Why is HIV incurable?

virus-1913183_1920This is something that’s come up often as I talk to people about my Honours project. “Why can’t we cure HIV?” It’s been around since the 50s, although it was only identified in 1983.

What’s going on?

HIV lifecycle

HIV lifecycle: At stage 4, the virus implants its DNA into ours. If a CD4+ T cell reverts to a resting memory state at this point, a latent viral reservoir is established. Credit: NIAID, licensed under Creative Commons

Early on during infection, HIV establishes something called the latent reservoir. What’s that? That is the reason we can’t cure HIV.

During the HIV lifecycle, the virus implants into the immune cells’ DNA prior to replication. These immune cells are the CD4+ T cells. If an infected CD4+ T cell survives long enough, it reverts back to a resting memory state – with the virus implanted in its DNA. And so the latent reservoir is established.

These memory T cells persist indefinitely. So even when it can’t be detected in the blood anymore, HIV-positive people still have the virus in their system – stored in their DNA, and thus unaffected by ARVs and immune responses. If a memory T cell becomes activated again due to an econcounter with an antigen (foreign body, eg: bacteria), latency may be reversed, and the virus becomes active again. So if the person stops ARV treatment, the virus will raise its head again, leading to full-blown AIDS.

So why don’t we have a vaccine yet?

I hear you – then we should have a vaccine so that people never get HIV at all. But unfortunately it’s not that simple. In order to create a vaccine, you need to be able to infect people with a weakened form of a virus, and that weakened virus must have the ability to induce the immune system to make neutralising antibodies. These antibodies usually appear at 12 weeks after HIV infection. The special thing about neutralising antibodies is that they can inactivate the virus.

BUT – and here’s the thing – HIV is a rapidly evolving virus. It constantly mutates during replication to create new variants… Which cannot be neutralised by the antibodies that are currently being produced. So the body creates new neutralising antibodies against the resistant forms, but HIV has already evolved another resistant form. This means that even if you can come up with a weakened form of virus for a vaccination, the elicited antibody will only be effective for a small percentage of the viral population, and the rest will persist.

There have been numerous failed vaccine trials, but scientists gain a greater understanding with each trial, and are getting closer and closer to being able to design an effective vaccine.

So, what’s the way forward?

In terms of latency, scientists are currently working on a way to “shock and kill” the virus – this means that they shock it out of the latent state, and kill it with ARVs. They have had moderate success so far.

As for vaccination, there are 2 vaccine trials currently under way:

As a followup to the RV144 Thailand vaccine trial, which showed a modest 31% increase in protection from HIV, a similar trial is being carried out in southern Africa. Since Sub-Saharan Africa holds 70% of the world’s HIV-positive population, a vaccine specifically tailored to the subtype C HIV that occurs here would be a really big deal.

In the second, a new kind of neutralising antibody, which can neutralise multiple variants of the virus, is being used for a non-traditional vacccine trial, in which antibodies are directly administered . These antibodies are called broadly neutralising antibodies, due to their broad neutralisation breadth across different HIV variants.

So, hopefully in the near future, we’ll see an HIV-free world.

References

HPTN & HVTN, AMP Study | About AMP. Available at: http://ampstudy.org/about

Morris, L. et al., 2015. Gearing up to test active and passive immunization for HIV prevention. Communicable Diseases Surveillance Bulletin, 13(4), pp.117–118. Available at: http://www.nicd.ac.za/assets/files/HIV Passive immunization.pdf

Rerks-Ngarm, S. et al., 2009. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. The New England journal of medicine, 361(23), pp.2209–20. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa0908492 doi: 10.1056/NEJMoa0908492

Siliciano, R.F. & Greene, W.C., 2011. HIV latency. Cold Spring Harbor perspectives in medicine, 1(1), p.a007096. Available at: http://perspectivesinmedicine.cshlp.org/content/1/1/a007096.abstract doi: 10.1101/cshperspect.a007096

Smith, M., 2016. “Shock and kill” strategy reduces virus reservoir during treatment. Available at: http://hivcure.com.au/2016/02/24/2679/

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