tube through the nose or mouth into the duodenum, where bile is secreted by the liver. The bile sample is sent to a laboratory for testing. The bile test can detect the presence of HAV antigens or RNA, which may be present in higher concentrations than in stool samples.

• Liver biopsy: A liver biopsy is a procedure that involves removing a small piece of liver tissue with a needle or a surgical instrument. The liver tissue is examined under a microscope for signs of inflammation, necrosis, and regeneration caused by HAV infection. A liver biopsy is rarely performed for the diagnosis of HAV infection, as it is invasive and carries some risks. However, it may be done in cases of severe or prolonged hepatitis, or when other causes of liver disease need to be ruled out.

Some additional points are:

• The laboratory diagnosis of HAV infection should be interpreted in conjunction with clinical history, physical examination, and epidemiological data.
• The laboratory diagnosis of HAV infection may be affected by factors such as vaccination status, immunosuppression, cross-reactivity with other viruses, and specimen quality.
• The laboratory diagnosis of HAV infection may have implications for public health measures, such as contact tracing, outbreak investigation, and prevention strategies.

There is no specific treatment to cure Hepatitis A Virus infection. Mild cases do not require treatment, and they resolve without any permanent liver damage . Treatment usually focuses on keeping comfortable and controlling symptoms. You may need to:

• Rest. Many people with Hepatitis A Virus infection feel tired and sick and have less energy .
• Get adequate food and liquid. Eat a balanced healthy diet. Nausea can make it difficult to eat. Try snacking throughout the day rather than eating full meals. To get enough calories, eat more high-calorie foods. For instance, drink fruit juice or milk rather than water. Drinking plenty of fluids is important to prevent dehydration, especially if vomiting or diarrhea occurs .
• Avoid alcohol and use medications with care. Your liver may have difficulty processing medications and alcohol. If you have Hepatitis A Virus infection, don`t drink alcohol. It can cause liver damage . Talk to your health care provider about all the medications you take, including medications available without a prescription .

Medications that might cause liver damage or are metabolized by the liver should be used with caution . Patients with fulminant hepatic failure require aggressive supportive therapy and should be transferred to a center capable of performing liver transplantation . (See \"Acute liver failure in adults: Management and prognosis\" .)

Vaccination is the best way to prevent hepatitis A infection and its complications. Hepatitis A vaccine is safe and effective, and it can provide long-term protection against the virus.

Hepatitis A vaccine is recommended for:

• Children aged 12 to 23 months, who need two doses of the vaccine given at least six months apart
• Infants aged 6 to 11 months who are traveling to areas with high risk of hepatitis A exposure, who need one dose of the vaccine before departure and two additional doses at the recommended ages for long-term protection
• Older children and adolescents aged 2 to 18 years who have not been vaccinated previously
• Adults who have not been vaccinated previously and who are at increased risk of hepatitis A infection or its complications, such as travelers, men who have sex with men, people who use drugs, people with chronic liver disease, people with HIV, people who work with hepatitis A virus, people who have close contact with international adoptees, and people experiencing homelessness
• People who have been exposed to hepatitis A virus within two weeks and who have not been vaccinated previously, as a post-exposure prophylaxis

Hepatitis A vaccine can be given as a single antigen vaccine or as a combination vaccine with hepatitis B vaccine. The combination vaccine requires three doses over six months . Hepatitis A vaccine can be given at the same time as other vaccines.

Hepatitis A vaccine is generally well tolerated and has few side effects. Some people may experience mild pain, redness, or swelling at the injection site. Other possible reactions include headache, fatigue, fever, or loss of appetite. These symptoms usually go away within a few days .

Hepatitis A vaccine is contraindicated for people who have had a severe allergic reaction to a previous dose of the vaccine or any of its components. People who are moderately or severely ill should postpone vaccination until they recover .

Hepatitis A vaccine does not provide protection against other types of hepatitis viruses, such as hepatitis B, C, D, or E. Therefore, people should also consider getting vaccinated against other forms of viral hepatitis if they are at risk.

Hepatitis A vaccine is an important public health measure that can reduce the burden of hepatitis A disease and its complications. By getting vaccinated, people can protect themselves and others from this potentially serious infection.

Prevention of Hepatitis A Virus Infection

The best way to prevent hepatitis A virus infection is to get vaccinated. The hepatitis A vaccine is safe and effective, and it can protect you from the virus for life after two doses. The vaccine is recommended for:

• All children at age 1 year
• Travelers to areas where hepatitis A is common
• People with chronic liver disease or clotting factor disorders
• Men who have sex with men
• People who use drugs, either injection or non-injection
• People who are homeless
• People who have close contact with someone who has hepatitis A
• People who work with hepatitis A virus in a laboratory or with nonhuman primates

If you are not vaccinated and you are exposed to someone who has hepatitis A, you can still prevent infection by getting a shot of immune globulin (IG) within two weeks of exposure. IG contains antibodies that can fight off the virus. However, IG is not as effective as the vaccine and it only provides short-term protection.

In addition to vaccination and IG, you can also prevent hepatitis A by practicing good hygiene and avoiding contact with contaminated food, water, or objects. Some tips are:

• Wash your hands thoroughly with soap and water after using the toilet, changing diapers, or before preparing or eating food
• Do not share personal items such as toothbrushes, razors, or eating utensils with someone who has hepatitis A
• Use condoms during sexual activity, especially oral or anal sex, with someone who has hepatitis A
• Avoid eating raw or undercooked shellfish from polluted water
• Drink bottled water or boil tap water when traveling to areas where hepatitis A is common
• Do not touch or handle any animals that may carry hepatitis A virus, such as monkeys

By following these preventive measures, you can reduce your risk of getting hepatitis A and protect your liver health.

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