HIV fights dirty, but scientists can learn its tricks.
HIV entered the human population in 1981, and since then, it has stealthily infected millions and become an invisible enemy to public health officials, patients, and doctors. They say you can’t hit what you can’t see, so to the scientists fighting for an HIV cure, knowledge is power. In our “Perspectives on HIV” mini-series, we’ll expose the tricks that HIV uses to infect humans, and explain how molecular biologists are designing a new generation of medicine that is specifically designed to hit HIV where it hurts. Here, we’ll answer the question “How does HIV attack the immune system” and explain how researchers are using that knowledge to develop a functional cure for HIV.
How HIV turns the immune system on itself
You may already be familiar with the idea that HIV causes AIDS by depleting the immune system, but a closer look at how this occurs reveals a prime opportunity for researchers. At a very basic level, you have millions of T cells in your body; these are white blood cells that are central to your body’s ability to recognize and respond to pathogens. Most T cells fall into one of two categories: CD4+ “Helper” T cells or CD8+ “Killer” T cells, and each T cell has a unique T cell receptor which lets it recognize one very specific molecular pattern:
- Some may recognize a pattern characteristic of bacteria like Listeria
- Others use their pattern-recognition receptor to identify a specific type of cancer
- Others may recognize a pattern on cells which are infected with viruses like HIV
When T cells find the pattern they’ve been looking for all their lives, they react. Vigorously.
This video from Cambridge University shows how the T cell, colored in green, recognizes cancerous or virally infected cells, colored in red. As you can see, when T cells recognize the pattern they’ve been “trained” to detect, they adhere to and kill their target. The wide diversity of T cells, each with a highly specific target, crawl through the body keeping you safe from almost any pathogen.
Your immune system’s remarkable power and precision come from a complex biochemical “conversation” between T cells, B cells, dendritic cells, macrophages, and so on. HIV disrupts this system by removing helper T cells from the conversation.
HIV rips through the Helper T cell population
HIV is able to infect a couple of different cell types, with the most prominent being the helper T cell. These cells have onboard defense mechanisms that can recognize viral entry and cause the cell to kill itself in self defense. A successful infection would mean that a DNA copy of the HIV genome slips past the helper T cell’s defenses and integrates into the cell's genome; but this only occurs in 5% of helper T cells. For the other 95% of helper T cells, when HIV enters the cell, it triggers the cell’s onboard defenses causing the cell to kill itself in self-defense using a flashy, inflammatory form of apoptosis called pyroptosis. As researchers Doitsh and Greene put it:
“[...] most cells are not dying because of a toxic action of products encoded by HIV. Rather, death occurs as a consequence of a powerful defensive innate immune response launched by the host against the virus leading to a cellular form of suicide rather than virological murder.”
By immediately killing 95% of the helper T cells it enters, HIV quickly and severely inhibits immune function. Additionally, HIV preferentially infects T cells that recognize HIV, allowing it to selectively cripple the anti-HIV response. While T cells that recognize something like the Flu or Strep would still be susceptible to viral infection, much heavier damage is done to the T cells that recognize HIV, effectively ripping a hole in your body’s immune response against HIV and allowing HIV to replicate with little resistance.
The 5% of cells that are successfully infected carry an HIV genome inside their nucleus, which masquerades as a human gene. These cells often divide, copying the HIV genome in the process and stealthily bolstering the number of HIV copies in the body. When these infected cells read the HIV genome, they may kill themselves through standard apoptosis, but all too often this does not occur before they have assembled infectious HIV particles, perpetuating the viral cycle.
HIV infection may not progress if cells are resistant to infection
Once the chain reaction of HIV infection begins, it inevitably leads to AIDS without medical intervention. However, there are exceptions that we can learn from. Individuals with natural HIV resistance, as well as HIV cure cases like the Berlin and London patients, teach us that if HIV is unable to efficiently enter T cells, the course of infection may look drastically different.
To enter a cell, HIV needs to bind to two receptors on the cell surface: CD4 and either CCR5 or CXCR4. The image below, from Harvard University’s Science in the News article, “The Man Who Was Cured of HIV,” shows how an HIV particle binds to CD4, then “falls over” onto the cell surface and binds to CCR5 or CXCR4 before ultimately fusing into the cell membrane to enter the cell.
