Treatment with a broadly
neutralising antibody plus an immune-stimulating drug led to long-term viral remission
after interrupting antiretroviral therapy in a monkey study, according to data presented
at the 25th Conference on Retroviruses and Opportunistic Infections (CROI 2018)
this week in Boston.
Monkeys that received
both the antibody, known as PGT121, and the TLR7 agonist GS-9620 maintained an
undetectable viral load without antiretrovirals for a median of 112 days,
according to Dr Dan Barouch of Beth Israel
Deaconess Medical Center in Boston. Five of eleven treated animals still remained
virally suppressed at six months.
Researchers working on a functional cure for
HIV – meaning sustained viral remission without antiretroviral therapy (ART) – have
studied various 'kick and kill' strategies aimed at reactivating the reservoir
of latent virus and helping the immune system attack it.
PGT121 is a broadly neutralising
antibody that targets the V3 glycan site on the outer envelope of HIV and SIV,
a related virus that infects monkeys. GS-9620 is a TLR7 agonist that stimulates
toll-like
receptors on immune cells, part of the innate immune system that promotes
recognition and response to viruses. Activating TLR7 enhances the activity of
T-cells, natural killer cells and other immune cells. Both agents are being
developed by Gilead Sciences.
At CROI 2016, researchers reported that GS-9620 alone led to T-cell activation in macaque monkeys infected
with SIV. These animals had a more pronounced decline in viral DNA levels in
their T-cells, lymph nodes and gut tissue. One monkey maintained an undetectable
viral load for about three months after stopping ART, but eventually they all
experienced viral rebound.
Hoping to improve on
this response, investigators tested GS-9620 in combination with a neutralising
antibody.
This study included 44
rhesus macaques infected with a human-simian hybrid virus known as SHIV. On day
7, during acute infection, they started ART consisting of
tenofovir, emtricitabine and dolutegravir. After two years of continuous
suppressive ART, they received infusions of PGT121 (10 mg/kg every two weeks
for five doses), oral GS-9620 (0.15 mg/kg every two weeks for 10 doses), both
PGT121 and GS-9620, or 'sham' (placebo) treatment. ART was discontinued four
months after the last doses of PGT121 and GS-9620.
Monkeys that received PGT121
had therapeutic antibody levels for 10 weeks, followed by a decline to
undetectable levels in their blood,
lymph nodes and gut. ART was discontinued
after antibodies were no longer present.
After stopping ART, all eleven monkeys
in the sham treatment group experienced rapid viral rebound in a median of 21
days. Nine of the 11 animals treated with PFT121 alone, and 10 of the 11 treated
with GS-9620 alone, also soon experienced viral rebound.
Six of the eleven monkeys
treated with PGT121 plus GS-9620 experienced viral rebound, but this took
substantially longer – a median of 112 days. Five monkeys in this group (45%) continued
to maintain undetectable viral load for at least 168 days after stopping ART,
Barouch reported.
Even after rebounding,
monkeys that received the combination treatment had lower viral load setpoints
and lower viral DNA levels in their lymph nodes, suggesting a decrease in the
viral reservoir and some level of immune control over the virus.
"PGT121 combined with GS-9620 during
ART suppression substantially delayed and controlled viral rebound following
ART discontinuation in SHIV-infected rhesus monkeys that initiated ART during
acute infection," the researchers concluded. "These data suggest that
[broadly neutralising antibody] administration together with innate immune
stimulation during ART suppression may effectively target the viral reservoir."
"There is
no cure for HIV, and any such intervention is a long way off, but this early
stage preclinical data suggest that long term viral remission might in fact be
possible," Barouch told reporters at a CROI press briefing.
Experts are cautious about the
prospects for a functional cure after various apparently promising
interventions over the past several years have turned out to have only a
temporary effect.
Dr John Mellors of the University of Pittsburgh School of Medicine, who
moderated the briefing, noted that this is the "first
evidence of induced immune control in macaques—but in humans we haven't hit
that milestone yet."
Barouch added that even if this approach prevents
viral rebound for several months, that doesn't preclude the possibility that
virus is still present and could reactivate months or even years later. Even
the most sensitive tests available today cannot detect all latent virus, he
said.
The PTG121 plus GS-9620 combination is now being
studied in human clinical trials, according to a press release from the US National Institute of Allergy and
Infectious Diseases. A Gilead press release indicated that GS-9620 is now in a phase 1b dose-escalation study in
people with suppressed viral load on ART, and a derivative of PGT121 known as
GS-9722 is starting phase 1 testing.