L6 - Hepatitis C virus I - Andrew Davidosn Flashcards
(93 cards)
1
Q
What is hepatitis?
A
Inflammation of the liver which isn’t characterised as a single disease but many
2
Q
What role do viral infections play on liver issues?
A
Many viral infections involve the liver
3
Q
How many viruses specifically infect and damage hepatocytes?
A
at least six eg. dengue, yellow fever, hepatitis A-E…..
4
Q
similarities and differences between transmission routes of Hepatitis Viruses
A
Hepatitis A and E are both spread through the faecal-oral route while Hepatitis B, C and D are transmitted sexually
5
Q
What is the latency perioid of different hepatitis viruses
A
A: 2-6 weeks
B and D : 3-6 months
C: 2-9 weeks
E : 1 month
6
Q
which Hepatitis Viruses are most similar
A
Hepatitis A and E are similar
Hepatitis B and D are similar
(Hepatitis C is on its own where it has similarities and differences - not quite like A or B)
7
Q
which Hepatitis Virus is most likely to be the cause of jaundice and short term illness
A
A and E
8
Q
Which hepatitis viruses are more likely to have a long term effect
A
Hepatitis B and C (and E) –> these are more fatal with more complications such as liver cancer and failure
9
Q
what is the distribution of Hepatitis C and chronic carriers
A
worldwide distibution with ~ 50 million chronic carriers globally, a decrease from previous estimates of up to 170 million due to improved treatments and awareness.
10
Q
How does the prevalence of HCV vary worldwide with examples
A
The prevalence of HCV varies significantly by region, ranging from about 0.7% to 1% infected worldwide.
Examples include:
UK: ~0.3%
USA: ~1.0%
Egypt: ~11% (This was a peak prevalence and is now decreasing due to successful treatment programs).
11
Q
Why is the incidence of HCV higher in the USA?
A
Because people were paid to donate blood which attracted prisoners, homeless people, drug users …. which meant that HCV spread a lot through blood transfusions
12
Q
While blood transfusion screening has been highly effective in preventing HCV transmission, what are some of the challenges or issues associated with its global availability?
A
issues with availability persist globally. These include:
- Cost: Implementing and maintaining sophisticated screening programs can be expensive, particularly in low- and middle-income countries.
- Infrastructure: Adequate laboratory infrastructure, trained personnel, and reliable supply chains are necessary for effective screening, and these may be lacking in some regions.
- Accessibility: Ensuring that all donated blood is screened consistently, especially in remote or underserved areas, can be logistically challenging.
13
Q
Can you provide an example of a historical scandal involving blood transfusions and the transmission of bloodborne viruses like Hepatitis C?
A
A significant historical scandal involved instances where individuals, particularly in the UK, received blood products sourced from the US that were known to carry a higher risk of contamination with viruses like Hepatitis C and HIV. Despite the availability of potentially safer blood supplies within the UK, these higher-risk products were knowingly administered to patients requiring blood transfusions. Tragically, many recipients contracted HCV and/or HIV as a result, leading to severe health consequences and ongoing legal actions seeking accountability.
14
Q
Why is the incidence of HCV so high in Egypt
A
Because there was a mass injection based campaign against the bilharzia parasie (between 1950s-1980s) often through reused syringes and needles which created a significant pathway for bloodborne transmission of HCV (which was not an identified virus until 1989)
15
Q
What is HCV the leading cause of?
A
Chronic liver disease, cirrhosis and hepatcellular carcinoma. Because of this it is the principle reason for liver transplantation in many countries
16
Q
How many deaths are caused by HCV infections every year (2022 estimate WHO)
A
around 242,000 deaths per year
17
Q
How many new HCV infections are there every year (2023 estimate WHO)
A
~1 million
18
Q
What percentage of acute and chronic hepatitis cases are attributed to HCV?
