Hepatitis A virus (HAV):
HAV belongs to the picornavirus group. HAV has diminished in importance over the past several decades in developed countires, but infection remains endemic in many regions of Central and Southeast Asia, Africa, and Central and South America.
structure
HAV has a relatively small ssRNA genome with a naked capsid with cubic symmetry.
Hepatitis A virus (HAV), an unusual member of the Picornaviridae family. Recent studies have shown that HAV exists in two forms—a regular, nonenveloped form and an enveloped form (eHAV), which is predominant in the sera of infected individuals. Although both forms are equally infectious, their means of cellular-membrane penetration—specifically, whether the two forms of HAV have separate pathways of entry into host cells or whether a unified pathway exists for this purpose—is unclear. While it is possible that eHAV has evolved its own separate mechanism for membrane fusion-based entry, no protein component analogous to glycoproteins of 9/11/25, 9:42 PM The VP4 Peptide of Hepatitis A Virus Ruptures Membranes through Formation of Discrete Pores – PMC enveloped viruses has been detected in the eHAV lipid envelope so far. Another plausible entry mechanism involves the conversion of eHAV into its nonenveloped counterpart during the initial encounter with host cells. The shedding of the lipid component would allow the viral capsid proteins to interact with the HAV cellular receptor 1 (HAVCR-1).
Symptoms are usually mild and not chronic (lasts up to 2 weeks) and can include pain in upper right quadrant, nausea, jaundice, dark urine, clay colored stool, enlarged liver. Development of IgG provides long lasting immunity. Effective inactivated whole virus vaccines are available.
The liver pathology caused by HAV infection is indistinbuishable from that cuased by HBV. However, unlike HBV, HAV cannot initiate a chronic infection and is not associated with hepatic cancer.
Transmission/prevention/vaccination
HAV has a short incubation time (15-45 days) and is transmitted by the oral-fecal route or anal intercourse. Contaminated water supplies (e.g., wells near sewers) can also serve as a source.
Populations at most rick of HAV include (1) travelers who have visited endemnic areas of Africa, Asian and parts of central and south America, (2) men who have sex with men, (3) homeless (4) incarcerated and (5) drug users. See Koenig. India is considered to be a hyper endemic region for HAV. See Arora
Vaccination: The primary way to prevent infection is by way of vaccination. In the US, the vacination is a 2 dose series licensed for all persons above the age of 12 months. The HAV vaccine is composed of an inactivated virus. Persons with recent exposure to the HAV can be adminsitered the single agent HAV vaccine within two weeks of exposure to prevent infection.
Solar disinfection (SODIS) is a HWTS method that has been gaining popularity over the last 30 years. The SODIS technique consists of exposing small-volumes (up to 3 l) of contaminated water with low turbidity (<30 NTU) in transparent containers (usually polyethylene-terephthalate [PET] bottles) to direct sunlight for at least 6 h (or 2 consecutive days if there is more than 50% of cloud cover) during the maximum intensity of radiation. Biocidal effects of SODIS are attributed to optical (UVA) and solar mildheating mechanisms SODIS showed significant (P < 0.05) reductions from 4.0 (±0.56) ×104 to 3.15 (±0.69) × 103 RNA copies/100 ml (92.1%, 1.1 log) for HAV. SODIS conditions induced a loss of infectivity between 33.4% and 83.4% after 4 to 8 h in HAV trials, and between 33.4% and 66.7% after 6 h to 8 h in MNV-1 trials. See Polo
Hepatitis B virus (HBV):
HBV belongs to the hepadnavirus group. HBV affects an estimated 300 million persons on a global basis. About 1.25 million people in the US are chronic carriers, defined as positive for hepatitis B surface antigen for more than at least 3 months. Although most carriers do not develop hepatic complications form chronic HBV, 15-40 percent will develop serious sequelae during their lifetime.
Populations at highest risk for HAV infection include travelers from high-income developed countries who visit endemic areas of Africa, Asia, and parts of Central and South America, men who have sex with men, close contacts (household or sexual) with infected persons, persons exposed to daycare centers, as well as the homeless, the incarcerated, and illicit drug userPopulations at highest risk for HAV infection include travelers from high-income developed countries who visit endemic areas of Africa, Asia, and parts of Central and South America, men who have sex with men, close contacts (household or sexual) with infected persons, persons exposed to daycare centers, as well as the homeless, the incarcerated, and illicit drug usersPPPopulations at highest risk for HAV infection include travelers from high-income developed countries who visit endemic areas of Africa, Asia, and parts of Central and South America, men who have sex with men, close contacts (household or sexual) with infected persons, persons exposed to daycare centers, as well as the homeless, the incarcerated, and illicit drug usersstructure
The genome of HBV is partically double stranded DNA, referred to as relaxed circular DNA (RC-DNA) and is about 3.2 kb in size, which is the smallest genome among animal DNA viruses. It contains four overlapping open reading frames, C, P, S, and X encoding seven viral proteins, including precore, core, polymerase X and 3 envelop proteins. Persistent HBV covalently closed circular DNA (cccDNA) and integrated DNA under antiviral therapy form the major barrier to eradication of HBV infection. (Yang, “Recent progress and future prospective in HBV cure by CRISPR/Cas” Viruses (2022))
Symptoms
In comparison with HAV, HAB has a long incubation time (70 days) and a gradual onset but more acute symptoms than HAV.
