Researchers discovered that macrophages (important cells of the immune system) temporarily switch off a protein that usually stops viruses such as HIV entering them. HIV exploits this window of opportunity.
In a study published in the EMBO Journal, the team - led by members of University College London (UCL) in the United Kingdom - describes how macrophages temporarily switch the protein off, and how HIV exploits this window of opportunity.
The researchers also discovered that treating the macrophages with HDAC inhibitors closes this window.
They suggest that the discovery solves another clue in the puzzle of how to cure people infected with HIV.
HIV destroys important cells in the immune system, leaving the infected person more susceptible to further infection and disease.
If untreated, HIV infection progresses to the most advanced stage: AIDS. This can take up to 15 years, depending on the individual.
While there is yet no effective cure, with appropriate antiretroviral (ART) therapy, HIV can be controlled.
Today, a person diagnosed with HIV who starts ART before the disease becomes advanced - and continues to take it correctly - can survive nearly as long as someone who is not infected.
HIV exploits 'window of opportunity' to invade
Macrophages are immune cells that reside in every tissue of the body. They rapidly attend sites of infection or damage, and engulf pathogens and cells destined for destruction.
- In the United States, more than 1.2 million people have HIV
- Approximately 1 in 8 of them do not know they are infected
- Young people are the most likely to be unaware of it.
Because of their capacity to clear pathogens and send instructions to other immune cells, macrophages play an important role in protecting the body. However, if this role is compromised, it is also a route to disease.
Viruses cause disease by entering host cells, hijacking their machinery to make copies of themselves, and then spreading them to other cells.
In their study background, the authors explain how macrophages defend against HIV invasion by making an antiviral protein called SAMHD1. The protein stops HIV from replicating in the cells.
Other viruses are able to switch off SAMHD1, but apparently HIV cannot. Therefore, there must be a way that HIV is evading this defensive mechanism.
The team discovered that there are times when the protein is naturally switched off, although it is not clear why.
Senior author Ravindra Gupta, a professor in UCL's Division of Infection and Immunity, explains: "We knew that SAMHD1 is switched off when cells multiply, but macrophages do not multiply so it seemed unlikely that SAMHD1 would be switched off in these cells."
"And yet," he adds, "we found there's a window of opportunity when SAMHD1 is disabled as part of a regularly-occurring process in macrophages."
HDAC inhibitors 'close the window of opportunity'
While they did not discover the reason, Prof. Gupta and colleagues suggest that perhaps the macrophages switch off SAMHD1 when they need to carry out DNA repair.
Researchers also discovered that when they treated the macrophages with HDAC inhibitors, which are drugs that are sometimes used to treat cancer, then they could close this window of opportunity and stop HIV invading the cells.
They tested the effect of HDAC inhibitors in both cell cultures of macrophages and on macrophages residing in the brain tissue of mice.
The team notes that macrophages can serve as a reservoir for HIV that persists even during therapy. Once infected, macrophages keep producing HIV, so "cutting off" that source of the virus could be a crucial step to protecting the whole immune system.
"Our findings could help explain why some people undergoing antiretroviral therapy for HIV continue to have HIV replication in the brain, as the infected cells in the brain are typically macrophages. While this is a barrier to achieving control of HIV in just a minority of patients, it may more importantly be a barrier to a cure."
Prof. Ravindra Gupta