A
HCV accounts for approximately 20% of acute hepatitis cases and a significant 70% of chronic hepatitis cases which can lead to hepatocellular carcinoma in 2.5% of chronic cases (high percentage result in chronic cases if left untreated unlike some other heaptitis)
19
Q
Progression of Hepatitis C over time for every 100 people who are infected with the virus
A
For every 100 people infected with HCV
–> 78-85 will develop chronic infection
–> 60-70 will develop chronic liver disease
–> 5-20 will develop cirrhosis
–> and 1-5 will die of Cirrhosis or hepatocellular / liver cancer
20
Q
What is the most important risk factor for HCV transmission?
A
frequent exposure to blood (including activities like injecting drugs with shared needles, unscreened blood transfusion and certain medical or dental procedures performed with inadequate steralisation)
21
Q
What is the current status of antiviral drugs and vaccines for HCV?
A
Very effective antiviral drugs have been recently developed for HCV, offering high cure rates. However, access rates to these drugs remain low globally. Currently, there is no vaccine available for Hepatitis C.
22
Q
What factors might explain why some individuals with Hepatitis C Virus (HCV) develop acute hepatitis and recover, while others progress to chronic infection?
A
While the exact mechanisms are complex and not fully understood, factors e.g. host immunity, viral factors, overall health (any pre-existing health conditions e.g. liver disease or immunosuppression or lifestyle factors e.g. high alcohol consumption) , age, genetics and access to early healthcare could play a role
23
Q
If someone with heaptitis C is treated with antiviral drugs at an advanced stage of liver disease e.g. cirrhosis, can they still develop liver cancer (hepatocellular carcinoma?)
A
Yes, because chronic HCV (even if you don’t realise you have it) often leads to significant fibrosis and cirhhosis over many years. this structural damage to the liver is permanent. On top of this the ongoing inflammation and regenerative processes in a cirrhotic liver creates an environment of increased cell turnover and genomic instability which increases the individuals susceptibility to malignant transformation. This is why surveillance and early detection is crucial
24
Q
Can Hepatitis C Virus (HCV) integrate its genome into the human host cell’s DNA?
A
No because their genetic information is encoded in RNA molecules. (it lacks reverse transcriptase so it never converts its RNA into DNA for integration to be possible)
25
Where does HCV genome replication and protein synthesis occur?
In the cytoplasm of the host cell (never enters the nucleus)
26
In what year was hepatitis C Virus (HCV) first identified
The Hepatitis C Virus (HCV) was first identified in 1989. This groundbreaking discovery by Harvey J. Alter, Michael Houghton, and Charles M. Rice (who later won the Nobel Prize) was crucial for understanding and ultimately treating the disease.
27
What did the discovery of HCV allow
For the development of tests to detect the virus which was essential for eliminating them from blood transfusions and developing effective drugs to treat disease
28
What key discoveries did Harvey J Alter, Michael Houghton and Charles M. Rice each make which contributed to the discovery of HCV?
1. Harvey J Alter : investigated hepatitis in patients who'd recieved blood transfusions and found that he could transmit the disease to chimpanzees through blood. He showed that it was a distinct form of viral hepatitis.
2. Michael Houghton: identified DNA fragments from a novel RNA virus in chimpanzee blood which was known to cause non-A and non-B hepatitis. By using antibodies from infected patients to screen a library of these fragments, he was able to identify and clone parts of the viral genome, allowing for the classification of the virus as Hepatitis A.
3. Charles M. Rice : engineered a genetically defined, infectious close of the HCV RNA. They then demonstrated that this engineered virus when introduced into chimps caused hepatitis. This provided the definitive proof that Hepatitis C virus was the causative agent of the previously unexplained cases of transfusion-associated hepatitis.
29
Describe the trend in the number of liver failure cases from the 1950s to the 2020s?
1950s - ~1975: Liver failure cases were very low.
~1975 - 2020s: Cases began to rise, reaching close to 2,000 around 1975 and then increasing exponentially to approximately 145,000 cases by the 2020s, where the numbers started to level off.
30
what did the exponential increase in cases likely reflect?
the delayed consequences of widespread HCV transmission that occurred before the virus was identifed and effective treatments were available
31
Describe the trend in the number of liver cancer cases from the 1950s to the 2020s,
The trend in liver cancer cases mirrored that of liver failure but at a much lower level.
