Geleziunas of Gilead Sciences told the symposium that the lesson of the Boston
patients, and of reservoir-purging drugs
like panobinostat that ‘kick’ HIV out of hiding, is that these are unlikely to
be sufficient to drive the virus out of the system or produce a functional cure
(long-term control of HIV without drugs) by themselves. They would have to be
combined with therapies that either delivered targeted toxins to cells (‘kill’)
or use a therapeutic vaccine to actively patrol the body and pick off the
remaining HIV-infected cells (‘contain’).
talked about a number of research directions Gilead and other companies are
first is an improved reservoir-purging drug called romidepsin. Like the HDAC
inhibitor drugs (panobinostat and relatives), it works by freeing immune system
cells from an enzyme that stops genes being active, but works in a
different way and produces a much longer burst of activity – 48 hours or more,
compared with six hours with panobinostat. This could give the immune system a
longer window in which to detect activated, HIV-producing cells and kill them,
but it could also be toxic; like the HDAC inhibitor, romidepsin is used as a
cancer therapy, and can cause a short-lived but general cytopenia (immune
suppression), though the doses used will be lower than those for cancer.
therapeutic vaccine may be needed to contain HIV infection by picking off the
remaining HIV-infected cells as they activate, but, Dr Geleziunas commented,
they have not worked as HIV treatments in themselves. This is generally because
the immune response they stimulate is ‘too little too late’. HIV has generally
already evolved to cope with the response they produce.
from last year unveiled at the 2013 AIDS Vaccine conference, however, were exciting,
said Geleziunas, a cytomegalovirus (CMV)-based vaccine given to monkeys
particularly so, not just because it appeared to produce a functional cure in
50% of the monkeys it was given to (though it is still a mystery why the other
50% did not respond) but also because it produced an immune response of a
breadth and persistence never seen before.
new generation of experiments in monkeys will look at the CMV vaccine as a
therapeutic rather than preventive vaccine, by giving it to monkeys after infection with the monkey
equivalent of HIV rather than before it, to see if it can contain a mature
infection. This vaccine will need cautious safety testing, because it involves
a life-long infection, albeit one by a virus engineered to be harmless.
reason therapeutic vaccines may not have worked is because the cells they
stimulate are unable to enter the parts of the immune system – the sanctuaries
in the lymph nodes – where HIV-infected immune cells differentiate and mature.
this reason, a therapeutic vaccine, as well as stimulating an anti-HIV T-cell
response, may need to contain an antibody component. Geleziunas talked about an
interesting set of experiments involving an antibody called PGT121 which is the
most broadly neutralising antibody yet seen, preventing HIV replication of 98%
of strains of HIV. In one experiment, administration of PGT121 to 21 monkeys
produced transient viral undetectability in all of them, but in three monkeys –
the ones with the lowest initial viral loads – the virus did not return, also
producing what looks like a functional cure.
is a mystery why administering an antibody, which only remains in the
body for 2 to 3 weeks, may produce a long-term effect.
of the reason may be that the antibodies stimulate another kind of immune
response called antibody-dependent cellular cytotoxicity (ADCC). In this, they
alert different branches of the immune system than those alerted by cellular
vaccines have an Achilles heel in that they respond to bits of virus displayed
on the surface of immune cells, so-called epitopes, and many people’s immune
cells only have a limited ability to do this, and one that HIV can adapt to. A
new class of so-called ‘bispecific’ antibodies have been found, that respond
directly to viral surface proteins and then directly go to immune CD8 cells and
stimulate them; this should in theory generate a faster and broader immune response.
‘short cuts’ are being tested. One is a class of drugs called TLR agonists,
which aim to generate an immune response
by switching on a stronger response not in T-cells but in dendritic cells, the
cells that carry HIV from the body’s surface into its bloodstream. These, in turn, sensitise immune cells, in a chain reaction. Gilead is testing an
orally dosed TLR agonist called GS9620 in HIV-negative volunteers.
there is a type of protein called PD-1, which switches on the mechanism that
leads immune cells to shut off and become quiescent and therefore invisible to
the immune system. Antibodies that block PD-1 or its cellular receptor could,
if dosed carefully, stop HIV-infected cells from joining the invisible and
inaccessible ‘reservoir’ of occult infection in the first place.
was some criticism at the cure symposium that some of these approaches are not
being pursued fast enough. Cure research, though, may be tricky, as the price
of failure may be at least to ‘re-seed’ the reservoir, turning a
slowly progressing infection into a faster one; and manipulating the immune
system can have unexpected adverse consequences. It is looking as if a cure may
be a complex and multi-stage matter for patients – especially people with
chronic infection – but many different approaches are being tried.
This news report is also available in Russian.