Individuals who lack normal CCR5 genes are highly resistant to strains of HIV that use CCR5 to get into cells. For Timothy Ray Brown, the first person to be cured of HIV, T cells lacking normal CCR5 were able to coordinate an anti-HIV immune response without becoming infected by HIV the way normal immune cells would. There are now 5 cases which demonstrate that cells lacking CCR5 have curative potential for HIV infection, shining light on one of HIV’s weak points – a weak point that Addimmune is happy to exploit.
AGT103-T repairs the immune system with HIV resistant T cells
In combination, these data points imply that the immune system is capable of suppressing – or possibly even clearing HIV – so long as the immune system has enough cells that can recognize HIV, and that those cells do not allow HIV to enter. While the methods used in the case studies where HIV was cured are risky and are not scalable, a clever gene therapist can learn from these case studies to design a safer, scalable intervention. At Addimmune, we’re in human trials for AGT103-T, a gene therapy specially designed to hit HIV where it hurts:
- Backfill the hole that HIV has ripped in the immune system.
- Repair the anti-HIV response by reintroducing T cells that can target HIV.
- Reinforce T cells with gene therapy so they become HIV-resistant.
- Remove CCR5 from the cell’s surface, blocking the virus from entering cells so the immune system can fight HIV without losing all of its “soldiers” to HIV infection.
- Give cells the ability to recognize and cleave genetic material that comes from HIV.
- Reimagine the immune response to HIV with an army of HIV-resistant T cells that can direct the immune system’s weaponry at the virus, but cannot be infected themselves. Since these cells can divide to make more HIV-resistant T cells, we hope to install a durable anti-HIV response capable of sustained viral suppression.
AGT103-T is currently in human trials, and our team releases data whenever we pass new milestones. Human trials are known to be lengthy processes, so while these trials are underway, our team will continue to explain the significance of the data that is released and show new perspectives on how the virus works. By understanding HIV’s strengths and weaknesses, we can expose HIV for what it truly is: a curable virus. Gene therapy is the next big thing in medicine, and if you want to know more about what it does, how it’s made, and how it’s performing in clinical trials, be sure to sign up for our newsletter, follow us on social media, and tune in for the next installment of Perspectives on HIV.
You made it to the end, thanks for reading. We understand that HIV science can be a complex topic, so here are some frequently asked questions and answers.
Question: How do researchers create cells without CCR5 on their surface?
Answer: There are multiple ways to stop the cell from making CCR5. Sangamo famously used zinc finger nucleases to cut the DNA that makes up the CCR5 gene. More recent approaches use RNA interference to cleave mRNA derived from the CCR5 gene, which allows researchers to avoid cutting DNA.
Question: You mentioned CD4+ “Helper” T cells and CD8+ “Killer” T cells, but what are CD4 and CD8, and if HIV uses CD4 to get inside of cells, does that mean that Killer T cells cannot be infected?
Answer: The Cluster of Differentiation (CD) naming system is used to identify unique proteins on a cell’s surface so they can be classified. CD8 is a molecule on the outside of killer T cells that helps the cell dock to the surface of cells and “check” on what the cell is making to ensure that no pathogenic signatures are present. CD4 is similar to CD8 but it is expressed on helper T cells instead of killer T cells and it allows the helper T cell to “look at” what a cell has eaten from the outside environment instead of what the cell is producing.
Question: You mentioned pyroptosis, and I’ve never heard of that before, what is it?
Answer: Cells can die in multiple distinct ways. Apoptosis is the most famous method of programmed cell death, and it’s a normal part of life, so the immune system does not normally need to react to this method of cell death. On the other hand, pryroptosis and necroptosis elicit immune responses. In the words of Bertheloot, Latz and Franklin: “While necroptosis and pyroptosis act as “whistle blowers”, resulting in the release of alarmins and other proinflammatory signals into the cellular surroundings, apoptosis is considered “silent” and dampens subsequent immune responses.” Pyroptosis is an important part of HIV pathogenesis because it can excite immune cells and lead to more HIV infections.
Question: What cells does HIV infect? Are there more than just helper T cells?
Answer: In addition to helper T cells, HIV can infect epithelial cells, follicular dendritic cells, dendritic cells, macrophages and others. These cell types are important, but helper T cells are central to the immune response, so protecting them from infection has curative potential due to their ability to coordinate an immune attack on HIV-infected cells, regardless of cell type.