HIV has been transformed into a manageable disease through anti-retroviral therapy (ART) but most people are unaware they are infected for months or even years. And when infected people are not treated – or can only afford sub-optimal amounts of ART – they continue to spread the disease.
Even when patients have proper medical treatment, studies show they are at risk of accelerated ageing, suffering health complications associated with getting old up to 15 years earlier than normal. These include chronic liver disease, kidney disease, clogging of the arteries and dementia.
Because it is not possible to identify everybody infected with HIV – and because of the problems treated patients still suffer – developing an effective vaccine is urgently needed to halt its spread.
At NIBSC we carry out fundamental research to investigate how viruses can evade the immune system, spread infection throughout the body and cause disease.
The immune system is highly complex and efficiently identifies and destroys many pathogens through multiple mechanisms controlled by numerous networks of communication, many of which we do not fully understand or even know about.
Our group is working on research projects investigating the pathology of HIV, aimed at finding ways to eradicate HIV.
Investigating the progress of infection and disease within intact tissues allows us to examine events within a fully functional immune system – something we cannot replicate in any other way.
The techniques of immunohistochemistry (IHC) and in situ hybridisation (ISH) are used to look at infected tissues and locate the position of specific cell types, viral genes/proteins and molecular messengers.
Tissues of the immune system develop clearly distinct regions defined both by the cells they contain and their function. IHC and ISH show how infected cells move through these areas and how the immune system responds, sending chemical messengers to mobilise specialist immune cells to interact and respond to the infection.
This information helps us understand how HIV causes the disease symptoms it does and identifies potential immune pathways and interactions that could be stimulated by a vaccine or targeted by new anti-retroviral drugs. We also assess how effective current experimental vaccine strategies are in preventing infection or changing how the virus and immune system interact.
We have used tissue staining to explore the infection characteristics of live attenuated vaccines (LAVs). Infection with a weakened virus can prevent subsequent infection by a wild-type, disease-causing virus. But some wild-type challenge viruses bypass this protection and we have not yet identified any antibody, CD4+ or CD8+ T cell correlates of protection.
IHC and ISH have identified characteristic positioning of infected cells within specific tissue regions for many viral strains and, for wild-type viruses which cannot overcome the LAV protection, this pattern of infected cells matches that of the viral vaccine.
For a virus which can overcome LAV protection, the pattern of infected cells is clearly different to those infected by the vaccine. This raises the possibility that some component of LAV protection may be due to vaccine-infected cells inducing an antiviral state in their local tissue regions, protecting susceptible cells from an incoming wild-type infection.
Viral strains which can overcome LAV protection may infect cells outside this protected region, too far away to induce an antiviral state. Multiple staining to further characterise cells infected by either vaccine or wild-type viruses and induced local immune responses will allow this theory to be explored further.
HIV-infected patients suffering accelerated ageing are a growing concern. Many complications are clinically managed using current treatments, but this is not the case for HIV-associated neurocognitive impairment (HIV-NCI) and to date no experimental treatments have worked.
Understanding why and how HIV-NCI develops is a challenge, especially when trying to determine which effects are due to the virus and which may be due to side-effects of ART.
NIBSC investigates the pathology of HIV-NCI using virus strains that naturally mimic how HIV initially replicates and is subsequently controlled by drug therapy. Crucially, this pattern of viral replication occurs without the use of anti-retroviral drugs, allowing us to look at pathology caused only by the virus.
When viral levels in the blood are undetectable, low levels of viral replication still occur in lymphoid tissues and the brain – these are known as viral reservoirs. It is possible that ongoing reservoir replication drives the immune inflammatory responses thought to be responsible for accelerated ageing.
We have shown virus enters the brain within days of infection, immediately causing an inflammatory response that spreads and is then maintained throughout the brain, even when viral replication can no longer be detected within the blood – a pathology that is also seen in ART-treated patients.
This work demonstrates viral infection alone can cause HIV patients’ neuro-inflammation, the inflammation starts immediately, and continues even when viral replication is greatly reduced to levels seen in ART-treated patients.
We are investigating if improved ART will help or if drug treatment is too late once a person is infected.
NIBSC is investigating how much damage HIV infection causes before treatment starts and whether pathways triggered during this time can be stopped. We are leading the way in this research using a virus that only replicates if the antibiotic doxycycline is present. This allows us to switch replication off when we choose and see how disease pathology is altered months after the virus has been stopped.
This cutting-edge research has major relevance to the latest clinical treatments investigating functional cure which aims to eradicate all forms of HIV from the body. If this can be achieved, our work raises the possibility that eradicating HIV may not be enough to stop the many inflammatory pathology cascades already triggered before treatment and implicated in the further complications patients suffer.