Cases started to rise around 1975 and peaked closer to 2010 at approximately 15,000 cases.
Similar to liver failure, this trend likely reflects the long-term consequences of chronic liver diseases, including HCV, with a delay between initial infection and cancer development.
32
Despite advancements in research and preventative measures, why have liver failure and liver cancer cases increased in recent years?
This is likely due to the long-term nature of the progression of liver disease. By the time of discovery many were likely infected (from intravenous drug use, unscreened blood transfusions (e.g. post WW2) and because HCV often remains asymtomatic for many years, this allows for significant liver damage to accumulate before diagnosis
33
what is the time lag between initial HCV infection and the development of cirrhosis or liver cancer
20-30 years or more
34
What percentage of the world population is estimated to be infected with Hepatitis C Virus (HCV)?
Approximately 0.6% of the world population, which equates to around 50 million people.
35
What is the estimated percentage of people infected with HCV who were aware of their infection in the past compared to 2022? What is a major contributing factor to this change and a remaining challenge?
* Past Awareness: Approximately 5% of infected individuals were aware of their HCV infection.
* 2022: Awareness increased to around 35%.
* Contributing Factor: This increase is largely due to increased screening efforts implemented in many regions.
* Remaining Challenge: Despite the improvement, low awareness due to the asymptomatic nature of early HCV infection remains a major problem, delaying diagnosis and treatment.
36
What percentage of people infected with HCV were not treated in the past compared to 2022? What are the reasons for the change and the remaining challenges?
* Past Untreated: Approximately ~95% of infected individuals were not treated.
2022: This decreased to around 80%.
* Reasons for Change: The development of highly effective direct-acting antiviral (DAA) drugs and their increased accessibility and affordability in some regions have led to higher treatment rates.
* Remaining Challenges: Despite progress, around ~45 million people still need treatment. Limited access to diagnosis and treatment in many countries and poorer regions remains a significant barrier to global HCV elimination.
37
Of the approximately 20% of people with HCV who receive treatment, what percentage experience a response?
~5% have no response
~95% have reduced risk of liver failure, cancer and death
38
What is the significant challenge in researching HCV and what tools have been developed to overcome this?
a significant challenge is caused from the difficulty in efficiently growing viral isolates in standard laboratory cell cultures however there are tools for growing the genome (of circulating types) into cell lines e.g. human hepatocellular carcinoma cells (Huh7 cells) which have been manipulated for research aka genetically modified to support HCV replication.
39
When was acute, infectious hepatitis first identified as a distinct clinical entity? What does this tell us about our historical awareness of liver disease?
Acute, infectious hepatitis was first identified as a distinct clinical entity in 1885. This indicates that while specific viral causes were unknown at the time, the medical community recognized that inflammation of the liver could be a transmissible disease relatively early in medical history. However, the understanding of its diverse etiologies (different viruses, toxins, etc.) developed much later.
40
When was the Hepatitis B surface antigen (HBsAg) discovered, and what is its significance?
The Hepatitis B surface antigen (HBsAg) was discovered in the 1960s. HBsAg is a key protein found on the surface of the Hepatitis B virus (HBV). Its discovery was a major breakthrough for marking active infection, foundation for diagnostics and vaccine development
41
When were diagnostic tests for HBV developed
in 1971 (~10 years after the discovery of HbsAG antigen)
42
When was the Hepatitis A Virus (HAV) first visualized and identified using immune electron microscopy (EM)? What is the principle behind this technique?
1973
43
What crucial advancements in molecular biology and virology occurred around 1989 that significantly impacted Hepatitis research, particularly for "non-A, non-B hepatitis"? What key findings emerged from the research enabled by these advancements?
In 1989, significant improvements in molecular biology methods provided the tools to tackle the mystery of "non-A, non-B hepatitis." Researchers could now:
- isolate and manipulate genetic material more effectively
- create cDNA libraries from infected tissues or fluids
- Use expression cloning techniques to identify viral antigens
This allowed scientists to take blood samples and use chimpazee models (only availble model at the time) to study the disease to see that the chimps would get similar patterns of infection to hepB albeit milder
44
How was the complementary DNA (cDNA) derived from the Hepatitis C Virus (HCV) genome initially isolated?
