When we understand how HIV replicates despite drug therapy, then we can stop it

The last two decades has seen great advances in the treatment of human immunodeficiency virus (HIV). Therapy can now be tailored to the patient, ensuring patients’ bodies can tolerate it and making the drugs extremely effective.

Those diagnosed with HIV before the virus has caused significant damage to their immune system can now expect to live long and healthy lives, similar even to those of people without the infection. This is simply an amazing success story for modern medicine. So what’s stopping us from eradicating the virus altogether?

HIV infects white blood cells called CD4 T-lymphocytes, important immune cells that protect the body against infections and cancers. Without treatment, HIV makes new copies of itself within each infected cell – new viruses that then leave the CD4 cells and infect new cells, starting the process over again. Eventually the loss of CD4 cells and damage to the immune defences are so severe that disease develops.

Treatment stops HIV production within the CD4 cells, preventing damage to the immune system and further progression of the disease. This works very well – provided the anti-HIV drugs are continuously present in the body. This means medication must be taken regularly and without missing doses for therapy to remain successful.

From left to right: a red blood cell, a platelet and a T-lymphocyte, pictured using a scanning electron micrograph.NCI-Frederick

HIV is a stealthy opponent

A preferable solution would be to eradicate HIV and cure the infection once and for all. However current HIV therapy, while remarkably successful in stopping virus production, cannot cure the infection and must therefore be carried out throughout a patient’s life. For those who are diagnosed with HIV in their thirties, this currently means around 40 years of uninterrupted daily therapy.

We have long understood that during treatment the HIV virus hides inside the CD4 T-lymphocytes, by inserting, or “integrating”, its own genetic information into the DNA of the CD4 cells. The integrated virus is invisible to both drugs and immune defences, and as soon as therapy is interrupted it fuels new virus production.

Research, such as my recent study, shows that the integrated HIV “reservoir” in the CD4 cells doesn’t diminish during treatment – even over a period of 14 years.

Why is the HIV reservoir so stable, even when the virus isn’t replicating itself during therapy and any integrated virus is expected to die with the host CD4 cell when it dies naturally? Understanding this is key to finding a cure for HIV.

How does HIV survive therapy?

We are making progress. The mechanism is relatively simple: whenever something stimulates the CD4 cells to multiply, any integrated HIV will also be split across the new cells with the rest of the cell DNA, a sort of silent HIV growth that does not require the cells to actually produce and release new viruses. So whenever a CD4 cell multiplies to produce more cells, it copies itself and the HIV at the same time, automatically incorporating the HIV at the birth of the new cell.

My research provides more evidence for this view, by showing that the amount of integrated HIV in CD4 cells is not a product of active virus replication. Instead, it’s associated with the body’s natural immune response, which stimulates CD4 T-lymphocytes to multiply – carrying the virus with them.

Finding a cure

In recent years there have been serious efforts from academia and pharmaceutical companies to find a way to eradicate HIV infection. One strategy is to stimulate immune cells in such a way that they are better able to fight the virus. However this study’s findings cast doubts on this strategy: stimulating the immune system may simply cause CD4 T-lymphocytes to multiply, expanding the virus reservoir as they do so.

Other strategies appear more promising: they aim to gently stimulate CD4 cells in such a way that active HIV production is started, so that the virus is recognised by both the drugs and the body’s natural immune responses, or perhaps by infusion of antibodies, and is killed off. This “kick and kill” strategy is currently being tested both in the laboratory and in clinical trials, and initial results are encouraging.

HIV is a clever virus, and clever strategies will be required to eradicate it – but recent research findings offer hope that a HIV cure may one day be possible.

Anna Maria Geretti receives funding for the work described from the European AIDS Treatment Network (NEAT) and the British HIV Association (BHIVA). She is affiliated with the Governing Board and is Secretary of the European AIDS Clinical Society (EACS).