Where is the HIV vaccine?

03 December 2017
Posted by Johnson Mak.

Where is the HIV vaccine? It is a fair question, is it not?

We have been told that our smart phones are millions of times faster than NASA’s computers back in the 60s’, which put humans on the moon. With improvements in the quality of our healthcare system and our rising social economic status, the average life expectancy at birth has steadily increased by 20 years compared with people born half a century ago. Surely, with all these advances, we can control this virus, can we not?

It’s been over 35 years since the first index case of AIDS was described and more than 30 years since HIV was discovered. Yet, with all our advanced technologies, how come we still cannot control or eradicate this tiny virus whose genetic makeup represents only 0.0003 % the size of our own genome?

Why is the HIV problem such a tough nut to crack?
A key issue is that HIV attacks cells called CD4 T lymphocytes, which sit at the very core of our immune systems. Without them we are immunological sitting ducks, almost powerless to defend ourselves against infection and disease. What’s also a challenge is that HIV doesn’t do this all at once. The process happens relatively slowly as the virus resorts to a combination of subterfuge, disguise and an error-prone nature, first to establish a successful infection, and then to remain hidden from the immune system as it systematically destroys it. It’s the eventual breakdown of the immune system, when the numbers of CD4 T cells fall below a critical threshold, that gives rise to AIDS – acquired immunodeficiency syndrome. At this point, the body becomes powerless to fend off even trivial infections that would normally be dismissed as mere microbial irritants. These eventually overwhelm the body and kill the individual.

When HIV first infects, more than half of the CD4+ T cells that normally reside in the gut are destroyed. This is particularly important, because these cells represent our largest population of lymphoid cells in the body. Such a massive hit on our immune system by HIV makes it much easier for the virus to establish its first foothold in the body, and it further weakens our ability to eliminate HIV and other infectious and opportunistic diseases.


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HIV particles budding from an infected cell

HIV is also able to run amok within the body because it is a master of disguise. The virus coats itself with sugar molecules, masking its true identity and reducing the chances of the particles being recognised and attacked by other parts of the immune system. This hampers the formation of neutralising antibodies that could otherwise help to tip the balance and eradicate the infection.

Another covert trick employed by HIV - and other members of the retroviral family to which it belongs - is the capacity to insert its genetic material into our DNA genomes. This allows the virus to enter a state called latency and invisibly "lie low". It can remain lurking like this for up to a decade or more, consisting of nothing more than a molecular passenger, hiding from the immune system as a short sequence of genetic code sequestered within our own DNA. Critically though, it can re-emerge from this dormant state and use the instructions written into its genetic sequence to generate a whole new clutch of HIV particles. This often happens when a patient stops taking anti-retroviral treatment.

Also in the HIV virulence armoury is the tendency of the virus to mutate its genetic code as it grows and multiplies. This happens regularly and rapidly and it occurs because the enzymes used by HIV to copy its genetic information frequently make genetic spelling mistakes. Roughly one in every ten thousand genetic letters is copied incorrectly. This introduces enormous diversity into the growing virus population, allowing it to continually change its appearance and create a moving target that is difficult for the immune system to keep up with.

Nevertheless, the immune system is not completely defenceless in the face of an assault by HIV. After a few years, a small number of patients can begin to produce antibodies in their blood called “broadly neutralising” antibodies. These antibodies are very effective at controlling the virus. In experimental animals they can completely block new HIV infections, so these antibodies are now being investigated as potential therapies for treating humans exposed recently to HIV. But the word “recent” is critical, because what these broadly neutralising antibodies cannot do is to clear the latent reservoir of HIV that builds up once the virus establishes itself within a patient’s body so a patient who makes them remains HIV infected. Nevertheless, the fact that the immune system does sometimes appear to be able to produce antibodies capable of stopping HIV in its tracks means that scientists are optimistic that the creation of an anti-HIV vaccine is a realistic prospect. But first we have to discover how to defeat the other tricks wielded by HIV, and how to produce a vaccine that can provoke an uninfected individual to produce broadly neutralising antibodies, and this has been a sticking point for many years.

Anti-retroviral drugs
In the meantime, we live in a world where we have instant access to information. Internet and smartphone technologies have fundamentally changed how we operate as a society. With such easy access of information and answers, it is not difficult to imagine how our own expectations could let us down. It is sometimes difficult for us to recollect that discoveries take time and money to develop. For example, the time and cost required to turn a laboratory discovery into a new pharmaceutical product takes 10 - 15 years and more than $2 billion dollars.

Luckily, HIV is one sector of medicine in which the translation of basic scientific research into clinical medicines has been extremely successful. Consequently, the repertoire of pharmaceuticals available to doctors to help them to manage HIV infection is extensive. Our understanding of how the virus evolves and changes in the face of a patient’s immune response and exposure to anti-HIV medicines means that we now routinely use several combinations of different anti-retroviral drug targeting different aspects of the virus’s life cycle to effectively treat and manage HIV.

PrEP
These same drugs are now becoming available for use as pre-exposure prophylaxis (PrEP) in people who do not have HIV but are at high risk of HIV infection. Recent clinical studies show that, when PrEP is taken daily, it is highly effective at preventing HIV. However, these drugs are costly, they need to be taken daily and they do have side effects, which can be unpleasant. The practice also raises the possibility of multi-drug resistant viruses developing as a result of complacency, missing dosages, diluting the effective drug dose, or patients being unable to access high quality drugs consistently. There are already cases of HIV drug resistance being observed in people commencing treatment having a strain of HIV that was resistant to some of the most commonly used HIV medicines. This has the potential to undermine the global progress made towards treating HIV and need for next generation HIV drugs and vaccines.

Importantly, we should be reminded that activism in response to the HIV epidemic and the demand for improved treatments was continuously driven by factors related to social injustice more so than from understanding the biology of this virus known as HIV. Gender equality, resource distribution, and embracing diversity were some of the key principles that brought us together to achieve such a positive impact towards controlling the HIV epidemic. Such actions from all of us will undoubtedly create a better world regardless of the time it may take for scientists to discover a vaccine or cure for HIV.

Great strides have been made in HIV research, and HIV infected patients can now live long relatively normal lives provided they have access to an adequate supply of anti-retroviral drugs to control the virus. Major efforts are in place by the global community to ensure anti-retroviral drugs are becoming readily available to patients in low- to middle-income countries. As our colleague, Andrew Lever (University of Cambridge), eloquently pointed out in his commentary, it is now becoming more of an expectation that we must exercise our responsibility as global citizens to care for all our brothers and sisters, and perhaps this is the one silver lining we should take pride in when we celebrate and remember on World AIDS Day.

It is essential that vigorous efforts from our scientists and clinicians are maintained to allow us to gain a better understanding of this tiny virus despite pressure from shrinking research budgets. It is also important to acknowledge that much of our current understanding and success came from the combined efforts of HIV support groups and activists, scientists and clinicians working together for a common goal. Let us not lose this window of opportunity to eradicate HIV.

 

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