Transmission/prevention
The disease is blood borne and transmitted sexually or from the mother at birth. For sexual transmission, HBV is often transmitted trhough unprotected anal sex or receptive oral sex (giving oral sex). See Mayo Clinic
HBV enters the body through a break in the skin or mucous membrane or by injection into the bloodstream.
Disease Pathology
An important factor in the transmission pattern of HBV is that it multiples exclusively in the liver, which continously seeds the blood with viruses.
Upon entry, HBV undergoes endocytosis and uncoating, and its genomic RC-DNA is translocated to the nuclei of infected hepatocytes, wehre the RC-DNA is converted to covalently closed circular DNA (cccDNA), probably through the host DNA repair mechanism. The HBV cccDNA is the template for viral transcription and replicaton. Pregenomic RNA is packaged into the capsid, where it undergoes reverse transcription inside. However, a small protion of RC-DNA is converted to double strand linear DNA, which either follows the fat of RC-DNA or integrates into the host genome. The integrated DNA is defective genome and failed to generate the pregenomic RNA so it cannot produce infectious viral genome. Nevertheless, it can transcrib ehte HBsAg mRNA so it forms a source for continuous production of HBsAg. Integrated HBV DNA can also promote the development of HCC, partly thorugh the mechanisms of insertional mutagenesis and transactivating activity. (Yang, “Recent progress and future prospective in HBV cure by CRISPR/Cas” Viruses (2022))
Persistance of hepatitus B surface and envelope antigens (HBsAg, HBeAg) is associated with poor prognosis whereas development of antibodies against these antigens is associated with recovery. HBV can be either “acute” or “chronic”. Acute HBV is a mild illness that can last a few weeks or months. While some people “clear” the virus, others go on to develop chronic HBV. HBV is a chronic disease in about 15% of the cases. A peculiarity of HBV infections is that the immune system often cannot completely resolve infections. Although “recovered” patients maintain protective immunity for the remainder of their lives, trace amounts of HBV DNA can still be detected sporadically. The basis for the apparent persistence is the covalently closed circular DNA (cccDNA) that persists in infected hepatocytes in the form of a minichromosome. See Tan
Replication:
HBV is a very small enveloped DNA virus that replicates via reverse transcription of an RNA intermediate, the pregenome. HBV replicates the following way: (1) HBV infects a liver cell and enzymes extend the short DNA strand of the viral genome. (2) the viral DNA migrates to the cell nucleus where it is copied into RNA. The RNA becomes the pregenome intermediate for further replication. (3) the pregenome is packaged in a newly made capsid. Polymerase enzymes begin to make a DNA copy of the pregenome. The new DNA strand is a duplicate of the original long strand in the viral genome. The pregenome disintegrates as the new DNA is completed. (4) polymerases begin reconstructing a complementary DNA strand from the long-strand template. (5) the viral DNA may persist in the cell long enough to become fully double stranded. It can then return to the nucleus for another round of replication. (6) if the new viral particle exits the cell instead of replicating again, the capsid is enclosed in a fresh envelope. The extension of the short DNA strand stops immediately.
Treatment/Vaccination:
Several drugs are under development for treating CHB including directly interfering the viral replication process and indireclty stimulating the human immune system to control viral spread. New drugs in development target hte essential steps of HBV life cycle, including entry inhibitors, capsid or core inhibitors, silencing RNAs, HBsAg release inhibitors and gene-editing agents. (Yang, “Recent progress and future prospective in HBV cure by CRISPR/Cas” Viruses (2022))
–Nucleos(t)ide analogues:
—-Entecavir is a compound sold under the trade name Baraclude® as a treatment of hepatitis B. Entecavir is a nucleoside analog composed of two regions: a carbocylic ring and a guanine base. It is a modified version of the natural nucleoside 2′-deoxyguanosine (deoxyguanosine). Nucleoside analogs are designed to mimic the activity of natural nucleosides, the building blocks of DNA and RNA but are modified slighly from their natural counterparts to interfere with the replication of viral DNA – which means that they can serve as possible antiviral compounds. Entecavir is structurally identical to deoxyguanosine except that it has a carbon-carbon double bond (also known as an exocylci methylene group) at the 5′ position of the carbocylic ring wehreas deoxyguanosine has an oxygen atom.
