In a study published recently in Cell, a Rockefeller University research team led by Michel C. Nussenzweig, Zanvil A. Cohn and Ralph M. Steinman take a look at why HIV drugs only suppress the infection.
“It has recently been shown that infected white blood cells can proliferate over time, producing many clones, all containing HIV’s genetic code,” study author Lillian Cohn, a graduate student in Nussenzweig’s Laboratory of Molecular Immunology, said. “However, we found that these clones do not appear to harbor the latent reservoir of virus. Instead, our analysis points to cells that have never divided as the source of the latent reservoir.”
The HIV virus injects itself directly into the host cell’s genome, targeting CD4 T lymphocytes, a type of T cell involved in producing an immune response, and producing an active infection. If the virus fails to produce an infection, the drugs attack nothing and the infection is not visible.
More often than not, the virus manages to get part of itself into the T cell’s genome, leaving it incapable of replicating itself.
“If a patient stops taking antiretrovirals, the infection rebounds,” Cohn said. “It is truly amazing that the virus can give rise to AIDS 20 years after the initial infection.”
Researchers now think the pool of latent virus may be hiding out in a type of long-lived memory cells that help the immune system remember particular pathogens and go through clonal expansion.
Follow-up work performed by Mila Jankovic, a senior research associate in the lab, Cohn and her colleagues has examined cloned and unique CD4 T cells in blood samples from 13 HIV-infected people.
“Given the size of the human genome, it is highly unlikely the virus would insert itself in exactly the same place more than once,” Cohn said. “So if multiple cells contained virus with identical integration sites, we classified them as clones. Meanwhile, if a cell had a unique integration site, one not shared with any other cell, then we assumed that cell was unique.”
The researchers also tested 75 viral sequences taken from the expanded clones of cells to see if they could potentially produce more of the virus, and the result showed none could.
“While we cannot rule out the possibility that a rare clone of cells may contain an active virus, it appears most likely that latent reservoir — and the potential target for therapies meant to cure HIV — resides in the more rare single cells containing unique integrations,” Cohn said.