The cDNA derived from the Hepatitis C Virus (HCV) genome was initially isolated using a technique called expression cloning. This method involved generating a comprehensive library of double-stranded cDNA clones derived from the blood of individuals infected with non-A/non-B hepatitis. This library was subsequently screened using antibodies from experimentally infected chimpanzees, allowing for the identification and subsequent cloning of viral genetic sequences that belonged to the virus without prior knowledge of the viral genome.
45
Once the entire genome of Hepatitis C Virus (HCV) was cloned, what critical advancements became possible in the fight against the virus?
- It allowed for the development of diagnostic tests including antibody tests (to detect past or current infection) and PCR-based tests (to detect the presence of viral RNA, indicating active infection and viral load).
- improved screening of blood products, virtually eliminating transfusion-associated HCV transmission in many parts of the world.
- development of antiviral therapies
- research into viral lifecycle, mechanisms of replication and pathogenesis e.g. how it causes liver damage
46
What is the approximate size of the Hepatitis C Virus (HCV) particle?
<50nm (very small)
47
Before the Hepatitis C Virus (HCV) was definitively identified, how did scientists determine that the non-A, non-B hepatitis agent was likely a virus, and how did they estimate its size?
based on its ability to be transmitted through blood and cause infection and they could estimate its small size by passing infected blood through filters with defined pore sizes (infectious agent could pass through filters that would retain bacteria - smaller than a bacteria so likely a virus)
48
what is post transfusion NANBH
Post-transfusion non-A, non-B hepatitis (NANBH) is a liver disease that can occur after a blood transfusion --> still caused infection after being filtered
49
What percentage of patients with post-transfusion NANBH were diagnosed with HCV
less than 80%
50
What did the inactivation of the non-A, non-B hepatitis (NANBH) infectious agent by organic solvents suggest about its structure?
This strongly indicated that it was likely an enveloped virus (that have outer lipid bilayers that get disrupted by organic solvents )
51
Describe the estimated trend of acute Hepatitis C Virus (HCV) infection incidence in the US from 1960 to 2001, highlighting key events that influenced this trend
The estimated incidence of acute HCV infection in the US showed distinct phases:
- Pre-1985: Before the recognition of non-A/non-B hepatitis as a bloodborne illness, HCV transmission likely occurred unchecked
- 1985 Onwards (Recognition of Bloodborne Transmission): Following the awareness that non-A/non-B hepatitis was spread via blood, a modest decrease in new infections was observed, likely due to increased caution regarding blood products and some early public health messaging.
- Post-1991 (Genome Sequencing and Blood Screening): A significant decline in new acute HCV infections occurred after the HCV genome was sequenced in 1989 and sensitive blood tests became available for screening. The implementation of routine blood screening effectively removed a major route of transmission. Additionally, the introduction of drug awareness campaigns and needle exchange programs contributed to reducing transmission associated with injecting drug use.
52
what are the sources of HCV infection and percentages
1. Injecting drug use (60% - now closer to 70/80% from sharing needles and paraphernalia (snorting drugs) which has been contaminated with blood)
2. Sexual (15% - now closer to 1-2%)
3. Transfusion (before screening) (10%)
4. Occupational (4)
5. unknown (10%)
6. Other
53
How can occupation increase the risk of HCV infection?
Healthcare workers can be exposed to HCV through needlestick injuries or contact with infected blood.
54
What are other ways of spreading HCV infection?
1. Mother to Child Transmission (Perinatal): HCV can be transmitted from an infected mother to her baby during childbirth, although this is relatively infrequent.
2. sharing personal items that may have come into contact with blood (e.g., razors, toothbrushes - more common if you share a household) and unsterile medical or cosmetic procedures (e.g., tattooing, piercing).
55
Around what year did Hepatitis C Virus (HCV) infection rates begin to increase in the United States after a period of decline and why?
Around the year 2010, which is largely associated with the opioid epidemic with an increase in intravenous drug use (IDU) - particularly prevelant among vulnerable populayions e.g. homeles, unemployed, those who may have barriers in accessing healthcare.
