0:00 between 130 and 150 million people globally have chronic Hepatitis C infections 0:07 . 0:07 A significant number of those who are chronically infected will develop liver 0:12 cirrhosis or liver cancer. 0:14 About 350,000 to 500,000 people die each year from Hepatitis C-related liver 0:23 diseases. 0:24 The Hepatitis C virus is a bloodborne virus, and so the main mode of 0:28 transmission is through blood, 0:31 most often due to unsafe injection practices. 0:36 In this video, we will look at the current knowledge of the Hepatitis C virus 0:41 life cycle in the liver cells of humans. 0:45 We begin this journey with the Hepatitis C virus itself that enters the extrace 0:51 llular matrix of the liver. 0:53 Let's first look at the virus structure. 1:02 So here we have the viral envelope, which is made up of a lipid bilayer, just 1:07 like human cells. 1:09 On the envelope, we have surface proteins, which we won't go into detail on the 1:14 names. 1:15 Then, within the envelope, there is a protein capsule that protects the genetic 1:21 material of the virus. 1:24 This protein capsule is called the capsid. 1:29 Well, in this case, it's called a nucleocapsid because it protects the nucleot 1:36 ides. 1:37 Now, the capsid is protecting the nucleotides, the genetic material, which is a 1:43 positive single-stranded RNA, 1:46 or positive-sense RNA. 1:51 We'll discuss why it is called positive later on. 1:55 So it has been shown that the Hepatitis C virus has the help of lipoproteins to 2:00 enter the hepatocytes, the liver cells, 2:05 because lipoproteins are usually recognized by the liver. 2:10 So here are the hepatic cells, the hepatocytes, which are attached to each 2:17 other by tight junctions. 2:20 In between the hepatocytes, we have bile ducts, where bile flows through. 2:25 Bile leaves the liver and is stored in the gallbladder. 2:32 Within the hepatocytes, we have the nucleus. 2:35 Well, each hepatocyte has a nucleus, where the genetic material of the cell is 2:40 stored, is kept. 2:42 Surrounding the nucleus is the endoplasmic reticulum. 2:46 In particular, this is known as the rough endoplasmic reticulum. 2:50 The rough endoplasmic reticulum houses many ribosomes. 2:54 That main function is to synthesize proteins from messenger RNA. 3:01 Okay, now that we know the cell that the hepatitis C virus will invade, let's 3:07 see how the virus invades the hepatocyte. 3:12 And how the virus, the hepatitis C virus replicates within the hepatocyte. 3:23 So let's go back to the hepatitis C virus, which is bound to the lipoprotein. 3:32 The lipoprotein and the hepatitis C virus will bind onto specific receptors on 3:39 the liver cell. 3:41 This process is called attachment, which will lead to viral entry into the cell 3:49 . 3:50 The liver cell will endostatize the hepatitis C virus, leading to viral entry. 3:58 An endosome will form that will contain the hepatitis C virus. 4:03 Next, the viral envelope. 4:07 The virus's lipid membrane will fuse with the endosome, a process known as 4:14 fusion. 4:16 This will result in the release of the nucleocapsid into the cytoplasm of the 4:22 liver cell. 4:24 The nucleocapsid will then uncoat, releasing the hepatitis C virus genetic 4:31 material, which is the positive single-stranded RNA, or positive-sense RNA. 4:38 So what will happen to this viral single-stranded RNA? 4:43 Well, it will actually use the host's ribosomes, which are around the endoplasm 4:49 ic reticulum, to make its own proteins. 4:53 The hepatitis C virus will use the host's machinery, the ribosomes, the amino 5:00 acids, to make their own proteins. 5:04 This process is known as translation. 5:07 Let's take a closer look at what is being made. 5:11 So here we have the membrane of the endoplasmic reticulum. 5:15 Here is the endoplasmic reticulum lumen, and here is the cytoplasm, the cytosol 5:24 of the cell. 5:26 And in this small box, we are looking at the translation of the hepatitis C 5:31 virus single-stranded RNA into polyproteins, into many proteins. 5:38 In order for the hepatitis C virus to make its proteins, they use the host's 5:43 ribosomes here. 5:45 And here is the positive single-stranded RNA, which will be translated by the 5:52 ribosomes to make many proteins, polyproteins. 