A number of other approaches were described by presenters. There
was the idea of activating the long-lived, latently infected cells in the
‘reservoir’ of HIV with the
HDAC inhibitors, cancer drugs like panobinostat, in the hope that the
immune system would then ‘see’ them and kill them off. Unfortunately, although
the cancer drugs certainly seem to flush some of the HIV-infected T-memory
cells out of hiding, these cells are deficient in the signal molecules that
alert the immune system to their presence, so are not easily picked off.
One of the most interesting presentations was by Stephen
Mason of drug company Bristol-Myers Squibb on drugs designed to block the
action of a cellular signalling molecule called PD-1. This is already a target
for cancer drugs.
‘PD’ stands for ‘programmed death’: this alarming-sounding
name is due to the fact that PD-1 receptor molecules accumulate on the surface
of activated T-lymphocytes as they mature and, after a certain point, cells with
abundant PD-1 on their surface show ‘anergy’: they no longer respond to
antigens (foreign substances) and eventually die. A PD-1 blocker could revive
and extend the life of the exhausted HIV-specific CD8 cells that seem to be an
important part of the immune response in many ‘controllers’, people who manage
to control their viral load without antiretroviral therapy (ART).
But PD-1 has a dual role. In regulatory CD8 cells, which are
at an earlier stage of the CD8-cell life cycle, it promotes rather than
suppresses their activity. What these cells do is to stop the immune system
over-reacting to foreign substances. In the case of HIV, it is a crucial step
in the development of latency: the phenomenon whereby HIV-infected cells stop
actively producing virus and become quiescent, thus establishing the long-lived
‘reservoir’ of HIV-infected cells.
A PD-1 blocker could in theory aid a cure in two ways.
Firstly it could prevent the reservoir of latent cells developing in the first
place. It could therefore have a role in treatment in early infection or, like
HDAC inhibitors, reverse the latency of the long-lasting reservoir cells.
Secondly, it could maintain a functional population of activated HIV-specific
T-cells that could pick off activated reservoir cells.
Experiments in monkeys not taking ART had demonstrated that
PD-1 blockers could produce a temporary dip in viral load and that whereas four out of five monkeys given an inactive antibody died within four
months of receiving it, four given a monoclonal antibody against PD-1 were all
alive five months after their injections.
Mason showed the results of experiments with a
monoclonal-antibody PD-1 blocker, BMS 936559, in eight monkeys that were
receiving ART but that were taken off it after receiving the anti-PD-1 drug.
Results were interestingly mixed. Two of the eight showed no response at all
with their viral load rebounding to pre-ART levels. Two showed an initial viral
rebound but then a slow drop in viral load from about 100,000 copies/ml to
around a thousand. In two more, viral load stayed at approximately a thousand
copies/ml after treatment was interrupted. And in the final two, viral load
stayed undetectable for more than two months and then rebounded to levels of 50
to 500 copies/ml.
In all but two of the monkeys given anti-PD-1, but not those given a control antibody, there was no increase in integrated
viral DNA within immune cells in the blood or gut, an important sign that the
PD-1 inhibitor might have been helping to prevent the ‘re-seeding’ of the viral
reservoir. Mason commented that the antibodies used in these experiments were
originally adapted from human antibodies and might not be the ideal ones for
monkeys: potentially, results in humans may be better.
He also showed experiments in mice that showed that a
therapeutic vaccine and a PD-1 inhibitor could complement each other, bringing
the viral load in these genetically ‘humanised’ mice down to undetectable