34. Viruses and Anti-Viral Resistance

MIT OpenCourseWare

12 May 202051:00

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TLDRThis video script covers a lecture on HIV and Ebola viruses. It provides an in-depth look at HIV, which targets and infects CD4+ T cells, causing immunodeficiency. The key steps of the HIV viral lifecycle are outlined, including binding to host receptors, membrane fusion, reverse transcription of viral RNA to DNA, integration into the host genome, and budding of new virions. Potential therapeutic targets like viral enzymes are discussed, as are combination drug therapies to prevent resistance. Though time was short, this content offers a mechanistic perspective on HIV to engage student interest.

Takeaways

😷 HIV is a retrovirus that specifically targets and impairs CD4+ T cells, critical for immune function
💉 Early HIV infection was essentially a death sentence, but antiviral drugs now allow management
🌡️ HIV emerged rapidly in the early 1980s, potentially originating from a zoonotic transmission event in Africa
🔬 HIV replication involves unique enzymes like reverse transcriptase and integrase which are antiviral targets
💊 Nucleoside analogs like AZT can terminate reverse transcription but resistance can develop
⚗️ HIV protease inhibitors block cleavage of viral polyproteins needed for virion maturation
🧬 Once reverse transcribed and integrated, HIV DNA persists lifelong in host chromosomes
📈 Combination drug therapies help prevent resistance by inhibiting multiple independent viral processes
🚀 Membrane fusion mediated by GP120/GP41 is an early step in infection, also targeted therapeutically
👩‍⚕️ Developing effective vaccines has been very challenging given HIV's effects on immune function

Q & A

What does HIV stand for and what does it target?
-HIV stands for Human Immunodeficiency Virus. It specifically targets and infects CD4+ T cells, which are critical for immunity.
Why is reverse transcriptase important for the HIV life cycle?
-Reverse transcriptase is the enzyme HIV uses to convert its RNA genome into DNA, which can then integrate into the host cell's genome and replicate.
What are the four main enzyme targets focused on for HIV treatment?
-The four main HIV enzyme targets for treatments are: viral fusion, reverse transcriptase, integrase, and protease.
How do combination HIV therapies help prevent drug resistance?
-Combination therapies make it less likely HIV will mutate all targets simultaneously in one cell, preventing drug resistance from emerging.
Why can't HIV infection be cured?
-HIV infection can't be cured because the viral DNA gets integrated into the host genome by the integrase enzyme, so infected cells contain HIV permanently.
How does the HIV fusion process work?
-The GP120 and GP41 viral proteins bind host receptors, changing shape and bringing viral and host cell membranes together to fuse them, releasing the viral contents into the cell.
What is azidothymidine (AZT) and how does it work?
-AZT is a nucleoside analog reverse transcriptase inhibitor prodrug. Cells convert it to the active triphosphate form which halts viral DNA synthesis.
What does the HIV protease enzyme do and why is it a good drug target?
-HIV protease chops up viral polyproteins into functional proteins needed to assemble new virions. Inhibiting it blocks viral maturation.
How does HIV resistance to drugs emerge?
-HIV mutates rapidly, resulting in amino acid changes in targeted proteins that prevent inhibitor binding but retain function.
Why are combination HIV therapies so important?
-Using multiple drugs targeting different viral enzymes makes it extremely unlikely HIV can simultaneously mutate all targets to become resistant.

Outlines

00:00

😷 HIV Structure and Classification

This paragraph introduces HIV - a retrovirus that causes immunodeficiency by targeting immune cells. It is classified as a Group VI retrovirus. HIV infection leads to AIDS. The virus particle has an outer membrane coated with glycoproteins like GP140, with RNA and reverse transcriptase inside.

05:02

🩹 How HIV Recognizes and Enters T-Cells

This paragraph explains how HIV specifically targets T-cells by recognizing the CD4 receptor on them. It also requires a coreceptor like CCR5. Binding leads to fusion of viral and cell membranes, allowing entry of viral contents into the cell.

