July 26, 2012
Steven Deeks, Daniel Kuritzkes, and David Margolis (photo: Deborah W. Campos).
Three research teams have shared promising findings in the search for a cure this week at AIDS 2012. "I think today might be considered the day when the cure research agenda moves from the basic science lab into the clinic," said Steven Deeks of the University of California, San Francisco, in a press conference on Thursday.
Harvard University's Daniel Kuritzkes described two HIV-positive individuals who underwent bone marrow stem cell transplants for the treatment of lymphoma (a type of cancer). The procedure was similar to the one that appears to have cured "Berlin Patient" Timothy Brown, but with a couple of key differences.
First, unlike in Brown's case, the transplanted cells did not come from a donor with the genetic mutation (known as CCR5-delta-32) that renders immune system cells resistant to HIV. (While any such transplant is still an arduous and expensive procedure, at least these didn't rely on finding a bone marrow donor who is both a good match for the recipient and a carrier of a rare genetic mutation.) Second, both individuals received a milder form of pre-transplant chemotherapy than did Brown, which allowed them to continue taking their antiretroviral therapy during the transplant period, Kuritzkes explained.
Although both had detectable HIV immediately following their transplants, over time the transplanted donor cells replaced the two individuals' HIV-infected immune system cells. Nearly two years later for one individual and three and a half years later for the other, sensitive tests have detected no traces of the virus in their blood plasma or CD4 cells. Levels of antibodies to HIV have also significantly declined, as would be expected with fewer copies of the virus in the body.
These individuals' new immune system cells are fully susceptible to HIV, said Kuritzkes, but his research team believes that the transplanted cells escaped HIV infection because antiretroviral therapy was maintained before, during, and after the transplant -- "a form of PrEP at the cellular level," Kuritzkes said. These data "provide another piece of the puzzle as we continue our work towards a cure that will be generalizable and applicable to HIV patients worldwide."
David Margolis of The University of North Carolina at Chapel Hill presented data on the use of the chemotherapy drug vorinostat to reach reservoirs of hidden HIV in "latently infected" CD4 cells. Ordinarily, HIV-invaded cells are killed by other immune system cells whose job is to snuff out infected cells in the body. CD4 cells that are inactive or "resting," however, are essentially invisible to the rest of the immune system, which allows these viral reservoirs to last for years. In addition, the HIV hiding out in these latently infected cells is not replicating (making new copies of itself); because currently available antiretrovirals only work by interrupting various stages in the replication process, the drugs are harmless to the non-replicating cells in these reservoirs.
In Margolis' study, eight HIV-positive people took a single dose of vorinostat in addition to their HIV meds. When the researchers then checked the individuals' resting CD4 cell populations, they found that signs of hidden virus increased significantly following administration of vorinostat, suggesting that this drug is able to "force the virus out into the open" where it can be targeted by antiretroviral drugs and other therapies. "The next steps that need to be done in the field," Margolis concluded, "are to understand how this can be done repeatedly and completely effectively with all the reservoir cells in the body, completely prevent infection of new cells, and perhaps also find ways to rapidly and efficiently kill or clear these infected cells."
In a third promising study, described by Asier Saez-Ciron of France's Pasteur Institute, researchers assessed whether early antiretroviral therapy might be employed to mimic the ability of some people -- nicknamed "elite controllers" -- to keep their HIV in check without treatment.
Saez-Ciron and his colleagues have to date identified 20 individuals in France whose HIV remained suppressed even after they stopped antiretroviral therapy; 14 of them are taking part in what's been dubbed the Visconti study. "The most interesting characteristic in all these 14 patients is that they were treated very early after their infection," said Saez-Ciron; the median (most common) timeframe was 40 days after acquiring the virus. After taking HIV meds for a median of three years, these individuals have now spent a median of seven years off treatment.
The researchers discovered that, like elite controllers, members of the Visconti cohort have small viral reservoirs that are decreasing over time, even without HIV treatment. "Very interestingly," said Saez-Ciron, "in patients in the Visconti study, the larger contribution of cells in the viral reservoir is cells that are shorter-lived" rather than the usual long-lasting cells, leading to a gradual decrease in the viral reservoir as the cells die off.
Following this clue, the researchers studied a broader sample of individuals to see how frequently this arrangement appears. Their preliminary work has found that between 5% and 15% of people who started HIV treatment very early and who stayed on treatment for at least 12 months are benefiting from the same arrangement of short- and long-lived cells in their viral reservoirs.
As Steven Deeks observed in his introduction to the press conference, this essentially represents a "functional cure" -- a cure that does not eradicate HIV from the body yet allows the virus to be suppressed without medication and without the risk of progression to AIDS.
All three studies, Deeks said, "provide reason for enthusiasm that ultimately we're going to get to where we need to go, which is a way to cure people with HIV infection."
No comments have been made.
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