T cells, such as this one, can be destroyed by an invading HIV army (red dots) that is transferred directly into the cell (Image: NIBSC/SPL)

It’s the world’s most studied virus, but HIV can still take us by surprise. It turns out that the virus can infect and kill immune cells by being pumped directly from one cell into another, during brief connections made between the two.

Until recently, we thought that HIV particles circulating in the blood were largely to blame for infecting and destroying crucial immune cells called CD4 T cells. According to this classic model, after a single virus has infected a T cell, it hijacks the cell’s machinery to build hundreds of copies of itself, which bud off into the blood and eventually wear out and kill the host cell.


This thinking was based on research using blood, a relatively easy way to study the virus. But work with newer tools suggests that this is only part of the story. Using tissue-culture methods, a team led by Warner Greene at the Gladstone Institutes in San Francisco, has shown that in fact large numbers of virus particles are often pumped directly from one CD4 T cell into another. And it seems that this process may kill the vast majority of CD4 cells – not infection by single viruses.

Blocking transmission

HIV armies storm neighbouring T cells by hijacking yet another cell system, the immunologic synapses. These are short-term connections between immune cells that allow them to send chemical messages between themselves, which HIV uses to flow from an infected CD4 cell to an uninfected one.

Evidence suggests that this process is hundreds, possibly thousands, of times more efficient than the traditional mode of external infection. Greene says that 95 per cent of the CD4 cells they studied died by this process, rather than from infection by free-floating particles.

This new understanding could open up ways to target the virus, as well as influencing what drugs we choose to treat the disease. Walther Mothes has been studying cell-to-cell HIV transmission at Yale University, and he says that although most antiretroviral drugs work against both forms of infection, the much higher efficiency of pumping viruses directly into a cell can overwhelm some of these drugs, making them less effective.

But the finding may open the way for new treatments. The monkey version of HIV can also be transmitted directly from cell to cell, but monkeys may be able to tolerate this process.

Unlike their human equivalents, monkey CD4 cells manage to survive being inundated with virus particles, and Greene thinks that they have evolved a way to avoid self-destructing. He hopes that anti-inflammatory drugs could be used to mimic this effect in human CD4 cells. One potential drug candidate, VX-765, looks promising in the lab.

Hunt for a vaccine

A better understanding of how the virus spreads directly between cells is probably an important part of the HIV puzzle, says Kenneth Mayer at the Fenway Institute in Boston. He suggests that neglecting to take this mode of transmission into account may at least partly explain the failure of recent vaccine research.

HIV vaccines would work by generating antibodies to fight the virus. But research suggests that different types of antibodies would be needed to kill viruses that are inside cells and viruses that are free-floating in the body. Viruses hiding out inside cells may be more likely to escape destruction, and could perhaps find it easier to evolve resistance to antibodies.

Carl Dieffenbach of the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, says that to better understand how to protect against cell infection, we need better vaccine candidates. “Is cell-to-cell transmission going to torpedo a vaccine? We don’t know the answer to this because we don’t have a safe, effective and durable HIV vaccine to understand the exact mechanisms,” he says.

Journal reference: Cell Reports, DOI: 10.1016/j.celrep.2015.08.011