Anti-HIV drug falters

Posted Dec 21, 2014 by Tim Sandle
Scientists have reported that compounds that they hoped would "wake up" dormant reservoirs of HIV inside immune system T cells, allowing them to be destroyed by targeted medications, have not been successful.
Scanning electron micrograph of HIV-1 budding (in green)
Scanning electron micrograph of HIV-1 budding (in green)
C. Goldsmith / Centers for Disease Control and Prevention
The aim of the research is to devise a strategy to reverse latency with the cells containing the virus and therefore make the cells vulnerable to destruction. The research has been conducted at the Johns Hopkins University School of Medicine and the Howard Hughes Medical Institute.
For some months the science group has been undertaking laboratory tests of HIV infected white blood cells. The cells were taken from patients infected with HIV.
The reason that the research was undertaken was based on the concept that while inactive, dormant HIV can lurk inside T cells but it does not replicate in the amounts needed to produce proteins that can be recognized by the immune system. Without that recognition, the immune system cannot eliminate the remaining HIV from the body. T cells or T lymphocytes are a type of lymphocyte (itself a type of white blood cell) that play a central role in cell-mediated immunity. They are called T cells because they mature in the thymus.
Another problem is that current treatment with antiretroviral drug regimens known as HAART (highly active antiretroviral therapy) does not target the dormant HIV. HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death.
Researchers are aware that these tiny reservoirs of HIV can be rekindled if a patient stops taking medication, a phenomenon that has proven to be the major barrier to a cure. The dormant virus is found in roughly one of every million white blood cells in someone with HIV.
Laboratory studies had suggested that with latent HIV-infected cells certain compounds, mostly a group of drugs called HDAC inhibitors, might reverse the latency and awaken the infected cells just enough to make them vulnerable to eradication. These inhibitors affect the genetic operation of viruses and have also been used in drugs that treat cancer and some neurological disorders.
What scientists hoped would happen is that by reactivating the very few remaining HIV reservoirs, while HAART is in use, the infected cells could be eliminated. At the same time, the HAART treatment would prevent any new cells from becoming infected. Therefore, if all of the cells with latent HIV could be eliminated, then anti-HIV drug therapy could be safely stopped and the infection essentially cured.
For the new study, the research team used a process called leukapheresis. In cancer treatment, leukapheresis may be performed to decrease a very high white blood cell count (this is because very high numbers of leukaemia cells in the blood may cause problems with normal circulation).
With this process, a patient with HIV is hooked to a machine. The machine then functions to remove the blood and separate out the red and white blood cells. The device then returns only the red blood cells to the body. By this method, the team collected a large enough sample of lymphocytes with latent HIV reservoirs to test the different inhibitors on the actual cells.
At this stage, the researchers set out to compare various latency-reversing agents against one another on these patient-derived cells to see which one was best at turning on the virus. Unfortunately none of these substances (inhibitors) proved to be successful.
The failure to reawaken the HIV-infected cells challenges the scientific notion that a single so-called latency-reversing agent can uncover the HIV hiding out in the cells of patients whose viral load is essentially undetectable with blood tests.
Commenting on the studies, Robert F. Siliciano, M.D., Ph.D., a professor of medicine at the Johns Hopkins University notes in a research brief: “Despite our high hopes, none of the compounds we tested in HIV-infected cells taken directly from patients activated the latent virus.”
Although the studies on the inhibitors were unsuccessful, the researchers have indicated that their experiments have led them to develop more sensitive assays to test for reactivation of the virus. The research has also led to a benchmark by which future successes with perhaps other compounds or combinations of therapies: If a T cell is activated in an HIV-infected person, that cell produces virus at the maximum level, essentially the equivalent of a 100-fold increase in viral RNA production. For the next phase, the researchers aim to study some of the drugs in combination using patient-derived cells. It could be that the sum is greater than the parts.
The outcome of the trial has been reported to the journal Nature Medicine. The research paper is titled “New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo”.