The reservoir of inactive HIV in the body of infected individuals may be up to 60 times larger than scientists anticipated, according to Howard Hughes Medical Institute (HHMI) scientists.
HIV attacks and eventually takes over the immune system’s T cells in order continue reproducing. However, one way that the sneaky virus manages to survive other immune defenses targeted at destroying it is to play dead, by remaining inactive and dormant (in what’s known as provirus form). Antiretroviral drugs successfully target actively dividing HIV, but scientists are still working on ways to find and kill the proviruses. And up to now, they vastly underestimated how widespread their enemy was.
To get a better idea of the size of the inactive reservoir of viruses, researchers tried to force T cells to start dividing, which in turn, scientists hoped, would also prompt the inactive HIV to emerge as well. But that strategy hasn’t always worked, so teams have also attempted to count viral genomes. This method, however, frequently led to an over-estimate of viral particles since it included many viruses that had mutated to become ineffective and therefore not a clinical risk.
In the latest study published in the journal Cell, however, researchers found a new way to estimate the dormant population by stimulating the T cells to activate and then focusing on the proviruses that remained inactive, to ensure that they got a more complete picture of the entire reservoir. They then analyzed the genomes of the non-activated viruses and found that while 88% were defunct and not potentially disease-causing, 12% contained intact genomes that were capable of replicating again.
“To our surprise, the non-induced proviruses that we judged to be intact based on their genetic sequence all replicated beautifully,” said lead study author Robert Siliciano, an HHMI investigator at the Johns Hopkins University in a statement. The researchers say the findings suggest that proviruses, rather than being inert, can be activated later on.
Since 12% of the inactive proviruses might still able to be activated, the researchers estimate that the actual reservoir size of HIV that, while dormant, could cause disease later on might be up to 60 times greater than previous estimates. So even if patients respond to antiretroviral drugs that stop active HIV replication and drop viral load to below detectable levels, the inactive viruses could serve as a new source of infection, even during or after treatment. The results also confirm the new push among AIDS experts to begin combination drug therapy as soon as possible after infection, in order to discourage these HIV reservoirs from forming.
“It doesn’t mean that it’s hopeless, but it does mean we need to focus on getting an even clearer idea of the scope of the problem,” said Siliciano. And use the knowledge to develop the next generation of anti-HIV drugs, which might be targeted at the dormant population of viruses as well.