56
HCV prevalence in the general population vs long term injection drug users in USA
2% of the general population vs 90% of long-term injection drug users
57
acute HCV cases in the states in : 1990 vs 2010 vs 2021
1990 - 300,000
2010 - 10,000 (big decline in 20 years)
2021 - 70,000 (big increase in 10 years)
58
Describe the genetic diversity of the Hepatitis C Virus (HCV). What are the implications of this diversity?
Hepatitis C Virus (HCV) has high genetic diversity, having evolved into at least eight major genotypes originating from a common ancestor. Within each genotype, there is further variation, resulting in over 80 identified subtypes. This extensive genetic diversity has led to the geographical clustering of specific subtypes in different regions of the world.
59
Which region has the highest prevalence of HCV infections?
North Africa and south Asia ( greater than 2.9%)
60
Which HCV genotype is the most common in Africa
HCV 4 (although they don't have much data collected)
61
Where is HCV1 the most common circulating subtype?
North America, South America, Europe, Asia and Australia
62
What is the disparity caused by where HCV is most common vs countries making drug treatments
North America and Europe were early leaders in HCV research, leading to a more comprehensive understanding of genotype 1 (HCV1), which was prevalent in these regions. Consequently, the first generation of antiviral drugs was often developed and optimized primarily for HCV1, resulting in variable treatment outcomes across different genotypes e.g. HCV4 (common in Africa who have the highest prevalence). Fortunately, the development of direct-acting antivirals (DAAs) has largely balanced treatment outcomes across different HCV genotypes. Current DAA regimens offer high cure rates for the majority of genotypes, although some minor differences in treatment duration or specific drug combinations may still exist.
63
What family is HCV apart of
Flaviviridae (italics) - large family of positive sense RNA (same as Dengue, Yellow Fever, Zika - many of which are arthropod borne which HCV is not - don't know if the viruses ability to spread by insects was originally there or acquired)
64
what is the closest relative to HCV and what is the biggest difference
HepG aka Human pegivirus. The biggest difference is that the pegivirus infects lymphocytes rather than hepatocytes ( thought to decrease HIV pathogenesis although not understood)
65
Where does most of the information we have on HCV come from
From chimpanzee studies because we can't take clinical isolates to grow them in the lab and they react similarly to humans (.... we hope)
66
Where does HCV primarily replicate after entering the bloodstream, and how quickly can this occur (based on animal studies)?
The liver is the primary target for HCV replication. In chimpanzee models, viral RNA can be detected in the liver within approximately 2 days after infection.
67
Where are the highest levels of HCV RNA found in the body? What proportion of these cells typically contain detectable HCV RNA and antigens?
Liver hepatocyte cells contain the highest levels of HCV RNA. However, only about 5-19% of hepatocytes are HCV RNA positive, and only 1-5% of liver mononuclear cells express HCV antigens.
68
apart from the liver, where has HCV RNA also been detected
1. Lymph nodes
2. Pancreas
3. Arenal glands
4. Bone marrow and spleen
5. Peripheral blood mononuclear cells ( although this is less certain)
69
what are liver mononuclear cells
cells located in the liver that form part of the innate and adaptive immune system e.g. small lymphocytes and large granular lymphocytes, monocytes and granulocytes
70
What is the approximate half-life of HCV virions in the bloodstream, and how many new virions are estimated to be produced daily?
The viral half-life is approximately 2-3 hours, and an estimated 10¹² (one trillion) virions are produced per day. the half life is rather short which is why the virus has to replicate so quickly to compenate
71
Why are chimpanzee animal models no longer used
Because other models are now more available which have fewer ethical concerns are more cost effective and more available e.g. mammalian cell expression systems, modified cell lines.
72
Why is it so difficult to capture HCV virions using an electron microscope?
Because the virion has a highly flexible and variable shape. This means that although they are found in abundance in the blood, they can take different forms making it hard to capture. There i also a theory that they either bind to or become completely enclosed in LDL droplets which mask them.