5:57 These proteins will fold and arrange themselves to form many things for the 6:03 hepatitis C virus. 6:05 But these protein structures that will form can be divided into two main 6:10 categories. 6:12 The proteins will be either structural proteins for hepatitis C virus, or non- 6:17 structural proteins for the hepatitis C virus. 6:22 Structural proteins means that these proteins will be used to form the 6:26 structure of the hepatitis C virus, such as the capsid, or the surface proteins 6:33 . 6:34 However, the non-structural proteins will form the replication complex in this 6:41 case. 6:42 So let's focus on what this replication complex is. 6:47 So here in the different box, we have again the endoplasmic reticulum membrane, 6:54 and there is the endoplasmic reticulum lumen, and here is the cytosol of the 6:59 cell. 7:00 Here are the non-structural proteins that will assemble to become the 7:04 replication complex for the hepatitis C virus, not the hepatitis B virus, as I 7:11 written. 7:13 So what the replication complex does in simple terms, or what will happen, is 7:18 that the hepatitis C virus, positive single-stranded RNA, will be replicated by 7:26 the replication complex 7:27 to a negative single-stranded RNA. 7:31 This negative single-stranded RNA will then be used as a template by the 7:36 replication complex, again, to form many single-stranded RNA positives. 7:44 So from this negative single-stranded RNA, the replication complex will produce 7:51 many positive single-stranded RNA. 7:55 So now looking at a big picture, here we have the replication complex forming. 8:02 It will use the negative single-stranded RNA to produce many positive single- 8:09 stranded RNA. 8:11 So we have many here. 8:18 So again, what happens is the assembly of the replication complex, which then 8:26 will replicate the viral RNA. 8:30 After these positive single-stranded RNAs are formed or produced, what will 8:35 happen is that viral particle assembly will take place. 8:40 This will occur firstly in the endoplasmic reticulum. 8:45 The process actually requires the help of a lipid droplet. 8:50 So let's just take a closer look at what is happening. 8:57 So here we have the endoplasmic reticulum, the lumen, and the cytosol. 9:05 Here is the lipid droplet, and the lipid droplet will essentially help form the 9:12 hepatitis C viral particle 9:15 by bringing in the structural proteins, if you remember, the surface proteins 9:22 and the capsid. 9:25 And these structural proteins were already produced from translation, if you 9:30 remember. 9:31 So in this box what we are seeing is hepatitis C, not hepatitis B, but 9:37 hepatitis C virus core trafficking and capsid formation. 9:42 The positive single-stranded RNA is also directed into this viral particle that 9:49 is being formed. 9:51 From here the hepatitis C viral particle will be transported to the Golgi 9:57 apparatus, where it will be packaged up. 10:01 So here we have the Golgi viral assembly. 10:04 So the viral particle has already been formed. 10:07 We have the surface membrane, surface proteins on the lipid membrane, the 10:13 envelope. 10:14 And then we have the nucleocapsid, which contains the genetic material of the 10:18 hepatitis C virus, which is a single-stranded RNA positive strand. 10:28 So the hepatitis C virus particle is packaged up from the ER to the Golgi 10:32 apparatus. 10:34 The Golgi apparatus will then package it up and put it in an endosome, which 10:41 then will be released into the extracellular matrix. 10:48 What I actually did not show is that the Golgi apparatus, when it's packaging 10:52 up the hepatitis C virus, it will also include a lipoprotein with it. 10:58 And the lipoprotein will help the hepatitis C virus invade other hepatocytes. 11:06 Finally, the hepatitis C virus, when it's packaged up, it can actually infect 11:11 adjacent hepatic cells through a cell-to-cell transmission. 11:17 And it's quite simple because the hepatocytes are tightly packed together, 11:23 allowing the hepatitis C virus to infiltrate and invade adjacent cells more 11:29 easily.
