Anti-HIV Agents – Antiviral Drugs

00:01 Now, here's a picture, a beautiful illustration of what the HIV particles look like.

00:06 Those little green dots are all HIV particles.

00:09 The red structure is a human white blood cell, and it's sitting on top of another cell and doing its job.

00:18 Clearly, this person has high viral loads of HIV.

00:22 Now, let's take a look at an HIV particle so that you can understand where each of these drugs are doing their job.

00:27 The HIV particle is an incredibly complex structure, and I'm just going to go over it in very quick detail.

00:34 For more detail about the HIV particle, I want you to take a look at the microbiology and infectious disease lectures here at Lecturio.com.

00:44 The first thing that I want to point out is something called the lipid membrane.

00:47 This is similar to other lipid membranes of other viruses.

00:51 We have a matrix protein kind of attached to the lipid membrane.

00:57 We have a capsid that surrounds nucleocapsids.

01:01 Now, that little pink string that you see in this illustration is where all of the genetic material of the virus is stored.

01:09 TAT, which stands for Transactivator of Transcription, is a protein that enhances the transcription of HIV genes.

01:16 While important in the viral life cycle, TAT is not currently a primary target for widely used antiviral drugs.

01:25 However, understanding TAT is crucial for grasping the overall complexity of HIV replication.

01:33 We have the viral RNA genome.

01:36 Remember viruses have RNA.

01:38 This is where we get our genetic information from from the virus.

01:44 We have another enzyme here called reverse transcriptase.

01:47 This is quite interesting in HIV because the very first drugs used to battle HIV were actually reverse transcriptase inhibitors.

01:56 Now, remember that reverse transcriptase from your biology lectures in pre-med is an enzyme that's used to generate DNA, actually complementary DNA, from your RNA template in the virus.

02:11 The other thing that I want to mention is something called integrase.

02:14 Integrase is an enzyme that's produced by a retrovirus like HIV that enables its genetic material to be integrated into the DNA of the host cell.

02:27 For example, the integrase helps take HIV DNA to integrate it into the patient's DNA in their cells.

02:37 A protease is an enzyme that helps break down proteins.

02:42 In this particular case, specific to pharmacology, we're going to be talking about the ones that are used to package up the proteins for release.

02:52 In pharmacology, we focus on protease inhibitors, which prevent the proper processing and packaging of viral proteins, thus blocking the maturation of HIV particles.

03:03 When we talk about proteases in general, you'll find that we have a very different kind of approach to proteases in pharmacology than we do to say infectious diseases or microbiology.

03:14 I'm only talking about one kind of protease that's relevant in pharmacology.

03:19 We also have a lot of proteins on the cell of both the host cell and proteins of the virus itself.

03:30 In terms of the virus, we have what we call the N-glycoprotein complex.

03:35 So there are several molecules involved in this.

03:38 There's the GP120 and the GP41.

03:40 There's other ones as well.

03:41 I'm not going to go into too much detail right now.

03:44 The other thing I want to mention is that these proteins can become glycosylated.

03:49 So the viral surface proteins act to bridge between the virus and the cell during attachment to the host cell.

03:58 There you have it.

03:59 Those are all the different parts of the virus.

04:01 And of course, in pharmacology, we only name parts that are relevant to us.

04:08 The HIV life cycle consists of seven critical steps, each of which is a target for specific antiretroviral therapies.

04:16 Understanding these stages helps in comprehending how HIV propagates within the host and how different drugs can intervene to stop this process. The first stage, binding attachment, occurs when HIV attaches itself to receptors on the surface of a CD4 cell.

04:34 This crucial initial step is targeted by CCR5 antagonists and post-attachment inhibitors, which prevent the virus from latching onto the cell.

04:44 Following binding, the virus undergoes fusion with the CD4 cell membrane, allowing it to enter the cell. Fusion inhibitors act at this point to stop the virus from merging with the host cell membrane and thus from delivering its viral contents into the cell.

05:00 Once inside the cell, HIV begins the reverse transcription process.

05:05 Here the virus uses its enzyme, reverse transcriptase, to convert its RNA into DNA.

05:11 This newly formed viral DNA then enters the nucleus of the CD4 cell.

05:16 This step is blocked by drugs known as nucleoside reverse transcriptase inhibitors, NRTIs, and non-nucleoside reverse transcriptase inhibitors, NNRTIs, which prevent the reverse transcription process.

05:31 The next stage, integration, involves the viral DNA being inserted into the host cell's DNA by the enzyme integrase.

05:39 Integrase inhibitors are designed to prevent this integration, which is critical because, once integrated, the viral DNA remains a permanent part of the host cell's genetic material.

05:49 After integration, the virus enters the replication phase.

05:53 During this phase, the host cell's machinery is hijacked to produce long chains of HIV proteins, which are the building blocks for new HIV particles.

06:02 There are no specific antiretroviral agents that target this replication process directly.

06:08 Following replication assembly occurs.

06:11 During this stage, the newly made HIV proteins and RNA move to the surface of the CD4 cell, where they assemble into immature non-infectious HIV particles.

06:21 Similar to the replication step, there are currently no antiretroviral agents that specifically target the assembly of these viral particles.

06:29 Finally, the immature HIV particles undergo budding, where they push out of the host CD4 cell.

06:35 During this process, the viral enzyme cleaves long protein chains into smaller functional HIV proteins, creating mature and infectious virus particles.

06:46 Proteus inhibitors are used at this stage to prevent the maturation of HIV, rendering the budding viruses non-infectious.

06:55 Lenacapavir is a first in class capside inhibitor that disrupts multiple stages of the HIV1 lifecycle, including nuclear uptake, virus assembly, and capside formation, making it effective against multi-drug resistant HIV1.

07:11 Clinical trials, such as Capella, have shown its efficacy in reducing viral load in heavily treatment experienced patients, leading to its endorsement by leading HIV medicine organizations for managing multi-drug resistant infections.