73
how could associating with the LDL increase HCVs pathogenicity
this could be a way of immune evasion (hide themselves from being detected)
74
What is the approximate size and a key immunological feature of Hepatitis C Virus (HCV) particles?
HCV particles are approximately ~50 nm in size and are reactive to HCV antibodies (Abs), indicating the presence of viral antigens on their surface that the host immune system recognizes.
75
What type of genome does the Hepatitis C Virus (HCV) have, and what is its approximate size?
HCV has a positive-sense, single-stranded RNA genome of about 9,600 nucleotide bases.
76
How is the HCV genome organized?
- The genome has non-coding regions at the 5' and 3' ends, flanking a long open reading frame (ORF).
- This ORF encodes a large polyprotein that is later cleaved into structural and non-structural proteins.
- the C, E1 and E2 (envelope proteins) are found at the 5' end and then the non-structiral proteins : NS2, NS3 NS4 A/B NS5 A/B are towards the 3' end
77
order of genes on the HCV genome
5'
1. C - Core
2. E1 - Envelope glycoprotein
3. E2 - Envelope glycoprotein
\/\/\/\/\/\/\/\/\/ Non structural \/\/\/\/\/\/\/\/\/
4. p7 - Protease
5. NS2 - Serine Protease
6. NS3 - Helicase
7. NS4A - Serine protease cofactor
8.NS4B - Membranous web
9. NS5A -?
10. NS5B - RNA dependent RNA polymerase
3'
78
What is the role of the 5' and 3' untranslated regions (UTRs) in the HCV genome?
The UTRs are essential for RNA replication and translation. The 5' UTR contains an internal ribosome entry site (IRES) that initiates translation.
79
What key similarity does the Hepatitis C Virus (HCV) genome share with Picornaviruses regarding its 5' end and translation initiation? Why is this similarity unusual for a Flavivirus?
Similar to Picornaviruses, the HCV genome possesses a highly structured region at the 5' IRES which allows ribosomes to directly bind to the viral RNA and initiate translation without the need for a 5' cap-dependent scanning mechanism, and typically shut down host cell translational machinery to favour the translation of their own viral proteins which HCV doesn't typically do This is considered unusual for a Flavivirus because other members of the Flaviviridae family, such as Dengue virus, typically utilize a different mechanism for translation initiation. This suggests that HCV may have acquired this IRES element through evolutionary processes
80
What is one hypothesis regarding how the Hepatitis C Virus (HCV) genome might have acquired the internal ribosomal entry site (IRES)?
the HCV genome might have acquired the internal ribosomal entry site (IRES) through the incorporation of sequences derived from microRNA (miRNA) or host cellular RNAs during its evolutionary history. This process, known as RNA recombination or capture, can lead to the acquisition of functional RNA elements that enhance viral replication or translation.
81
With what specific molecule does the ribosome associate on the HCV genome in liver cells (hepatocytes), and what are the functional consequences of this interaction?
the ribosome on the HCV genome associates with microRNA-122 (miR-122). This liver-specific microRNA binds to the 5' UTR of the HCV genome, acting as a viral internal ribosomal entry site (IRES). This interaction is crucial for genome stability, protecting the viral RNA from degradation, and for promoting viral translation, enhancing the production of viral proteins. The high abundance of miR-122 in the liver makes this interaction particularly important for HCV replication in its primary target tissue.
82
Describe the initial step in Hepatitis C Virus (HCV) protein synthesis and the subsequent processing of the resulting protein.
The HCV open reading frame (ORF) is initially translated as a large polyprotein which gets cleaved at specific sites by both viral enzymes (proteases), such as NS2 and the NS3/4A protease complex, and host cellular enzymes. This proteolytic processing is essential to generate the individual, functional structural and non-structural proteins required for viral assembly and replication.
83
Briefly outline the key steps in the Hepatitis C Virus (HCV) lifecycle.
1. Entry: The virus enters the host cell. Its positive-sense RNA genome is sufficient to initiate replication.
2. Translation and Replication Complex Formation: The viral RNA is translated into a large polyprotein which associates with the ER membrane, leading to the formation of a replication complex called the membranous web. This involves significant modification of intracellular membranes to create a suitable environment for viral replication.
