December 14, 2011
Animal Studies Suggest Anti-Reservoir Drugs May Help 'Functionally Cure' HIV
Drugs targeting HIV reservoirs in the body may result in spontaneous control of viral replication, in the absence of antiretroviral (ARV) therapy, according to a new study involving 18 monkeys conducted by Andrea Savarino, MD, PhD, of the Istituto Superiore di Sanità in Rome and his colleagues. The new findings, among the most noteworthy at an HIV eradication conference recently held in St. Maarten, in the Caribbean, could prove highly useful as researchers continue exploring ways to functionally cure HIV infection.
Though much attention is being paid to efforts to achieve sterilizing HIV cures—those akin to what was achieved in Timothy Brown, the “Berlin Patient,” who underwent high-dose chemotherapy and two stem cell transplants to render his immune system impervious to HIV and essentially snuff the virus out completely—there are also proposed strategies to achieve functional HIV cures. With a functional cure, HIV remains detectable in the human body, but no viral replication is found in the absence of ARV therapy.
Typically, discontinuing ARV therapy leads to a rapid rebound in viral load, likely because HIV persists in a large number of long-lived cellular reservoirs in the body that are not affected by standard medications. Some researchers believe that the immune system does have the ability to keep viral replication in check, but that the high volume of HIV that returns following ARV treatment discontinuation quickly overwhelms the immune system. In turn, some scientific teams have been interested in pairing drugs that attack cellular reservoirs of HIV with standard ARV therapy, to see if they can blunt the proliferation of virus following treatment discontinuation and therefore provide the immune system with an opportunity to maintain control of the virus on its own.
Researchers such as David Margolis, MD, at the University of North Carolina in Chapel Hill are studying HIV reservoir-targeting therapies in human subjects. Meanwhile, there is much to be gained from exploring similar approaches in animal models, notably macaques infected with SIV, HIV’s simian counterpart.
The experiments conducted by Savarino and his colleagues involved 18 SIV-infected macaques receiving ARV therapy and, in some cases, drugs targeting long-lived SIV reservoirs. Five macaques in particular received ARV therapy in combination with auranofin—an approved medication, sold under the brand name Ridaura, used to treat rheumatoid arthritis and previously shown to be capable of killing memory CD4 cells (a major long-lived HIV reservoir)—and the glutathione synthesis inhibitor buthionine sulfoximine (BSO), which has been shown to help eliminate HIV-infected cells.
After a series of treatment cycles combining ARV therapy first with auranofin and then with BSO, extremely low viral “set points”—viral loads below 200 copies in the absence of treatment—were maintained for more than 100 days in three of the macaques.
“The change in viral load set point was positively correlated with the number of drugs potentially acting against the viral reservoir that the monkeys had received,” Savarino and his colleagues wrote in the study abstract, “thus suggesting that drugs acting against viral targets alone”—such as antiretrovirals—“are insufficient to induce viral load containment in the absence of therapy.
“The results of the present study,” the authors conclude, “show that anti-reservoir strategies may indeed result in spontaneous control of viral load in the chronic phase of the infection and pave the way to a functional cure for AIDS.”
Search: macaques, savarino, auranofin, ridaura, buthionine sulfoximine, BSO, HDAC, set point, functional cure
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