12/5 - Infectious Diseases: HIV & Prions

HIV: A Viral Infection

• Last lecture on infectious diseases, focusing on viruses, specifically HIV.

• Second half covers infectious diseases caused by prions.

HIV Replication Summary

• HIV recognizes the CD4 receptor on host cells.

• Uses a coreceptor (typically CCR5, sometimes CXCR4) for fusion with the host cell.

• Reverse transcription of the RNA genome into DNA.

• Viral integrase imports the DNA genome into the host cell's nucleus for integration.

• HIV hijacks host cell machinery for transcription and translation of viral mRNAs.

• Proteins assemble into new virus particles to infect new cells.

Importance of CCR5 Coreceptor

• About 5% of people of European descent have a 32-base pair deletion in the CCR5 gene.

• They cannot express the coreceptor and are resistant to the HIV R5 strain.

Stages of HIV Infection

Acute HIV

• Weeks to months after infection.

• Rapid HIV virus reproduction.

• Some people develop flu-like symptoms.

Asymptomatic Stage (Chronic HIV)

• Years following acute infection.

• Slower HIV virus reproduction.

• Gradual reduction in CD4 positive T lymphocytes.

• Few external symptoms.

AIDS (Acquired Immunodeficiency Syndrome)

• CD4 positive T cell count falls below a threshold.

• Susceptibility to opportunistic infections like tuberculosis and aspergillosis.

Viral Load and CD4 T Cell Count

• Viral load (HIV RNA copies per ml of plasma) rapidly increases in acute HIV.

• Followed by a slow increase during the asymptomatic stage.

• A sharp increase occurs with constitutional symptoms and opportunistic diseases.

• CD4 positive T cells decrease initially, then stabilize, followed by a slow decline.

• Risk of complications increases as CD4 T cell count drops.

Epidemiology of HIV

• Considered an ongoing epidemic.

• In 2023:

  • 39.9 million people living with HIV.

  • 1.3 million new infections.

  • 630,000 deaths from HIV-related causes.

• Most people living with HIV are adults.

• Slightly more women are living with HIV, but more men are acquiring and dying from it.

Global Distribution

• Africa has a high incidence of HIV/AIDS.

• Russia, the US, and India also have notable cases.

Progress in the Fight Against HIV

• Steady decrease in new HIV infections and deaths since 1990.

• New HIV infections in 2023 decreased by 39% compared to 2010.

• HIV-related deaths decreased by 51% compared to 2010.

Increased Life Expectancy

• 25% increase in the number of people living with HIV compared to 2010 due to increased life expectancy.

• Advances in antiretroviral therapy (ART) have significantly extended lifespans.

Antiretroviral Therapy (ART)

• Combination of antiviral agents targeting different steps in HIV replication.

• Suppresses viral replication and preserves the immune system.

• Reduces inflammation associated with chronic HIV.

• First-line treatment: Dolutegravir combined with a nucleoside reverse transcriptase inhibitor.

Targets of ART

• Protease inhibitors.

• CCR5 receptor inhibitors.

• Reverse transcriptase inhibitors.

• Integrase inhibitors (e.g., Dolutegravir).

Impact and Access to ART

• ART has transformed HIV treatment, often involving a single daily pill.

• Increased access to ART, with the goal of universal treatment.

• 77% of people with HIV had ART in 2023, compared to 2% in 2003.

Prevention of HIV Transmission

• HIV is transmitted through bodily fluids and secretions (unprotected sex), mother to baby (pregnancy, birth, breastfeeding), sharing needles, and contaminated blood.

• Vaccines are not available yet.

Prevention Methods

• Consistent condom use reduces transmission by 70%.

• Interventions for safe drug use.

• U=U (undetectable = untransmittable): People on ART with undetectable viral load cannot transmit the disease.

• Pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) using antiretrovirals.

• Male circumcision may reduce transmission by 59%.

HIV Diagnosis

• Early diagnosis is important for treatment and reducing transmission.

• Rapid tests are available, including at-home tests.

• Combination of tests used, including:

  • Nucleic acid tests (NAAT) to detect HIV RNA.

