At the 19th
Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle last month there
were three main areas of discussion. Prevention and hepatitis C (which we cover
in News from CROI 2012 and in Full speed ahead to curing hepatitis C) were the first two.
The third hot topic was a
permanent cure for HIV. We covered the approaches being explored in Towards a cure for all in HTU 204, a year ago,
and followed with Matt Sharp’s account, in HTU 206,
of being a pioneer participant in a trial of one of the ideas being explored:
genetically altering people’s CD4 cells to make them resistant to HIV.
Many other avenues are
being explored. In symposia, poster presentations and a community-sponsored
meeting before the main conference, many of these were presented.
There are four key
approaches being explored. They are largely in early stages so predicting their
future importance is difficult, and an effective cure might need to combine
more than one:
- Eliminating the
‘sleeper’ cells that contain latent HIV.
low-level viral replication without drugs.
- Making cells
resistant to HIV.
Researchers were calling
the first approach ‘kick and kill’ at CROI. A small number of long-lived
‘reservoir’ cells in the body hold on to the instructions for making HIV in
their genetic cores. As soon as you stop taking the HIV drugs that inhibit
them, they start spewing out HIV again, which is why HIV infection is lifelong.
They also appear to maintain smouldering HIV replication even in the presence
of HIV therapy, which keeps the number of these cells constant.
The idea is to use drugs
that stimulate the reservoir cells to come out of hiding (‘kick’) and then
either hope the business of actively producing HIV will kill them and enable
non-infected cells to take over or to use special molecular missiles to pick
them off (‘kill’).
Several classes of drugs
are being investigated for their ability to do this. A generalised immune
activator could be highly toxic: you could both set off a lethal immune
over-reaction and end up seeding a new generation of cells with HIV. So you
need drugs that unblock the processes that suppress HIV reproduction by the
cells, without overstimulating them. One example is the cancer drug vorinostat,
which in one study1 involving five people produced an up-to-tenfold
increase in HIV expression within resting cells, despite their being on HIV
treatment, but did not cause HIV to enter the bloodstream.
Drugs like vorinostat are
like flooring the accelerator when it comes to HIV production within infected
cells; another approach is more like taking the brake off. A cellular protein
called PD-1 is responsible for keeping the HIV reservoir cells dormant and
antibodies can be devised that neutralise the keep-quiet message that PD-1
sends round the immune system.
The results are similar to
vorinostat, but with an added promising twist: it’s beginning to look as if
HIV-infected cells won’t die off by themselves but will only do so if viral
replication is accompanied by an increase in the CD8 cells that destroy
HIV-infected cells. In one monkey study2, giving previously
ART-treated animals anti-PD-1 antibodies not only produced an increase in HIV
production but also, while not increasing the number of anti-HIV CD8 cells, did
increase their sensitivity.
A research consortium has
been set up in the name of the late treatment activist Martin Delaney, and one
of the avenues it is exploring is the development of aptamers: these are ‘flag’
molecules that stick to specific cell-surface molecules. The idea is that if
you enticed HIV-infected cells out of hiding, you could inject aptamers at the
same time and these would stick to the cells’ markers of immune activation.
These would serve either as beacons for cell-killing drugs or contain cytotoxic
A therapeutic vaccination
that helps the body contain HIV replication has long been an unrealised
ambition in cure research. A team from the Norwegian company Bionor Pharma,
using a vaccine against the HIV p24 protein called Vacc-4x, produced a nearly
threefold decline in the ‘set point’ average viral load of a group of
participants taken off ART for a treatment interruption. Results like this have
been seen before, but HIV usually manages to mutate its way round the immune
response produced by the vaccine. However, a therapeutic vaccine could contain
viral replication in people where the number of reservoir cells had been
reduced to the bare minimum.
As well as scientific
barriers to overcome, there are practical ones. Cure researcher Steven Deeks
told the community symposium that, as there have been with HIV vaccine
research, mechanisms needed to be put in place that achieve sustained funding
for plausible but hard-to-achieve strategies, while also finding cash for
left-field approaches and serendipitous discovery. And since a cure will
probably combine several approaches, we need to start thinking now about ways
highly disparate academics, companies and government bodies could work together.
There may be many wrong
turns in cure research but at least we now believe it actually exists as a