by the new work is this: In HIV-infected people on powerful treatment that completely shuts down the production of new viruses, why don’t all of their infected cells disappear within a few years as the long-lived immune cells die off? One possibility is that some infected cells still produce new HIVs that manage to dodge antiretroviral drugs and infect virgin cells, constantly refilling the pool. Evidence suggests this occasionally occurs, particularly in tissue that drugs have difﬁculty reaching (Science, 23 December 2011, p. 1614), but many researchers doubt that it happens routinely. A more likely explanation, they believe, is that the infected
HIV Integration Sites on MKL2 Gene Patient 1
Selective advantage. An HIV-infected patient on long-term antiretrovirals has cells with the viral DNA repeatedly integrated in a small region of a cancer gene, but in a control experiment (bottom) the virus has no such preference.
meeting last year (Science, 8 March 2013, p. 1134). That child, now 3, also was started on antiretroviral drugs shortly after birth, but now has been off treatment for 23 months without any sign of the virus returning. In the new case, which made the front page of The New York Times, the 9-month-old child remains on treatment. “It’s premature to get excited,” says virologist Douglas Richman of the University of California, San Diego. One reason Richman and others are so cautious is that the AIDS virus is something like the proverbial cockroach that survives a nuclear blast. HIV can hide deep inside cells, weaving its DNA into human chromosomes, impervious to drugs and immune attack as long as it remains dormant. Pools of these latently infected cells, or reservoirs, can survive for decades and have become the bane of attempts to cure HIV infection. At the meeting, two studies detailed a novel mechanism that would help explain how reservoirs persist. The riddle addressed *Conference on Retroviruses and Opportunistic Infections, 3–6 March.
cells make copies of themselves, a cloning process known as homeostatic proliferation. The two new studies examined blood cells taken at different points in time from a total of eight HIV-infected people who had received antiretroviral treatment for up to 14 years. All told, the researchers determined the precise locations at which the HIV DNA had integrated in more than 2500 instances. When a person becomes infected with HIV, the virus makes billions of copies of itself that go on to infect new cells. In the genome of each new cell, the virus integrates its genetic material largely at random, with the result that viral DNA can be found at millions of different sites across the population of cells. But that’s not what the researchers found in their long-term patients. Clinical virologist Thor Wagner of the University of Washington (UW), Seattle, explained how in three of them, 40% of the integration sites were identical in two cells or more. That suggested that infected cells were duplicating themselves, keeping the viral DNA in its original integration site. “Homeostatic proliferation has been
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Published by AAAS
a theory for a long time,” says Wagner, who works with the well-known team of pediatrician Lisa Frenkel and virologist James Mullins. “We think this is the best proof yet that it occurs.” Anne-Mieke Vandamme, an epidemiological virologist at the Rega Institute for Medical Research in Leuven, Belgium, agrees, saying, “these were very, very exciting data.” A team led by Stephen Hughes, director of the National Cancer Institute’s HIV Drug Resistance Program in Frederick, Maryland, found roughly the same things in its five patients. “The integration sites we saw are not random,” Hughes says. Indeed, in one person, about half of the infected blood cells had HIV DNA integrated at the exact same place in the human DNA. A form of natural selection probably explains the dominance of a few integration sites. The researchers suggest that clones in the reservoir gain an evolutionary advantage if HIV has integrated in their genome at sites that speed up cell growth—a ﬁrst step toward cancer. Hughes’s group dramatically showed this with one patient who had 15 separate integrations in a relatively short stretch of one cancer gene (see illustration). Although a growing body of evidence reveals higher rates of cancers in HIV-infected people who receive long-term treatment, the causes have been difﬁcult to pin down because of the effects of age, antiretroviral drugs, and other confounding factors. “I would suspect that this may be linked to why people with HIV have more cancers, but we haven’t yet proven that,” says Frenkel, also of UW Seattle. Wagner says both groups’ ﬁndings call into question the “kick and kill” strategy that attempts to purge the reservoir. Several research groups are testing drugs that aim to kick the transcription process into gear and force latently infected cells to produce virus; the idea is that the infected cells will die as they release virus, while antiretrovirals will mop up the freed HIVs. Wagner, however, worries that kicking cells will simply crank up homeostatic proliferation. “I think you need strategies to directly target the infected cells,” he says. The cancer connection may hold a clue. Much cancer research today attempts to selectively eliminate cancer cells and not harm healthy ones, but applying that strategy to HIV is a tall order. “I don’t know what the solution is going to be,” Wagner says.
CREDIT: ADAPTED FROM STEPHEN HUGHES/NATIONAL CANCER INSTITUTE
BOSTON—Upbeat headlines from a major HIV/AIDS conference* here focused on an HIV-infected baby that started antiviral treatment 4 hours after birth and now has no detectable virus, raising hopes that it has been cured. But perhaps the most eyeopening ﬁnding at the meeting struck a cautionary note, revealing how HIV quietly persists in the body even when the infection appears to have been vanquished. That work also raises ominous questions about the risk of cancer in people on HIV drugs long-term. The celebrated infant, from Long Beach, California, mirrors the famous case of the “Mississippi baby” revealed at this same
Downloaded from www.sciencemag.org on March 16, 2014
Cancer Genes Help HIV Persist, Complicating Cure Efforts