  • Antibody tests.

  • Antigen tests (proteins from HIV).

Timing of Tests

• Eclipse period: 5-10 days after infection, all tests are negative.

• NAAT can detect HIV RNA about 10 days after infection.

• Antigen tests can detect p24 protein around day 18-19.

• Antibody tests take longer; retesting is recommended 28 days later if initially negative.

Potential Cures for HIV

• At least three people have been cured of HIV following stem cell transplants for cancer treatment.

• Donors had a 32-base pair deletion in the CCR5 gene, making them HIV-resistant.

• This treatment is not scalable due to risks and the effectiveness of antiretrovirals.

Summary of HIV

• Viruses rely on host cells to replicate.

• HIV is a retrovirus that invades T lymphocytes with CD4 receptors.

• Leads to AIDS.

• Antiretrovirals extend lifespan but do not cure.

• HIV is preventable.

Prions: Introduction

• Prions are non-living pathogens.

• Collection of rare, progressive neurodegenerative disorders (transmissible spongiform encephalopathies).

Characteristics of Prion Diseases

• Spongiform appearance of brain tissue due to holes or vacuoles.

• Deposition of abnormal prion protein.

• Long incubation periods (years).

• Rapidly progressive and always fatal.

• Resistant to degradation.

• No nucleic acid detected.

Types of Prion Diseases in Humans

Spontaneous Forms

• Sporadic Creutzfeldt-Jakob disease.

• Sporadic fatal insomnia.

• Variably protease-sensitive proteinopathy.

Genetic Forms

• Due to mutations in the PRNP gene.

• Genetic Creutzfeldt-Jakob disease.

• Gertzmann-Sträussler-Scheinker syndrome.

• Fatal familial insomnia.

Acquired Forms

• Iatrogenic Creutzfeldt-Jakob disease (caused by medical treatment).

• Kuru.

• Variant Creutzfeldt-Jakob disease.

• Extremely rare; sporadic forms are most common.

• Outbreaks of acquired forms have drawn attention.

Mad Cow Disease (Bovine Spongiform Encephalopathy)

• Outbreak primarily in the UK.

• Cows had seizures months or years after infection.

• Related to scrapie in sheep.

• Spread by consuming brain or spinal cord tissues from infected animals.

• Prevention: Destroy infected animals, avoid using animal products containing brain/CNS tissue in livestock feed.

Timeline of Mad Cow Disease Outbreak

• 1986: Bovine spongiform encephalopathy recognized as a new disease.

• 1995: First confirmed case of spread to humans (variant Creutzfeldt-Jakob disease).

• British beef export was banned.

• Peak of disease in cows: 1992.

• Peak in human cases: 1999 (consistent with long incubation time).

• Beef export resumed in 2006.

Nature of Prions

• Disease-associated transmissible agent lacking nucleic acid, consisting of aggregated protein only.

• Prion = proteinaceous infectious particle.

• Misfolded form of host cell protein (PRPC for cellular).

• PRPC is important in the brain (myelin sheaths).

• Misfolded version = PrPSC (scrapie-like).

• Misfolded PrPSC forms stable polymers and fibrils, making it infectious.

• Resistant to detergents and sterilization treatments.

Prion Replication

• Normal prion protein binding to abnormally folded prion protein.

• Misfolded protein facilitates the conversion of normal protein into the misfolded form.

• Fragmentation of fibrils creates new seeds for growth.

Prion Disease Treatment

• Always fatal; no treatment available.

• Supportive care only.

• Research focuses on:

  • Reducing production of cellular protein (PRNP gene).

  • Blocking conversion of normal protein to misfolded protein.

  • Preventing aggregation of misfolded protein.

  • Speeding up degradation of misfolded proteins via lysosomes.

  • Stopping apoptosis of cells.

Summary of Prions

• Transmissible spongiform encephalopathies involve a new type of infectious agent: the prion.

• Rare but always fatal.

• Infectious agent: a misfolded version of our own cellular protein, which serves as a template for misfolding cellular protein.

• Further research needed for better understanding.