Biomarker Opens New Door in HIV Cure Research

Molecule could be first step to eradicating virus ‘reservoir’

By: Michael Smith

North American Correspondent,

MedPage Today

March 16, 2017


For the first time, investigators have found a biomarker that identifies some cells latently infected with HIV.

The molecule, dubbed CD32a, is found on the surface of about half of the latently infected CD4-positive T cells, but not on uninfected cells or those with an active HIV infection, according to Monsef Benkirane, PhD, of the Institute of Human Genetics in Montpellier, France, and colleagues.

The findings, reported online in Nature, open a new door for research aimed at destroying the so-called HIV “reservoir” — the pool of cells that allows the virus to rebound when antiretroviral drugs are stopped.

“This is hot and important,” commented Sharon Lewin, MD, of the Doherty Institute in Melbourne, Australia, who has been a leader in the revived drive to find a cure for HIV infection.

“It will need to be confirmed by others but this indeed looks to be a good marker for latency,” she told MedPage Today. Lewin added that it’s not clear why the CD32a molecule marks the latently infected cells, but it “could be a ‘bystander’ for another functional marker.”

“Either way,” she said, “this work will open up many new avenues of important work and could potentially define new ideas for interventions.”

Like all viruses, HIV hijacks the cell’s own mechanisms to replicate and produce copies of itself, a process that in most cases kills the cell. But most experts now think some infected cells do not die; instead they go into a resting state with HIV integrated into their genome. (Another possibility is that HIV directly infects some resting cells.)

When those cells are reactivated for any reason, they begin the cycle of HIV replication all over again. That’s why, when antiretroviral drugs are stopped, HIV rapidly rebounds.

Many research groups have been working on a cure strategy dubbed “kick and kill” — activate the resting cells to kick the latent HIV into activity again and then kill it with antiretroviral drugs.

But that strategy has been hampered by an inability to find the reservoir cells efficiently, according to Douglas Richman, MD, of the Center for AIDS Research at the University of California San Diego.

In an accompanying News & Views article, Richman noted that when an HIV patient has suppressed the virus using drugs, only about one in a million CD4 cells are latently infected.

“Markers for these cells have been lacking,” he wrote.

To try to fill the gap, Benkirane and colleagues used their recent discovery of a way to generate large numbers of resting T cells without activating them. Then they compared latently infected cells with uninfected cells to see what, if any, host genes were differentially expressed.

All told, they found 103 genes that were up-regulated in the latently infected cells but not in the controls and, of those, 16 code for transmembrane proteins — molecules that might allow cell identification and sorting.

The most highly expressed gene, FCGR2A, encodes the protein CD32a, a receptor for a fragment of immunoglobulin G (IgG) antibodies.

In a series of experiments, Benkirane and colleagues showed that CD32a is expressed on the surface of resting HIV-infected T cells, but not on those with active infection or with no infection at all. If CD32a can be used to target the latent cells, it might be a step toward eradicating HIV reservoirs, they argued.

But, Richman noted, the finding immediately raises new questions. For instance, the CD32a marker is only found on about half of the resting cells, which implies that other markers will be needed to eradicate the reservoir.

It’s also not clear how targeting CD32a would affect other cells that use the molecule.

As well, the analyses used CD4 cells found in blood but such cells account for no more than 2% of the CD4 cells in the body: It’s an open question, Richman said, whether CD32a would mark latently infected cells in the lymph nodes, bone marrow, gut, and elsewhere.

Those are excellent questions, commented Steven Deeks, MD, of the University of California San Francisco, adding he and his colleagues, as well as other groups, will be trying to find some of the answers.

“This story is just the beginning,” Deeks told MedPage Today, but it is “a very big deal.”

filed under: HIV