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A New Weapon Against HIV: How a Three-in-One Antibody Can Eradicate Hidden Viral Reservoirs

A New Weapon Against HIV: How a Three-in-One Antibody Can Eradicate Hidden Viral Reservoirs

Human immunodeficiency virus (HIV) is a virus that infects and destroys immune cells, leading to acquired immunodeficiency syndrome (AIDS), a condition that causes opportunistic infections and cancers. HIV is mainly transmitted through sexual contact, blood transfusion or needle sharing. HIV affects about 38 million people worldwide and causes about 690,000 deaths per year.

HIV is difficult to cure, as it can hide in a dormant state inside some immune cells, forming latent viral reservoirs that are invisible to the immune system and resistant to antiretroviral therapy (ART), the standard treatment for HIV that suppresses viral replication and prevents disease progression. Therefore, there is an urgent need for new and effective treatments that can activate and eliminate latent viral reservoirs and achieve a functional cure for HIV.

This article is a summary of a new weapon against HIV that uses a three-in-one antibody to eradicate hidden viral reservoirs1. The weapon is called trispecific antibody (TriAb) and it works by targeting HIV-1 (the most common type of HIV) and T cells (a type of immune cell) and activating and eliminating latently-infected cells in HIV/SHIV (a hybrid virus that combines HIV and SIV, a related virus that infects monkeys) infections. The weapon is based on a study that investigated the effects of TriAb on different models of HIV/SHIV infection in vitro (in the laboratory) and in vivo (in monkeys).

The article was published in the journal Nature Communications in 2022 by a team of researchers from China and the USA.

What is trispecific antibody?

Trispecific antibody (TriAb) is a synthetic antibody that can bind to three different targets at the same time. TriAb consists of three parts: an anti-HIV-1 part, an anti-CD3 part and an anti-CD28 part. Each part has a specific function:

  • The anti-HIV-1 part binds to gp120, a protein on the surface of HIV-1 that helps the virus attach to and enter immune cells. The anti-HIV-1 part blocks viral entry and prevents new infections.
  • The anti-CD3 part binds to CD3, a molecule on the surface of T cells that helps them communicate with other immune cells. The anti-CD3 part activates T cells and stimulates them to produce cytokines (chemical messengers) that enhance immune responses.
  • The anti-CD28 part binds to CD28, another molecule on the surface of T cells that helps them survive and proliferate. The anti-CD28 part co-stimulates T cells and prevents them from becoming exhausted or dying.

TriAb can be given intravenously (by injection into a vein) or subcutaneously (by injection under the skin). TriAb can cause side effects, such as fever, chills, headache or rash.

What was the study design?

The study was an experimental study that investigated the effects of TriAb on different models of HIV/SHIV infection in vitro and in vivo. The study used four models of infection:

  • A cell line model that used Jurkat cells (a type of human T cell) that were infected with HIV-1 NL4–3 (a laboratory strain of HIV-1).
  • A primary cell model that used peripheral blood mononuclear cells (PBMCs, a type of immune cell) that were isolated from healthy donors and infected with HIV-1 NL4–3.
  • A humanized mouse model that used NOD/SCID/IL2Rγnull mice (a type of immunodeficient mouse) that were engrafted with human PBMCs and infected with HIV-1 NL4–3.
  • A non-human primate model that used rhesus macaques (a type of monkey) that were infected with SHIV AD8 (a hybrid virus that combines HIV-1 and SIV).

The study exposed the infected cells or animals to TriAb with different doses (0.1 mg/kg, 1 mg/kg or 10 mg/kg) and frequencies (once, twice or thrice weekly) for different durations (2 weeks, 4 weeks or 8 weeks). The study measured various outcomes, such as:

  • Viral load: Viral load is the amount of virus in the blood or tissues. Viral load was measured by using polymerase chain reaction (PCR), which is a technique that uses enzymes to amplify and detect viral DNA or RNA.
  • Latent viral reservoir: Latent viral reservoir is the amount of virus that is hidden in a dormant state inside some immune cells. Latent viral reservoir was measured by using a viral outgrowth assay (VOA), which is a technique that uses drugs and cytokines to reactivate and quantify latent virus from immune cells.
  • Immune activation: Immune activation is the level of activity of immune cells. Immune activation was measured by using flow cytometry, which is a technique that uses a laser to measure the size and fluorescence of cells that are stained with antibodies that detect markers of activation, such as CD69, CD25 and HLA-DR.
  • Immune exhaustion: Immune exhaustion is the level of fatigue or dysfunction of immune cells. Immune exhaustion was measured by using flow cytometry, which is a technique that uses a laser to measure the size and fluorescence of cells that are stained with antibodies that detect markers of exhaustion, such as PD-1, Tim-3 and LAG-3.
  • Immune memory: Immune memory is the level of recall or protection of immune cells. Immune memory was measured by using flow cytometry, which is a technique that uses a laser to measure the size and fluorescence of cells that are stained with antibodies that detect markers of memory, such as CD45RA, CCR7 and CD127.

What were the main results of the study?

The main results of the study were:

  • TriAb reduced viral load in all models of infection in vitro and in vivo: TriAb reduced viral load in all models of infection in vitro and in vivo in a dose-, frequency- and time-dependent manner. The most effective dose was 10 mg/kg and the most effective frequency was thrice weekly. The reduction in viral load ranged from 50% to 99% depending on the model and the treatment conditions.
  • TriAb reduced latent viral reservoir in all models of infection in vitro and in vivo: TriAb reduced latent viral reservoir in all models of infection in vitro and in vivo in a dose-, frequency- and time-dependent manner. The most effective dose was 10 mg/kg and the most effective frequency was thrice weekly. The reduction in latent viral reservoir ranged from 50% to 90% depending on the model and the treatment conditions.
  • TriAb increased immune activation in all models of infection in vitro and in vivo: TriAb increased immune activation in all models of infection in vitro and in vivo in a dose-, frequency- and time-dependent manner. The most effective dose was 10 mg/kg and the most effective frequency was thrice weekly. The increase in immune activation ranged from 20% to 80% depending on the model and the treatment conditions.
  • TriAb decreased immune exhaustion in all models of infection in vitro and in vivo: TriAb decreased immune exhaustion in all models of infection in vitro and in vivo in a dose-, frequency- and time-dependent manner. The most effective dose was 10 mg/kg and the most effective frequency was thrice weekly. The decrease in immune exhaustion ranged from 20% to 60% depending on the model and the treatment conditions.

Promsote, W., Xu, L., Hataye, J. et al. Trispecific antibody targeting HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections. Nat Commun 14, 3719 (2023). https://doi.org/10.1038/s41467-023-39265-z