Pre-CROI HIV Cure Review Workshop Organized by Community Advocates- Meeting NotesNelson Vergel
itself but rather at the surrounding
workshops. This seemed to be the case this year. Before the official opening of
the Retrovirus Conference, American activists organized a cure workshop.
Among the 60 or so participants there were even some high-profile researchers
and FDA employees underlining the quality of this workshop.
Trials Group (ACTG) in the field of the cure, this being meanwhile the focus
of the work of this study network. He emphasized the importance of asking the
right questions first:
suppressed by intensification?
drugs (functional cure)?
methodically and what to measure.
patients recruited, further 40 patients identified as suitable)
groups (acute / chronic infected, elite controller, blipper, patients failing
therapy / resuppressing)
viral decay is much faster with Raltegravir-containing regimens, the pecularities of
this combination should be looked at.
recruiting, so far no tolerability issues)
is not being resorbed and therefore active only in the gut). Can the microbial
translocation and the resulting systemic inflammation be mitigated? Also the
influence on the reservoirs is to be studied.
forced out of latency with antibodies against the PD1-receptor and start
producing virus. This study is still in concept phase.
also acts as HDAC-inhibitor that can activate latent cells but isn‘t mutagenic
in the Ames test as other drugs of this class) on the reservoirs: concept
(or lack of)
therapies will have to compete with established ART which is generally well
tolerated and harbors usually only minor risks.
gave an overview of his company‘s activities in this area.
of latency with high numbers of samples at the same time. Already several new
drugs have been discovered that can wake cells from latency. One of these,
GSI-002 has the advantage of not being mutagenic and not activating T-cells
itself. Some other compounds they found have such unbelievable names as “Thapsigargin“ or “Tyrphostin A“.
to the production of type-1 interferons (IFN alpha/beta). GS-9620 is a
TLR7-agonist that has been shown to lower RNA and viral antigen production in
several animal models. In a next step they will look whether this drug can play
a role in eliminating HIV-infected cells. The mechanism of HIV latency needs to
be understood still more fully and new drugs need to be discovered that play a
role in or can interfere with this process.
method of his company to knock out the gene for the CCR5-receptor with sequence
specific zinc finger nucleases. This leads to CD4-cells that are immune against
infection with CCR5-tropic HIV. Unfortunately, they didn‘t show any new data.
The procedure seemed to have worked exceptionally well in one patient, who is
heterozygous for the Δ32-mutation, i.e. he has only one functional CCR5-gene
per cell. Therefore, the next studies will recruit preferentally such patients.
Furthermore, the procedure will be adapted for stem cells. The problem is, that
the introduction of the zinc finger nuclease into the cells also triggers the
differentiation process and the cells wouldn‘t be stem cells any more.
Sometimes the devil is lurking in the details… Good news is, that the
procedure has been automated, so more patients can be treated which facilitates
with only 19 employees presented a very interesting approach: They changed
certain highly conservated regions of the p24 protein in a way that makes it
much more effectively recognized by human immune cells. For some time it was
already known that infected people with a strong immune response against p24
have a slower disease progression. In order to further strengthen the vaccine
response, they use their product called Vacc-4x together with GM-CSF (a growth
factor for granulocytes/macrophages). Four primary and booster immunizations in
40 patients led to 92% showing a immune response with good tolerability. In
another study patients were immunized while on ART, then there was a 10 week
waiting period to allow the immune system to calm down and finally ART was
stopped. In all patients the viral load rebounded upon interruption, but the
vaccinated patients reached a new setpoint that was about 0,4 log lower (i.e. average
viral load 20.000 cp/ml instead of 60.000). They hope to further lower the
setpoint with more round of vaccination. In addition they try to improve the
immune response with immune modulators like lenalidomide.