3.RNA Replication: Within the membranous web, negative-sense RNA is synthesized from the positive-sense RNA genome. The negative-sense RNA then serves as a template to produce more positive-sense RNA, amplifying the viral genome.
4.Fate of Viral RNA: The newly synthesized positive-sense RNA can undergo one of three fates: it can be further translated to produce more viral proteins, it can be replicated again to increase the viral RNA pool, or it can be packaged into new virus particles for release.
5. Assembly and Release: The structural proteins and the viral RNA genome assemble into new virions. These are then released from the cell, often associating with lipoproteins, and can go on to infect other cells.
84
describe the HCV entry process steps 1-4:
1 LVPs attach to the cell surface by interacting with Heparin sulphate proteoglycans (HSPG), (ow density lipoprotein receptors (LDLR), and scavenger receptor class B member 1 (SRB1) . SRB1 might break-down HCV-associated lipoproteins which induces conformational changes in the E2 glycoprotein that exposes the CD81-binding site.
2. E2 interacts with CD81, activating signal transduction through EGFR and HRAS, as well as through RHO GTPases.
3. Signaling events promote lateral movement of HCV-CD81 complexes to sites of cell-cell contact, interaction of CD81 with CLDN1, and HCV internalization via clathrin-mediated endocytosis.
The low pH of the endosomal compartment induces HCV fusion.
85
What traffics the cleaved proteins to their specific sites?
Signal sequences
86
characteristics of proteins to be imbedded into the membrane
They have hydrophobic characteristics which get imbedded and hydrophilic characteristics which stick out
87
what are characteristics of proteins that face the cytoplasmic side
these proteins are typically required for viral replication and the parts of the parts that face the cytoplasm are hydrophillic
88
Describe the processes involved in the early and late stages of Hepatitis C Virus (HCV) assembly and secretion.
Early :
1. The HCV genome is translated into viral proteins
2. Viral proteins and RNA associate to form the replication machinery
3. The E1-E2 glycoprotein complex and the p7-NS2 complex are retained within the ER for glycosylation
4. core protein dimers are transported to cytosolic lipid droplets (cLDs) via a process mediated by cytosolic phospholipase A2 (cPLA2)
5. These lipid droplets are formed through the enzymatic activity of diacylglycerol-O-acetyltransferase (DGAT1)
Late Events :
1. viral RNA moves from sites of replication and translation towards assembly sites
2. Interaction between p7-NS2 and the NS3-4A complex facilitates the recruitment of the viral core protein to the assembly site
3. New virus particles are formed by recruiting the E1-E2 glycoprotein complexes and budding into the ER lumen
4. The secretion of both very low density lipoproteins (VLDL) and HCV particles is involved with maturation into low buoyant density particles which get secreted through the p7-buffered secretory pathway
89
How was a functional HCV made in labs?
esearchers, notably the Rice group, were able to create a functional HCV system by focusing on a highly infectious strain of the virus which was identified to have all the necessary genetic components for efficient replication. By ensuring that the complete set of structural and non-structural genes from this infectious strain were present and functional within their in vitro replication system (often using engineered viral RNA or cDNA clones transfected into permissive cell lines), they achieved sustained viral replication in the lab. This breakthrough bypassed the previous difficulties in culturing clinical HCV isolates.
90
What does elevated Alanine Aminotransferase (ALT) in the blood typically indicate?
marker for liver damage or inflammation (when liver cells are damaged they release ALT into the bloodstream)
91
During an acute Hepatitis C Virus (HCV) infection, approximately when do serum levels of Alanine Aminotransferase (ALT) typically peak?
between 2-3 months post infection. However, it's important to note that ALT levels can fluctuate and may even be normal during acute HCV infection in some individuals. Elevated ALT suggests liver inflammation, but its absence doesn't rule out infection
92
In individuals who spontaneously clear an acute Hepatitis C Virus (HCV) infection, approximately how long does it take for serum HCV RNA levels to become undetectable?
serum HCV RNA levels typically start to drop and become undetectable within approximately 3 months post-infection.
93
