Shock and Kill
Research unveils new info about latent HIV reservoirs, signaling a possible cure setback
by Jeannie Wraight
Amid several recent successes in the pursuit for an HIV cure, a new study from a leading HIV researcher reports a significant setback to the “shock and kill” strategy, a heavily researched and promising cure approach. Investigators ascertain this major blow may make finding a broad-based cure to HIV even more formidable then previously expected.
Dr. Robert Siliciano, a professor at the Johns Hopkins University School of Medicine and a Howard Hughes Medical Institute investigator, reported results of the sobering study published October 24 in the journal Cell. Dr. Siliciano and his research team found that latent HIV reservoirs, a major barrier to clearing HIV from the body, may be as much as 60-fold larger than previously thought. This presents a greater challenge to activating these reservoirs, part of the most sanctioned strategy being researched to eradicate HIV.
Scientists have long known that a major barrier to clearing HIV lies in penetrating viral reservoirs where HIV hides in resting CD4 cells and macrophages. HIV is either in an active or inactive state. When active, antiretroviral medications can eliminate HIV. But when inactive, in a resting state, HIV can lie dormant, untouchable by current anti-HIV drugs. Scientists hypothesize that if we can activate these dormant cells, drawing them into the reach of antiretroviral therapy or other specialized medications, that we may be able to eliminate HIV. For this approach to succeed, all latent cells must be activated.
HIV reservoirs are born from the immune system’s attempts to eliminate HIV. When the immune system encounters HIV, T-cells can rapidly multiply producing cells called effector cells, which seek to destroy the virus. After this immune response is complete, most of these cells die, but a small number revert back to a resting state where they will remain dormant until they encounter the same antigen and reactivate. Sometimes these cells are infected with HIV while they are in the process of transitioning back to a resting state. HIV inserts its genetic material into the DNA of the cell creating a provirus. The provirus then becomes inactive. When this happens these cells become part of the latent reservoir.
Scientists have collectively set their sights on these reservoirs with several projects designed to wake up these resting cells and kill them off. Two of the major problems of this strategy are finding drugs that can activate latently infected cells without harming uninfected cells and not knowing where or how much latently infected cells exist.
Proviruses in latent reservoirs are difficult to find and measure by current assays. Knowing the size of these reservoirs is vital to producing an effective strategy to eliminate them. Dr. Siliciano and his team developed a new technique that allowed them to activate provirus previously thought to be incapable of reactivating, allowing them to more accurately measure the size of the reservoir.
Researchers isolated provirus from 8 people with HIV and found that twelve percent of proviruses that had been believed to be defective were actually capable of activation and replication.
“Our study results certainly show that finding a cure for HIV disease is going to be much harder than we had thought and hoped for,” states Robert Siliciano.
Other methods of functional cures or HIV remissions have shown success in particular individuals over the past couple years. These successes have provided hope that researchers may find ways for more people to eventually discontinue or decrease the frequency of what is now lifelong antiretroviral therapy.
Other methods being researched in hopes of discovering a functional or eradication cure include viral host restrictive factors, monoclonal antibodies, macrophage clearance strategies, gene therapies, cell-based therapies, and therapeutic vaccines.
Although the recent research conducted by Dr. Siliciano is disheartening, hope of curing HIV remains alive and well. One lesson we should take away from this research is the need for funding to investigate a wide range of therapies and strategies. While research investigating the “shock and kill” approach has rightfully garnered much attention and its share of research dollars, other drugs and approaches continue to wait their turn to be adequately explored. Advocacy and activism for research dollars that can be directed to a wider array of potentially promising approaches is sorely needed and may help us get to the finish line quicker.
More Cure Resources:
The Reference Portal on HIV Reservoirs and Eradication Strategies (articles and thoughts from some of the great minds of HIV cure research): www.hiv-reservoir.net
Virochannel (HIV Conference coverage with video interviews, written reports and an online community to discuss new research):
PubMed.gov (Search HIV cure related abstracts. You will not be able to access the full abstract but can get a good idea of the study, methods and results): www.ncbi.nlm.nih.gov/pubmed/?term=hiv+cure
Jeannie Wraight is the editor-in-chief and co-founder of HIV and HCV Haven (www.hivhaven.com) and a blogger and writer for TheBody.com. She is a member of the Board of Directors of Health People, a community-based organization in the South Bronx and an advisor to TRW (Teach me to Read and Write), a community-based organization in Kampala, Uganda. She lives with her husband in the Bronx, New York.