Although anti-HIV drugs can significantly prolong life, patients must take the drugs for the rest of their lives. New approaches to therapeutics may hold the answer to finding a cure for HIV.

The bottom line is 60 million immune systems have had a crack at eradicating HIV and all have failed.

Andrew Lever

It was in Los Angeles in 1981 that the first report emerged of an unusual cluster of patients whose immune systems appeared to have failed. This report is now acknowledged as the first scientific account of an infectious disease that was to become the HIV/AIDS global epidemic, infecting 60 million people and killing 25 million to date

Three decades later, and with more than 20 antiretroviral drugs to combat HIV, treatment can now significantly prolong life and reduce the rate of viral transmission. For some patients, life expectancy with uninterrupted treatment is now similar to that of someone who is not infected with HIV – not the death sentence it once was – and the global rate of new infections is at last declining.

Yet, current therapies do not fully restore health and, in resource-poor settings, patients often lack access to antiretroviral drugs. Moreover, because the virus has the ability to insert its genetic material into the genetic material of the patient’s cells, ‘latent’ viruses can re-emerge at any point, necessitating lifelong drug treatment.

“There is no imminent prospect of a vaccine, and there may not be one in the way that we have for measles and mumps, where our own immune system can clear the virus,” explained Andrew Lever, Professor of Infectious Diseases in the Department of Medicine and Honorary Consultant Physician at Addenbrooke’s Hospital. “The bottom line is 60 million immune systems have had a crack at eradicating HIV and all have failed.”

The virus is both adaptable and versatile, escaping drug treatment by mutating the structure of its proteins. Patients require combinations of drugs – an approach known as highly active antiretroviral therapy (HAART) – because this reduces the chance that a virus will mutate sufficiently to escape all.

Continued research efforts are therefore urgently required, as Lever explained: “The big areas in HIV research are finding new drugs to complement the ones we’ve got already, so as to outrun the virus in terms of resistance, and finding a means to eradicate the latent virus.”

Lever’s research, which has been investigating the mechanisms of HIV infection for almost 25 years, is helping to tackle both of these challenges.

Structural traps

Anti-HIV drugs typically target viral proteins that are involved in the process of entering or exiting the cell. But, as Lever explained, this lies at the heart of resistance to the virus: “Proteins are very adaptable. Time and again the virus escapes the drug by altering its protein structure so that it still functions but the drug no longer recognises it. We decided instead to target the virus’ RNA genetic material.”

Lever’s previous studies had provided fundamental insights into the way in which RNA is packaged, a process that he realised could provide a remarkable opportunity for a completely new type of antiretroviral therapeutic.

For the virus RNA to be packaged and released from the cell as an intact virus particle, it must twist itself into a three-dimensional knot-like structure. It was this structure which Lever and colleagues discovered is used as a packaging signal by the virus. To form the structure, the sequence of the RNA must be highly conserved between viruses. As a result, opportunities for ‘escape mutation’ are limited. A virus protein called Gag uses the knot-like structure to pick out the viral RNA from the thousands of cellular RNAs that are an integral part of the process by which a cell translates the information in its DNA into molecules that enable the cell to function.

Interfering with Gag binding can potentially stop the virus spreading from cell to cell. In collaboration with Professor Shankar Balasubramanian and Dr Neil Bell in the Department of Chemistry, and researchers at the University of Sussex, Lever is now using this phenomenon as the basis for designing novel antiviral drugs. In parallel, work with Professor David Klenerman in the Department of Chemistry is providing the first high-resolution data on the precise conformation of the RNA structure.

The goal is to create a ‘structural trap’ in which small-molecule drugs lock the RNA in a conformation that can no longer interact properly with Gag. Targeting the function of RNA through its 3D structure is a new direction for antiviral drug discovery, and sufficiently challenging to receive funding from the Medical Research Council Milstein Fund – specifically intended for ‘high-risk, high-reward’ studies.

Using an assay they developed for measuring the interaction between Gag and RNA, the team is now screening a library of small drug-like molecules for those with potential to interfere with the process. “Although it’s very early stages, the molecular hypothesis that we started with for targeting this structure has taken us to a situation where we have molecules that look like they are doing something interesting in the assay,” said Balasubramanian. “Being able to target RNA in this way would be a paradigm shift in terms of new therapeutics for HIV, and other infectious diseases.”

Will RNA-directed therapeutics overcome viral resistance? “It’s a good question and untested,” added Balasubramanian. “Once we find a good small molecule that disrupts binding and packaging then we can address exactly this question.”

Curing HIV

Drug discovery is a key area for the future. However, the scientists also have their eyes on an even bigger prize – a cure for HIV – and a new collaboration between five UK Biomedical Research Centres (BRCs) is now working towards understanding how to rid the body of latent virus.

“Because latent virus exists only as genetic material, essentially indistinguishable from the genetic material of the patient’s cells, it’s effectively hidden. The patient’s immune system can’t see these infected cells and the drugs can’t target them,” explained Lever. “The reservoir of infection sits there for years because it’s in very long-lived immune cells. Even if you suppress the virus right down using drug treatment, as soon as you stop the drugs it bounces right back with viruses that, based on their genetic sequence, are historically very old, so these have been latent for a long time.”

The new project, CHERUB (Collaborative HIV Eradication of Viral Reservoirs: UK BRC), funded by the National Institute for Health Research, brings together researchers from Imperial College, King’s College Biobank, University of Cambridge, University College London and University of Oxford, and is the first pan-BRC cooperative project to compete internationally in a new field of biomedical research.

Lever leads the Cambridge contribution along with Dr Mark Wills and Dr Axel Fun from the Department of Medicine. “Until we learn how to eradicate the latent virus then all we can do is contain it,” Lever explained. “CHERUB will work in collaboration with NHS Trusts and the pharmaceutical industry to recruit new patient cohorts for studies that range from fundamental laboratory research through to large-scale clinical trials of novel agents.”

The Cambridge researchers will develop an assay to detect latent virus that will be used to provide a measure of the relative success of drugs, as well as expand current research areas to learn new ways to rouse the virus from its latency.

“All HIV patients have latent virus – it’s a fact of life,” added Lever. “You can suppress active viruses with current conventional drugs so that the patient’s immune system recovers but you can’t get rid of the latent virus. The aim now is to suppress the virus to the point where the immune system recovers but at the same time to wake up and eradicate the virus from the latently infected cells. And then we are talking about a cure.”

For more information, please contact Louise Walsh at the University of Cambridge Office of External Affairs and Communications.

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