To cure HIV, attack the reservoir

CALTECH (US) — Chronic infectious diseases like HIV survive by forming reservoirs. These small populations of a bacterium or virus persist despite attacks from the immune system or drug treatment.

While these reservoirs are not always well understood, researchers believe they have begun to decode how a reservoir of infection can persist in HIV-positive populations.  They propose that a type of HIV infection that uses infected cells to get close to uninfected cells and then discharge a large load of virus on them, may be the reason small populations of HIV-infected cells hang in even when antiretroviral drug treatment has been successful in suppressing most other infections.

For chronic infections such as HIV, the end game for scientists is to remove “chronic” from the disease’s name—by finding a cure. Many believe better understanding of viral reservoirs may be the key to eradicating them, and thus the disease.

So for the current study, published in the journal Nature, researchers led by David Baltimore, professor of biology at California Institute of Technology (Caltech) started at the beginning of the process, looking for clues into how an HIV reservoir is formed in the first place.

There are two known ways that HIV can infect cells, and the human body: cell-free transmission, in which the virus infects immune system cells called T cells it encounters while floating free in plasma; and cell-to-cell transmission, in which the virus moves between T cells by using an infected donor cell as its vehicle.

Once an uninfected target cell is found, the donor cell can then directionally discharge its viral load upon the target. To replicate both types of transmission, the team infected target cells using both cell-free HIV and previously infected donor cells.

They used donor cells that lack a natural marker, HLA-A2, usually used in matching human organ donors to recipients. The target cells did have the marker, and this helped the scientists keep track of which cells were the donors and which were the targets. The target cells were infected either in the absence or in the presence of antiretroviral drugs.

What the researchers found was that while the antiretroviral drugs caused a steep drop in the number of newly infected cells infected via cell-free transmission, the decrease in the number of newly infected cells for the cell-to-cell infected T cells was much more moderate, even when they had large doses of the drugs thrown at them.

“We saw that with cell-to-cell infection, you wind up with a lot more virus infecting a single cell,” says lead author Alex Sigal, a postdoctoral scholar. “When this happens, the chance of at least a single virus getting past the drugs is much larger.”

This may explain why, while antiretroviral drugs work very well, they don’t eradicate the infection completely. The drugs are probabilistic by nature, meaning that they don’t kill 100 percent of the virus.

So, as the number of transmitted viruses gets larger, the chance of at least one virus slipping by the drugs and infecting another cell becomes greater. “And you only need one virus to infect a cell and keep the cycle going, forming a reservoir of infection,”  Sigal says.

Another possibility for why HIV cannot be eradicated is that it goes into latency. A latent reservoir would consist of cells that contain the HIV virus in their DNA, but are not currently making any virus and therefore are not affected by drugs. Sigal says it’s possible that both types of reservoirs are present and interact with each other.

“It’s important to determine whether or not cell-to-cell replication is causing a reservoir, particularly in terms of finding a cure,” he says. “You can’t treat it the same way as you would a latent reservoir.”

Theoretically, virus in a latent reservoir could be eradicated by flushing out the virus from the cells by activating it, and treating the patient with a lot of drugs at the same time so that the released virus can’t enter new cells. This would not work if the virus could get into new cells anyway, despite the drugs.

“For us, the next step is to look at the process on a more physiological level by looking at how HIV infects in organs such as lymph nodes where cell-to-cell transmission actually happens,” says Sigal.

“We’re really looking for a cure, but to get to a cure, you have to fully understand the disease first,” he says.

The research was supported by the National Institutes of Allergy and Infectious Diseases and the Bill & Melinda Gates Foundation.

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