antibodies against the C5-region of gp120 cannot neutralize the virus, but they
still lead to a slower disease progression. This is probably because the
complex of C5 and gp41 bears some similiarity with the human HLA-complex and can
hyperactivate the immune system. Antibodies can block this hyperactivation and
so slow down the disease progression. In animal trials it was possible to
produce antibodies with the Vacc-C5 vaccine. Trials in humans are planned. Both
approaches together would make use of the cellular as well as the humoral arm
of the immune system and such a combined approach could be an important step on
the way to a cure. The main problem right now is money because studies are
expensive and a small company like Bionor is heavily dependent on investors.
state of stem cell research in the area of HIV. It was a stem cell transplant
that led to the cure of the “Berlin patient” and brought cure research back on
the scientific agenda of the HIV researcher. But it is still unknown which
factors were important for this experiment to succeed. Some researchers think
that the graft-vs.-host-reaction, which almost killed the patient, was crucial
– in addition to the radiation and the intense chemotherapy. So far, there is
no second “Berlin patient”, probably because the combination of the right
tissue antigens and the CCR5-Mutation is rather rare. That‘s why they try to
introduce the required CCR5-mutation artifically in bone marrow cells of
donors. Another possibility to get stem cells is cord blod from newborns. But
again here is the problem of the rare occurence of a CCR5-Mutation so there are
plans to found a blood bank of cord blood with CCR5-Mutation. Alltogether the
field of stem cell therapy is still in it‘s infancy. In patients who don‘t need
a stem cell transplant for medical reasons (i.e. lymphoma), the risks are still
too high. This method has only a chance for broader use when there will be new
developments making radiation and chemotherapy unnecessary.
Apart from collaboration with Sangamon in the field of zinc finger nuclease
(see above), the group also tries to increase the CD8-mediated killing of
HIV-infected cells by providing the CD8s with a new T-cell-receptor that can
recognize HIV much better than it‘s natural counterpart. Clinical studies
including 16 weeks of ATI and rectum biopsies are planned. And there is renewed
interest in the long known antiviral activity of interferon alpha against HIV.
In a study with HIV patients that had undetectable viral load, stopped therapy
and used pegylated interferon alpha as monotherapy, the viral load could be
kept below 400 cp/ml in 45%. At the same time, the number of integrated HIV
genomes in the circulating CD4-cells went down. Interestingly, this effect was
also seen in a group of patients receiving only half of the standard dose (90
µg instead of 180 µg interferon alpha per week) – with much better
the workshop, did a internet survey about the willingness of patients to
participate in clinical studies that are not of immediate benefit to them but
maybe even have some serious risks. They found among many other things, that
unexpectedly many patients would consider participating in such studies for
mainly altruistic reasons.
persistence of HIV:
harboring transcriptionally inactive HIV genome (latently infected)
divide to make up for natural decay, the integrated HIV genome will also be
distributed to the daughter cells and the number of latently infected cells
therefore decreases very slowly)
stimuli, e.g. interactions with HIV infected CD4-cells in tissue.
how to overcome them, e.g. antibodies against PD1 to reverse latency.
their efforts to
reservoirs will be attacked with different tools: One idea is to mark infected
cells with siRNA-probes to make them visible for the immune system so that
killer cells can get rid off the infected cells. Another method uses “homing
endonucleases”, special restriction enzymes from yeast. The enzyme Y2-Anil has
been changed in a way to recognize HIV-specific areas in the genome and cut
them. These cuts will be recognized by the cells repair system and the gaps
will be filled with random nucleosides. This leads to “nonsense“ viral sequence
that doesn‘t produce active virus anymore. This method has a big advantage
against the Tre-recombinase that has been described some time ago. Y2-Anil
recognizes longer, very conserved regions of HIV so that it could be effective
against a broad range of different HIV types whereas Tre recombinase is limited
to the LTR region of HIV (in fact the efficacy of Tre recombinase has been
shown only against a very artificial laboratory strain of HIV and not the wild
not raise premature and unrealistic hopes in patients. First steps have been
made but we need many more successes in analytics, basic science and
translational research in the animal model as well as in patients before the cure
will be within reach.