Part of the reason that a cure for HIV continues to elude us is that the virus hides away in cells of our immune system, forming a persistent reservoir that can’t be eliminated by drugs. Many scientists believe that if HIV can be forced out of these lingering pools, then a cure could be on the cards. Now, researchers studying the immune cells of HIV-infected patients have gained fresh insight into which cells do and don’t harbor these so-called latent viral reservoirs, which could ultimately help scientists towards reaching this goal. The work has been published in Cell.
HIV, or human immunodeficiency virus, predominantly targets a type of white blood cell called a CD4+ T cell, which ironically usually plays a crucial role in protecting our bodies from infection against a variety of pathogens. After the virus enters the cell, its genome becomes inserted into our own DNA during a process known as integration. After this, there are two main pathways that the virus may follow. Either the virus hijacks our cell’s own equipment in order to make new copies of itself which then go on to infect and ultimately kill more cells, or alternatively it may enter a quiet, or dormant, state, ceasing to replicate and establishing what is known as a latent reservoir.
Although antiviral drugs have been designed to effectively disrupt different stages of the HIV life cycle, they are only able to attack actively replicating HIV. This means that while treatment can control the infection and severely reduce the amount of virus in the body, there will always be a lingering supply that can rebound as soon as the patient stops taking the therapy.
It was believed for some time that the predominant source of latent virus was a type of T cell, called a long-lived memory cell, which can persist in the immune system for extended periods, ready to protect against any repeat invasions by a particular pathogen. If these cells encounter such a pathogen, they rapidly mount a response against it and proliferate, a process known as clonal expansion. Previous work hinted that this process was critical to maintaining the latent reservoir, but new research suggests that this may not be the case.
For the study, scientists from Rockefeller University investigated the replicative capabilities of viruses obtained from both clonally expanded T cells and unique cells obtained from infected individuals. The researchers were able to distinguish between these based on the site of integration. Because the human genome is so large, the chances of the virus inserting itself in exactly the same place twice are exceedingly slim. Therefore, if multiple cells had viral DNA integrated into a particular spot, these were classified as clones.
To their surprise, they found that the clones actually contained defective viruses that were incapable of completing the viral life cycle. This meant that, in contrast to prior belief, clones do not appear to harbor the latent reservoir. Instead, the researchers explain, the reservoir is more likely to reside in less common cells containing unique integrations. Although there are still many barriers to a cure, this new information may ultimately help scientists explore novel ways to force these latent viruses out of hiding.