10:06

🌡️ Havoc Caused by HIV Infection

This paragraph describes the havoc caused by HIV infection - it knocks out T-cells involved in immune responses, making the body susceptible to other infections. It emerged rapidly in the early 80s, originally circulating in the gay community.

15:07

🔬 Key Aspects of HIV Replication Cycle

This paragraph outlines key aspects of how HIV replicates - binding to host cell receptors, fusion, entry of viral RNA and enzymes, reverse transcription to DNA, integration into host genome, transcription and translation to make new viruses.

20:08

💉 Four Drug Targets in HIV Replication

This paragraph introduces four critical steps in HIV replication that have been targeted for developing antiviral drugs - fusion, reverse transcription, integration and proteolytic cleavage of viral polyproteins.

25:11

🔒 Inhibiting Viral Fusion

This paragraph explains strategies for inhibiting viral fusion using peptides that bind the fusion complex and prevent the conformational changes needed for membrane fusion.

30:12

🧬 Blocking Reverse Transcription

This paragraph discusses blocking reverse transcription, which converts viral RNA to DNA, using nucleoside analogs like azidothymidine (AZT) that get incorporated but prevent further elongation.

35:15

🔗 Preventing Viral DNA Integration

This paragraph introduces integrase inhibitors that prevent the integration of viral DNA into the host genome - a critical step for lifelong infection.

40:19

✂️ Stopping Viral Polyprotein Cleavage

This paragraph describes protease inhibitors that bind the HIV protease enzyme and prevent it from cleaving viral polyproteins into functional units, inhibiting viral maturation.

Mindmap

Keywords

💡HIV

HIV stands for Human Immunodeficiency Virus. It is a retrovirus that attacks and destroys T cells, which are critical for immunity. HIV causes immunodeficiency, making people more vulnerable to infections. The video discusses HIV in depth - its structure, life cycle, and how it has been targeted for drug development.

💡fusion

Fusion refers to the process by which the HIV virus particle attaches and enters the host cell. The HIV envelope glycoproteins bind to receptors on the host cell, bringing the membranes together. Then the viral and cell membranes fuse, allowing the viral contents to enter the cell. The video shows an animation of this process.

💡reverse transcriptase

Reverse transcriptase is a unique viral enzyme delivered inside the HIV particle. It converts the single-stranded viral RNA into double-stranded DNA inside the host cell. This step is essential for HIV replication. Reverse transcriptase was one of the first targets for anti-HIV drugs.

💡integrase

Integrase is another important HIV enzyme. It inserts the viral DNA into the host cell genome. This integrates the viral genome into the host DNA permanently. Integrase inhibitors are a newer class of anti-HIV drugs.

💡protease

HIV protease chops up viral polyproteins into functional proteins needed to assemble new virions. Protease inhibitors block this process, preventing viral maturation. They are a key component of combination HIV therapy.

💡nucleoside analog

Nucleoside analogs like AZT were among the first anti-HIV drugs developed. They mimic nucleosides but terminate DNA synthesis. AZT stops reverse transcription of HIV RNA into DNA.

💡combination therapy

Using a combination of drugs that target different steps in the HIV life cycle helps prevent resistance. The video stresses the importance of combination therapy in treating HIV.

💡retrovirus

HIV is a retrovirus, meaning its genetic material is single-stranded RNA instead of DNA. Retroviruses use reverse transcriptase to create DNA from their RNA.

💡CD4 receptor

The HIV envelope protein GP120 specifically binds to the CD4 receptor on helper T cells. This allows HIV to directly infect and kill T cells.

💡viral load

The video mentions that HIV integrates into the host genome and establishes lifelong infection. This viral load persists even when the patient feels better, indicating the need for lifelong therapy.

Highlights

First significant research finding

Introduction of new theoretical framework

Notable contribution to field

Transcripts

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