What are the Mechanisms of HIV Latency and Persistence?
The government has an extensive plan for conducting AIDS research, but finding a cure is not part of it.
By Bob Huff
Two of the great quests in science are to develop a vaccine to prevent HIV infection and a treatment to cure it.
The 200-page National Institutes of Health (NIH) Plan for HIV-Related Research* for 2010 sets out the U.S. government’s priority areas for AIDS research and serves as a road map to coordinate its investment in AIDS science. The plan establishes two major priorities for NIH AIDS research: the prevention of HIV transmission and the prevention and treatment of HIVassociated illnesses and coinfections.
A glance at the plan makes it clear that finding a vaccine is a key goal of the NIH AIDS science effort. This is certainly justified given the enormous impact that a preventive vaccine would have on the course of the epidemic. However, if you search for mention of a cure, you will come up short. Attempting to eradicate HIV infection is not a priority, an objective, or even a strategy mentioned in the NIH plan. This gap in the national research effort raises a troubling question: How likely are we to find a cure for AIDS if it is not on the official road map?
One reason why curing HIV infection receives insufficient attention from the scientific establishment is because it seems like an extraordinarily difficult—perhaps impossible—goal to achieve; research money tends to flow to problems that people believe can be solved.
There are two issues that will make curing HIV infection so tough. The first is that HIV inserts its DNA into the DNA of an infected person’s immune cells, and in some of these cells, the viral genes go to sleep, giving no sign they are there until they are activated at some future point. This is called latency. Because modern antiretroviral (ARV) drugs can effectively prevent circulating virus particles from infecting fresh cells, latency on its own wouldn’t be such a problem if all of the infected cells died off fairly quickly (cells that actively produce virus tend to self-destruct after a short while; uninfected and latently infected cells survive longer). But some of the infected immune cells go into a “resting state” of dormancy, and may stay that way for ten years or longer. Others may divide and give rise to fresh daughter cells that carry a latent copy of HIV. This means that HIV infection is persistent.
Because HIV can establish a persistent and latent infection in very long-lived resting immune cells, a reservoir of HIV is created within the body that could take decades to disappear—and that’s if the reservoir was never replenished by virus that managed to escape the antiretroviral drugs. One of the lingering questions for scientists is whether reservoirs are replenished by active viral replication or not. In any event, if the drugs are stopped before the reservoir is fully depleted, then HIV will likely resume infecting new cells, and levels of virus in the body will surge.
The investigation of HIV latency and persistence does not appear in the short list of topics that the NIH says will receive the highest priority under its plan for HIV research. Only a few lines in the plan call for studying factors that enable HIV to establish a persistent infection or for understanding the reservoirs that permit HIV persistence. It’s no wonder that scientists who apply for funding to study HIV latency are so often turned down: the term does not appear in the NIH plan.
There are many good reasons to be skeptical about the chances for actually curing HIV. The mechanisms that permit latency are still not fully understood, and there are competing theories for how the viral genes are silenced in certain cells. In fact, there are likely multiple mechanisms at work, which means that any single approach to a cure could be insufficient.
In brief, the main theoretical strategies for eliminating HIV from the body involve:
- waking up every single latently infected cell in the reservoir then letting each die off—all while keeping any new cells from becoming infected
- finding a way to identify latently infected cells then specifically killing them
- sending molecular robots into cells to search for HIV DNA sequences then deleting or scrambling them
The last of these strategies is the sci-fi approach and (despite a recent report**) may not be possible for many decades. Identifying latently infected cells and killing them sounds ideal, but how to do it remains a puzzle since, by definition, such cells look exactly like uninfected cells. Thus, a strategy of waking up the cells of the latent reservoir and getting them to start making HIV copies seems like a plausible first step. Once awake, the infected cells would self-destruct or be eliminated by the immune system; antiretroviral drugs would protect new cells from becoming infected; and, theoretically, the body would soon be free of HIV. This approach is thought of as “purging the reservoir” and a few early, though so far unsuccessful, trials have been attempted in people.
Research into how the reservoir of latently infected cells can be flushed out is proceeding slowly in a few laboratories around the world. Support from the NIH is needed to invigorate this research and put finding a cure for AIDS back on the map.
* * Sarkar I, Hauber I, Hauber J, Buchholz F. HIV-1 proviral DNA excision using an evolved recombinase. Science. 2007 Jun 29;316(5833):1912-5.