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How HIV Hides in the Brain

HIV-positive people are particularly susceptible to the early onset of dementia.

HIV-positive people are particularly susceptible to the early onset of dementia. Credit: Mehau Kulyk/Science Photo Library

By Lachlan Gray

With the introduction of the latest drugs and treatments, infection with HIV no longer represents a death sentence. However, HIV-positive people are particularly susceptible to the early onset of dementia and several other conditions of ageing, such as cardiovascular disease, frailty, cancers and bone disease. New research has found that when the HIV virus gets into the brain, it infects a key cell type, the astrocyte, leading to its dysfunction. This, in turn, triggers the development of HIV dementia, and at the same time provides HIV with a hideout where it is protected from the immune system and antiviral drugs.

The human immunodeficiency virus (HIV) infects the cells of the immune system, rendering the body defenceless to opportunistic infections and cancers and ultimately leading to the development of acquired immunodeficiency syndrome (AIDS) and the death of the patient. HIV is a blood-borne virus, and is predominantly transmitted via the exchange of bodily fluids during sexual contact, sharing of contaminated needles, and during pregnancy and breastfeeding.

HIV/AIDS remains one of the world’s biggest health problems, affecting 33.4 million people worldwide in 2009, the vast majority of which are in low- and middle-income countries. HIV/AIDS is the world’s leading infectious killer, claiming more than 27 million lives, with an estimated two million deaths each year.

Medical research into HIV/AIDS has made many advances since HIV was identified as the causative agent of AIDS in 1981. Through this research we now understand a lot more about how the virus replicates and infects cells. These discoveries have enabled us to design antiviral drugs that target key processes in the HIV life cycle.

Despite the development of many successful antiviral drugs, drugs alone are unable to cure HIV. Additionally, all vaccine candidates to date have failed to provide protective immunity.

The major problem we face in designing an effective vaccine against HIV is its high mutation rate. When someone becomes infected with HIV they are infected with a “swarm” of viruses that differ slightly from one another due to genetic mutations. As a result the immune system must target millions of different viral particles, with each mutation detected as a different virus.

HIV’s tendency to mutate not only helps it avoid being destroyed by the immune system but also aids in the development of drug resistance. Therefore, combination antiretroviral therapy has been developed because it’s harder for the virus to develop resistance to three drugs than a single drug in isolation.

In the early era of the HIV epidemic, people contracting the virus were often given a death sentence and told they only had a maximum of 10 years to live. Today, patients in the developed world have access to life-saving antiretroviral drugs that, when used in combination as an antiviral cocktail, are able to effectively control viral replication. Antiviral therapy is now capable of delaying the onset of AIDS and may prevent the occurrence of AIDS entirely.

Unfortunately many people that require antiviral treatment are not receiving it. This is a major problem where the HIV epidemic is most pronounced, such as in Sub-Saharan Africa, which bears 50% of the global HIV burden.

Antiviral therapy has led to a partial restoration of life expectancy for HIV-infected individuals but fails to restore it to levels equivalent to the uninfected population. Importantly, due to the increased period of time that patients are living with HIV, we are now seeing a different face of HIV disease emerging.

Recent findings have highlighted a role for HIV in the premature ageing of infected individuals. Conditions such as heart disease, frailty, brittle bones and dementia are becoming increasingly common within the HIV community. Diseases that we would normally associated with a much older demographic are now occurring in HIV-infected individuals up to 20–30 years earlier than the general population.

In fact, HIV dementia is now the leading cause of dementia in people aged less than 40, and its prevalence is increasing. Current estimates suggest that 20% of HIV-infected individuals will develop HIV dementia, and this number increases to 50% when you include milder forms. HIV dementia often predicts an increased mortality rate, job loss, poor medication adherence and progression to more severe impairment.

HIV enters the brain early after the initial infection but usually doesn’t give rise to dementia until later in the disease’s course. HIV can infect a range of different cell types within the brain, although not all cell types there are capable of supporting the production of new viral particles. The brain’s astrocytes are infected by HIV but are not believed to support viral production.

Astrocytes serve an important function within the central nervous system (CNS), providing most of the supportive and maintenance requirements for all the other cell types. However, when astrocytes are infected by HIV they become dysfunctional and are unable to carry out their normal housekeeping roles. As a result, the neighbouring cells around these astrocytes start to behave abnormally or die off, which leads to clinical dementia.

Although infected astrocytes may not contribute to virus production within the CNS they clearly play a role in the development of dementia. HIV also uses astrocytes to hide from the host’s immune cells to avoid being killed, and can remain silent with little or no viral proteins produced.

Recent work at the Burnet Institute and Monash University has aimed to characterise the infection of astrocytes, focusing on how the virus becomes silent. We are interested in understanding how the virus replicates within the brain and the steps involved in the development of HIV dementia.

We believe we have identified the mechanism that leads to the non-productive infection of astrocytes. We’ve shown that viruses derived from the brain have dysfunctional production machinery, leading to little or no virus production.

In our study we analysed brain and non-brain tissue (blood, spleen and lymph node) taken from the autopsy samples of HIV dementia patients. We recovered the virus from these separate compartments to determine if there were any differences in their capacity to replicate.

When we analysed the region of the virus that is responsible for producing new viral particles we found that the viruses in the brain had reduced activity. This difference was only evident when the cells were in a resting state. The brain environment would normally exist in a resting state and only ever become activated if there was some sort of injury or infection within the brain. We believe this property of brain viruses will allow them to keep a low profile and persist undetected in the brain.

The brain is considered a privileged site within the body, with the entrance of cells and molecules tightly controlled. We know that immune surveillance of the brain is reduced compared to the rest of the body.

Similarly, the antiviral drugs used to treat HIV infection don’t efficiently gain access to the brain, with the majority being excluded. Therefore it appears that HIV prefers to hide in the brain where there is reduced immune surveillance and penetration of antiviral drugs. This suggests the virus has evolved this strategy to promote long-term survival and viral persistence.

Persistence of HIV in the brain also poses problems for the eradication of HIV in general. Modern drugs are very good at controlling the virus, but they are unable to eradicate it from “sanctuary” sites like the brain. The combination of HIV’s tendency to hide, reduced immune surveillance and reduced drug penetration allows the virus to replicate unopposed in the brain, eventually leading to the development of dementia.

These findings will allow the development of future therapies aimed at modulating the outcome of viral infection in astrocytes, and potentially lessen the incidence of HIV dementia. Furthermore, we believe that the same discovery can be used to assist current eradication strategies that aim to flush out any virus that is hiding in cells.

Ultimately, reducing the occurrence of HIV dementia will improve the quality of life for people living with HIV and also reduce the demand on community mental health services.

Lachlan Gray is a Postdoctoral Research Fellow at the Burnet Institute and Monash University.