“However, the recent advances in treatment and pathogenesis do warrant a close examination of the feasibility of eradicating HIV-1 from an infected person.”
As it turned out, the surprise was lurking in the same issue of Nature, which included a report by Robert Siliciano’s group at Johns Hopkins University School of Medicine in Baltimore that used a sophisticated assay to identify a reservoir of cells in which HIV infection was latent. Ho’s calculations had not included these cells. Siliciano’s measurements, however, would show not only that they were detectable in all HIV-infected people, regardless of the virus levels found in their blood, but that they were, by nature, extremely long-lived.
HIV selectively infects and destroys CD4s, a type of white blood cell called a T cell that coördinates immune attacks. The cells are so named because of the receptor, CD4, on their surfaces–one of two that HIV needs to start the infection process. Once the virus successfully docks on the CD4 cells, it unloads its RNA, which is transformed into viral DNA that weaves itself into the human chromosomes in the cell’s nucleus. In most cases, the virus makes millions of progeny within a day; they burst out of the infected cell, either killing it directly or marking it for destruction by the immune system. But in some CD4 cells, the viral DNA integrated into the chromosomes lies dormant.
Histones, proteins that keep DNA in tight coils, are modified by a process called acetylation, causing the viral DNA to unspool. Transcription factors are then able to bind, and viral proteins form. They assemble into new copies of HIV, which emerge from the cell.
The circumstances that cause this to happen are somewhat random, says Eric Verdin, a researcher into the molecular biology of HIV latency who is based at the Gladstone Institute of Immunology and Virology at the University of California, San Francisco. Perhaps the HIV has infected a CD4 cell that is in a “resting” phase of its life cycle, or perhaps the viral DNA has infiltrated an odd part of a chromosome that prevents its genes from operating. “Latency is not a biological property of the virus,” says Verdin. “HIV couldn’t care less whether it becomes latent.” When it does, however, the virus can effectively hide from the immune system–and from antiretroviral drugs. The trouble begins when a resting CD4 cell becomes active after infection or other events somehow activate the virus. Then this latent HIV can launch a new round of viral replication.
In 1999, Siliciano showed that a person on antiretrovirals who has otherwise undetectable viral levels in the blood will still harbor around a million latently infected cells. He calculates that it would take more than 50 years of fully suppressive treatment to clear these reservoirs as the latently infected cells slowly died or the dormant HIV came out of hiding on its own. Indeed, when the patients that Ho’s team was studying stopped taking their drugs after their infection had been suppressed for an average of 3.2 years, the virus quickly came back in all cases. Every other research group that tried this experiment had the same dispiriting results. By the turn of the millennium, it was clear that curing an HIV infection would require a new line of attack. Siliciano says, “It’s now well accepted that this latent reservoir is going to be a barrier to eradication, and that it’s extremely stable and it’s never going to decay significantly without specific interventions.”
Some scientists argued that HIV returned because the drugs were simply not keeping all of the active virus from copying itself, even in people whose infection was undetectable on standard tests–which can detect the virus if there are only 50 copies in a milliliter of blood. They speculated that a low level of viral replication was sufficient to refill the pool of latently infected cells faster than they could be eliminated. So in several studies these people received extra antiretrovirals, a strategy called intensification. “Absolutely nothing happens,” Siliciano says. “The level of virus doesn’t budge at all.”
Ho and others still believe that the current drugs may be able to fully suppress the virus. But the question has largely become academic, because no intensification effort has yet reduced latent infection in any significant way. Siliciano thinks people should stop expecting more from anti-HIV drugs. He says, “We’ve reached the theoretical limit.”
In the spring of 2006, Gero Hütter, an oncologist then working at the Charité Medical University in Berlin, saw a 40-year-old patient who had been on anti-HIV drugs for four years. The virus was undetectable in his blood, and his immune system was reasonably intact. But he had another,