HIV cure research

HIV cure research

HIV cure research

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The HIV Reservoir - Hiding in Plain Sight

HIV Latency and Reservoir Formation in CD4+ T Cells

  • What: A pool of long-lived, resting memory CD4+ T cells (and other cells like macrophages) harboring integrated but transcriptionally silent HIV provirus.
  • Mechanism: HIV DNA hides within the host cell's genome, remaining dormant and invisible to the immune system.
  • Problem: Standard antiretroviral therapy (ART) only targets actively replicating virus. It cannot eliminate this latent reservoir, which can reactivate and produce new virus if ART is stopped.

⭐ The half-life of the latent reservoir is estimated to be over 44 months, making it the primary barrier to a cure.

Shock and Kill - Luring Out the Enemy

The "Shock and Kill" strategy aims to eliminate the latent HIV reservoir in a two-step process.

  • Step 1 (Shock): Use Latency-Reversing Agents (LRAs) to force latent HIV out of its dormant state in CD4+ T-cells.
    • Examples: HDAC inhibitors (e.g., Vorinostat), PKC agonists (e.g., Prostratin).
  • Step 2 (Kill): Once reactivated, the infected cells become visible to the immune system and are destroyed, or are killed by Antiretroviral Therapy (ART).

Shock and Kill strategy for HIV cure and Nef effect

⭐ A major challenge is that no single LRA can reactivate all latent proviruses without causing global, toxic T-cell activation.

Gene & Cell Therapy - Snipping and Swapping

  • Primary Goal: To permanently alter host cells, making them resistant to HIV or enabling them to eliminate the integrated provirus.

  • Gene Therapy (e.g., CRISPR-Cas9):

    • Aims to "snip" out the integrated HIV proviral DNA from the host cell's genome.
    • Alternatively, it can disable the gene for the CCR5 co-receptor, which is essential for the entry of R5-tropic HIV strains.
  • Cell Therapy (Stem Cell Transplant):

    • Involves transplanting hematopoietic stem cells from a donor with a natural resistance to HIV.
    • The classic example uses donors homozygous for the CCR5-delta32 mutation.

CRISPR-Cas9 for HIV-1 provirus and CCR5 co-receptor editing

⭐ The 'Berlin patient' (Timothy Ray Brown) is the first person considered cured of HIV, following a hematopoietic stem cell transplant from a CCR5-delta32 homozygous donor.

Immunotherapy - Boosting Host Defenses

  • Broadly Neutralizing Antibodies (bNAbs):

    • Potent antibodies that recognize and neutralize diverse HIV strains.
    • Mediate clearance of infected cells via antibody-dependent cell-mediated cytotoxicity (ADCC).
    • Engineered for longer half-lives and greater potency.
  • Therapeutic Vaccines:

    • Aim to induce a potent and broad anti-HIV immune response in infected individuals.
    • Goal: Enable long-term, ART-free viral control or clearance, unlike preventative vaccines which aim to block initial infection.

⭐ Infusions of bNAbs have been shown to delay viral rebound after stopping ART, demonstrating their potential for long-term remission.

HIV-1 bnAb development from precursor B cells

High‑Yield Points - ⚡ Biggest Takeaways

  • The main barrier to an HIV cure is the latent reservoir in resting CD4+ T-cells.
  • "Shock and kill" uses Latency Reversing Agents (LRAs) to reactivate latent HIV for immune clearance.
  • "Block and lock" aims for a functional cure by permanently silencing HIV transcription.
  • Gene therapy (e.g., CRISPR-Cas9) targeting the CCR5 co-receptor prevents viral entry.
  • Broadly neutralizing antibodies (bNAbs) can provide long-term viral suppression off-ART.
  • Therapeutic vaccines seek to improve immune control over HIV.

Practice Questions: HIV cure research

Test your understanding with these related questions

A 49-year-old homeless man comes to the emergency department because of fatigue, cough, and worsening shortness of breath for 2 weeks. He was diagnosed with HIV-infection 25 years ago but has never had any symptoms. He has always refused to take antiretroviral medication. Pulmonary examination shows diffuse crackles over bilateral lower lung fields. An x-ray of the chest shows diffuse, symmetrical interstitial infiltrates. His serum level of beta-d-glucan is elevated. Further testing shows a heterozygous mutation that prevents entry of HIV into macrophages. Which of the following proteins is most likely affected by the mutation in this patient?

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Flashcards: HIV cure research

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Individuals with _____-zygous CCR5 allele mutations are resistant to HIV infection

TAP TO REVEAL ANSWER

Individuals with _____-zygous CCR5 allele mutations are resistant to HIV infection

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