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The road to a cure
We remain many years away from a cure that could be offered to the almost 37 million people living with HIV throughout the world. But, as Craig McClure and Darian Taylor report, in 2018, researchers will explore a number of approaches that might one day bring an end to the need for people with HIV to remain on lifelong treatment.
Finding a way to eliminate latent HIV reservoirs in people living with HIV is the Holy Grail of cure research. Many approaches now being tested towards finding an HIV cure involve either 'shocking and killing' (also known as 'kicking and killing') HIV-infected cells in latent reservoirs using latency-reversing therapies, or 'blocking and locking' those cells. Other approaches include ways to make cells resistant to infection, to remove their susceptibility to infection, or to use antibodies and other means to allow immune functions to work against the virus even without kicking or locking.
Understanding more about what is going on in the immune system in early HIV infection and how to create 'better' immune responses against HIV in people who are recently infected, is an important step in improving treatment for HIV, moving toward “sustained viral remission” without therapy, and creating a vaccine against HIV.
To date, little is known about the mechanisms of sustained HIV remission. It may be a delicate balance between using drugs early enough to keep the HIV reservoir small, but not so early that the immune system is not able to encounter enough HIV to develop a good memory response to be used if and when the virus rebounds.
Upcoming Thai clinical trials will hopefully answer the question of when to treat during acute HIV infection for the purposes of creating an effective immune response that will permit long periods of sustained viral remission. These clinical studies are designed to reduce viral reservoirs and increase immune control during hyper-acute HIV infection. Another study is also underway in South Africa. The results of these studies will strongly inform understanding about whether manipulation of viral reservoirs and immune responses during the earliest stages of viral infection does indeed translate into beneficial effects such as sustained HIV remission after the withdrawal of ART.
Gene therapy aims to identify genetic characteristics that help to naturally control the virus in some people living with HIV known as 'elite controllers' or 'long term non-progressors' and to develop mechanisms for transferring these genetic characteristics to others who do not have that ability. This strategy may have its limitations since elite controllers may still experience inflammation that enhances other disease risks.
One of the main targets for research in the field of gene therapy is the CCR5 receptor — a crucial entry point for HIV to infect healthy CD4 cells. This strategy is being researched in three different ways, all of which require the genetic alteration of immune cells. The first strategy, preventative in nature, aims to genetically edit cells to remove CCR5 so that HIV cannot infect them. A second strategy would enable immune cells to find and fight HIV more efficiently. The immune cells are genetically modified to better detect HIV-infected cells in latent reservoirs in the body. The third approach is the most complex, and involves removing or 'editing' HIV from the DNA of infected cells.
Gene therapy involves extracting immune cells from HIV-positive individuals and then genetically modifying them. There are many challenges in this area of cure research. It has been difficult to detect and extract resting white blood cells infected with HIV, i.e. one of the components of the latent HIV reservoir. Researchers are working on developing a method to deliver gene-editing technology directly into the body. The hope is that this approach will quickly spread modified genes through the whole body.
Learning from cancer
Immune checkpoints are molecules on the surface of cells that either 'turn up' or 'turn down' (accelerate or inhibit) the strength of a molecular signal sent by the immune system to disease- controlling cells. HIV infection — like many cancers— is able to disrupt the immune system’s efforts to prevent or minimise the effects of infection, by turning down the T-cell signal that tells the immune system to do its work. HIV-infected cells are particularly rich in these immune checkpoint receptors, as are cancer cells. Current research aims to develop drug therapies that target immune checkpoint receptors which prompt the cell to stop whatever immune job it is doing and revert to its latent state. A few drugs to target these molecules are already available to treat some forms of cancer.
From shock and kill to block and lock
The shock and kill HIV cure strategy, which proposes the use of latency-reversing drugs, has received attention in recent years. This cure strategy aims to flush (or shock, or kick) the virus out of latent reservoir cells into activity in the bloodstream using latency-reversing agents. Once the infected cells are activated, other drugs — perhaps a yet-to-be discovered therapeutic vaccine or antibody-based therapies which would harness the body’s own response to HIV — would then kill the HIV-infected active cells. The harnessed response might be sufficient even without flushing out the virus.
Some of the latency-reversing agents being considered are currently used as cancer treatments, although researchers are also trying to discover new drugs. One of the agents currently under investigation is called a Histone deacetylase (HDAC) inhibitor. However, repeated experiments with different HDACs have shown that they wake up reservoir cells and, although they are short-lived, no HDAC has been able to prevent new cells being ‘seeded’ with HIV and then returning to latency in a reservoir.
All of the above research will have implications for what we know about HIV prevention, HIV testing and diagnosis, the treatment of HIV with new therapies and, finally, a possible cure for HIV. People living with HIV and our allies need to learn more about what is happening along the road to the cure of HIV in order to determine how best we can contribute. Our perspectives are unique and important, and need to be heard in the development of strategies that might one day bring an end to the need for people living with HIV to remain on lifelong antiretroviral therapy.