|Courtesy of Roberto Borea|
To test that hypothesis, a team led by Robert Siliciano, professor of medicine at the Johns Hopkins University School of Medicine, began a longitudinal study of HIV patients to investigate the decay rate of these hidden reservoirs. If the reservoirs emptied in an average of, say five years, that might herald a cure. Unfortunately, the news wasn't good. As reported in this paper, they found that the half-life of the reservoir was 44 months, and they estimated that it would take 60 years of therapy to eliminate it entirely. They performed the study by isolating CD4+ T cells from peripheral blood and then growing them in conditions that encouraged the production of new viral particles.
The results conflicted with earlier studies in which researchers predicted the reservoir's complete eradication within two to three years.3 But those researchers were looking at a drop in viral levels that probably was caused by either a less stable form of HIV DNA in T cells or the turnover of infected macrophages. "We had a hypothesis that the virus was persisting in resting T cells. That population really wasn't detected very well in the initial studies," says Siliciano.
The team reported data for patients up to three years, and the scientists now have collected data out to five years. The decay is essentially nonexistent. "Statistically, we can't say the slope of the decline is any different than zero," explains Siliciano. "We're pretty confident that we're talking about a lifetime [of therapy] to get rid of these cells. It will not be possible with the current treatment."
The long latency might be a reflection of the immune system's intrinsic biology. The resting cells are memory cells. "Their job is to wait until you are exposed to an antigen you were previously exposed to. What it looks like to us is that HIV has taken advantage of the most fundamental aspect of the immune system, [which] is its capacity to respond to previously encountered infections. Resting T cells turn off most of their genes, except what they need to recognize an antigen. It's a perfect cell for HIV to hide in," says Siliciano.
It is also possible that this interlude isn't really a latent infection, and that low-level viral replication is going on throughout the treatment, which counteracts the decay, says Siliciano. "The implication in terms of treatment is that the latent reservoir is an archive of all the previously circulating forms of the virus, so if patients are treated incorrectly and develop resistance mutations, those drug-resistant viruses will enter a latent state and persist for years, even when the patient is not being exposed to the drugs. Once you have resistance to a drug, you never get rid of that resistant form."
Since their paper was published, the researchers have continued to look for latently infected cell decay. "What we see is that they don't decay at all-we're at five years now. We've been determining the mechanism of latency, and it appears that it is a true latency; there is no HIV gene expression that we can see," says Siliciano.
If low levels of viral replication are maintaining the viral load, Siliciano reasons, there should be some change in the genetic composition of HIV particles. "We don't see any change over time," he says. An absolute verification that memory T cells are carrying the virus will be difficult to find. "That's a very hard thing to do. I don't know if we'll ever be able to prove it in vivo."
1. R.M. Gulick et al., "Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy," New England Journal of Medicine (NEJM), 337:734-9, 1997. (Cited 614 times)
2. S.M. Hammer et al., "A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less," AIDS Clinical Trials Group 320 Study Team, NEJM, 337:725-33, 1997. (Cited 806 times)
3. A.S. Perelson et al., "Decay characteristics of HIV-1-infected compartments during combination therapy." Nature, 387:188-91, 1997. (Cited 337 times)