Although current antiviral therapies like pegylated interferon and nucleos(t)ide anlalogues have dramatically reduced the mortality and morbidity of CHB, neither can acheive HBV eradication. NAs can suppress serum viral load to a level below the detection limit by inhibiitng viral polyemrase, but rebound viremia frequently occurs after discontinuation unless los of HBV surface antigen is acheived. In addition, long term anitviral therapy soemtiems causes the emergence of drug resistance. (Yang, “Recent progress and future prospective in HBV cure by CRISPR/Cas” Viruses (2022))
–CRISPR-Cas9: system has revealed the revolutioanry potential in clinical applicaoitn becasue of its extraordinary flexibility and convenience. By simply designing the guide RNA (gRNA) complementary to the target DNA sequence, the CRISPR-Cas9 can be redicreted to specifically cleave any desired DNA genome, resulting in site specific DNA double strand breaks. The erro prone nonhomologous end joining induced by DSBs often casues frameshift mutaitons, so the resultant gene deletions or insertions (indels) produce nonfunctional truncated prtoeins, elading to inactivaiton of the target DNA genome. Although the CRISPR/Cas9 system provides strong evidence to support its utility in destriction of HBV, there remain challenges. First, the cleavage of the integrated HBV DNA can casue host DNA DSBs with resultant alrge deletions and complex rearrangements of host genome, which increase the risk of genome instability and carcinogenesis. Second, the off target efect of CRISPR/Cas9 needs to be carefully evaluated. Third, HB is featured by the high sequence heterogeneity within and between genotypes, which poses difficulty in finding effective gRNA taht can target conserved HBV sequences across different genotypes. Lst, the large size of CRISPR/Cas9 gene renders in vivo delievery challenging. (Yang, “Recent progress and future prospective in HBV cure by CRISPR/Cas” Viruses (2022))
The CRISPR/Cas9 system as mentioned not only destructs HBV cccDNA, but also cleaves the integrated HBV DNA. The latter leads to DSBs of the host genome and may induce complex genome rearrangement and alrge genes deletions. The cytosin base editor (CBE) is a newly developed CRISPR derived base editing tool that allows for precise conversion forom a C-G base pair to a T-A base pair in the arget genomic locus without DNA DSBs, so it is particularly suitable for inactivating integrated HBV DNA. The BEs are initially designed by tethering the APOBEC deaminase to “ead” SpCas9 (dCas9) which is catalytically inactivated by inroduction of both mutatons D10A/H840A. To further improve the efficacy of BE, the uracil glycosylase inhibitor (UGI) is fused to Cas9 nickage (Cas9n) inread of dCas9, resulting in BE3, a single protein consisting of tripartite compouents, including APBEC1, Cas9n and UGI. The further evolved BE called BE4Gam is developed for increasing the C-G to T-A efficacy and reducing the indel formation by fusing the condon-optimized BE3 with Gam from bacteriophage Mu. (Yang, “Recent progress and future prospective in HBV cure by CRISPR/Cas” Viruses (2022))
To overcome the obstacle of cargo capacity, two Cas9-fragment system or split-intein Cas9 system in which a full functional Cas9 protein is plit into two non-functional fragments has been sued. Upon devliery to the garget cells, the two fragments of Cas9 is reconsititued to a fully fucntional protein through either recomibination or the intein-mediated trans-splicing mechanisms, but this approach usually requires high viral titers because co-delivery of dual AAVs into the same cells is elss efficient.
Vaccination:
The primary prevention for HBV infection is vaccination. A vaccine called Pediarix contains protection agasint HBV, diphtheria, tetanus, pertussis and polio. It is recommended for children between 6 weeks and 7 years.
Other Hepatitis Viruses
Hepatitis delta virus (HDV): have a small ssRNA genome. It is a defective virus in that it needs HBsAg for replication. So vacination for HAB will also protect one from HAD. HDV is transmitted via blood and blood products just like HVB. The occurrence is rare in the U.S. Interferon is the only licensed drug for treating chronic hepatitis D, but the relapse rate is high after discontinuation. HDV has two forms of viral proteins, large and small hepatitis D antigens (HDAg).
Hepatitis D is an enveloped RNA virus. It is actually a subivrus satellite of HBV, that is, it can propagate only in the presence of HBV.
Hepatitis E virus (HEV): are classified in the genus Hepevirus and are a causative agent of human hepatitis. The virus capsid is non-enveloped and the nucleocapsid containing positive-sense singe-stranded RNA has a diameter of 27-34 nm. See ssRNA genome. Transmission (fecal-oral route) and disease is similar to HAV. HEV is seen mainly in 3rd world countries. HEV is endemic in humans, swine and several wild animals such as deers and boars. Four genetoypes of HEV that infect humans have been identified. The hepatitis E virus is transmitted mainly through the fecal-oral route due to fecal contamination of drinking water. This route accounts for a very large proportion of clinical cases with this disease. The risk factors for hepatitis E are related to poor sanitation, allowing virus excreted in the feces of infected people to reach drinking water supplies. The incubation period following exposure to HEV ranges from 2 to 10 weeks, with an average of 5 to 6 weeks. The infected persons excrete the virus beginning from a few days before to 3-4 weeks after onset of the disease. See WHO
Hepatitis G virus (HGV): is a flavivirus which can only be identified by PCR. Interestingly, there is an association with slower progression to AIDS in & HGV dual infection.
Hepatitis X virus: is disgnated for those patients with hepatitis where tests for all known hepatitis virsues are negative.
Fuminant viral hepatitis: is a condition that manifests only rarely in humans (less than about 0.01% of the hepatitis population. It has both non-viral (e.g., drug) and viral causes. Fulminant viral hepatitis can be cause by a number of different agents such as HepA and HepB, as well as the non-hepatitis ABCDE viruses.