Luis J. Montaner DVM, D.Phil, of the Wistar Institute in Philadelphia, Pennsylvania has been studying the effects of interferon on HIV DNA and its ability to reduce the size of HIV viral reservoirs for several years. The current understanding of HIV cure research is dedicated to the idea that viral reservoirs are the main barrier to eradicating HIV or producing HIV remission.
In February of 2014, The National Institutes of Health granted Montaner’s lab a four-year, $6.2 million grant to conduct a multi-site trial to investigate interferon. The study will be the largest clinical trial of a potential cure strategy to date, and continues earlier research of interferon that showed promising results.
Interferon is a protein naturally produced by cells when a microbe, such as a virus or bacteria, is detected. Interferon belongs to a group of proteins called cytokines. Cytokines are messenger proteins that help cells to communicate between each other. Interferon up=regulates defense host mechanisms designed to protect the cell from viral infection and activates immune cells, such as natural killer cells and macrophages. Early on in the HIV pandemic before antiretroviral use, pegylated interferon was investigated as a means of controlling the virus and delaying disease progression. Although there was some effect when used in patients who were antiretroviral-naive, interferon was not pursued as soon as ART was available. The idea of studying it again with ART is to see if interferon can eliminate HIV by activating anti-viral mechanisms newly recovered due to ART.
Montaner explained in a presentation at ID Week in San Diego, California, this past October 2015, that the production of interferon is an early immune response. It is triggered by the presence of microbes (in this case HIV) to produce a response that attempts to overpower the virus, creating pressure to prevent uninfected cells from becoming infected. Interferon-mediated cells interact with at least nine points during viral replication including reverse transcription, integration, packaging and budding of the virus from the cell, providing numerous targets to potentially reduce the amount of virus being produced. When a cell is infected with HIV, the virus produces its own countermeasures against interferon, but by boosting interferon and its ability to make more uninfected cells resistant to any incoming HIV, it may be possible to slow the production of HIV and reduce the number of infected cells.
In 2013 results were published from a study that Montaner conducted using pegylated interferon (PegIntron) to determine if individuals with suppressed viral loads could stop taking their antiretrovirals for a period of time with the help of weekly injections of interferon. The study, although small, produced very intriguing results.
Twenty virally suppressed study participants with high CD4 counts were given interferon in addition to their ARV regimens for five weeks, after which the ARVs were discontinued and participants continued weekly injections of interferon as a monotherapy. At week 12, almost half of the study participants maintained viral loads under 400 copies. Given the option to conclude the study or continue taking interferon while remaining off ARVs, nine individuals elected to stay on interferon for a full twenty-four weeks. Of the nine, seven maintained viral loads below 400 copies for the course of the study. Surprisingly, aside from viral load, when the amount of HIV inside cells was measured, it was lower than before they started interferon. This would indicate that the interferon decreased the size of viral reservoirs. Despite these results, some of the participants did not respond to interferon for reasons not yet known.
Three separate studies performed by researchers studying interferon in HIV/HCV co-infected individuals, also noted a decrease in HIV, adding further weight to Montaner’s study.
A second study was conducted by Montaner’s lab using interferon alpha IIb which was completed in August. This study enrolled twenty individuals, out of which seventeen completed the study. Much of the data has not yet been released but what we do know so far that a decrease in HIV RNA was seen in rectal tissue in about half of the participants. Interferon was said to be relatively well tolerated by study participants.
Montaner’s lab is currently enrolling the NIH-funded study mentioned at the beginning of this article. It is a Phase II clinical trial that will be conducted at three sites in Philadelphia. The study will measure the extent of decrease in integrated HIV proviral DNA in the blood and tissues with the use of pegylated interferon alpha-2b with or without a period of interferon monotherapy after an interruption of ART. This will determine if the size of viral reservoirs are decreased and if interferon should potentially be further studied as part of a combination cure strategy.
by Jeannie Wraight
For more information on the study and its sites, please log on to: www.clinicaltrials.gov/ct2/show/NCT02227277.