HIV and its monkey cousin
SIV can carry the alpha-4 beta-7 integrin receptor in their outer envelope,
which helps the virus enter gut cells during early infection, according to
research presented at the recent Conference on Retroviruses and Opportunistic
Infections (CROI 2017) in Seattle. This finding may help explain how an
antibody against alpha-4 beta-7 produced sustained viral remission in monkeys.
In a report greeted with much excitement last autumn, Anthony Fauci of the US National Institutes of
Allergy and Infectious Diseases (NIAID) and colleagues
announced that they had induced
sustained remission of SIV in macaque monkeys treated with antiretroviral
therapy (ART) plus antibody therapy. Treated monkeys not only had undetectable
viral load for up to two years after stopping ART, but they also showed
replenishment of key immune cells in the gut.
The researchers used a 'primatised' version of
a monoclonal antibody against the alpha-4 beta-7
integrin that is similar to the drug vedolizumab (Entyvio), which
is used for treatment of inflammatory bowel disease.
At the time of the report, the researchers said they
did not know how the alpha-4 beta-7 antibody
kept the virus in check.
At CROI Christina Guzzo of NIAID presented results
from laboratory studies that clarify the role alpha-4 beta-7 plays in HIV infection and offers a mechanism
for how an antibody that blocks the receptor can help control HIV and
SIV. Dr Guzzo participated in a media briefing at CROI, joined by Dr Fauci via
Soon after infection,
SIV and HIV establish reservoirs in long-lived CD4 T-cells, where viral
genetic material can remain in an inactive state indefinitely. ART keeps viral
replication under control, but once the drugs are stopped the virus reactivates
and resumes its attack on immune cells. T-cells in the gut are especially
vulnerable during early infection.
Drs Guzzo and Fauci explained that the alpha-4 beta-7 integrin receptor on T-cells helps
them 'home' or migrate to gut tissue. Previous studies have shown that cells
expressing alpha-4 beta-7 are
highly susceptible to HIV infection, and that blocking alpha-4 beta-7 leads to
reduced transmission of SIV and lower viral load in monkeys.
"To make a long story
short, we found out almost by accident that, unbeknownst to us, the alpha-4 beta-7 molecule on CD4 T-cell
is a receptor for the HIV envelope," Fauci said.
In the study reported last October, among the eleven
monkeys treated with alpha-4 beta-7 antibody
infusions, two maintained viral
suppression after stopping ART – the longest for nearly two years of follow-up – while six others experienced temporary viral rebound followed by
resuppression. In contrast, all seven monkeys that received placebo infusions
experienced high-level sustained SIV rebound.
"It was a striking finding, but we didn't know
what the mechanism was – we just knew that the result was very profound,"
Dr Fauci recalled.
Dr Guzzo explained that the gut lining contains epithelial cells that express adhesion molecules such as ICAM1 and MAdCAM1, which wait to capture cells that
express the appropriate receptors. MAdCAM1, which is
largely confined to the gut, looks for the alpha-4 beta-7 receptor, and thus attracts CD4 T-cells that carry this
The latest research shows
that the same mechanism may attract SIV or HIV itself to the gut. As newly
created virus particles burst out of a host cell, they capture part of the
cell's membrane, and its alpha-4 beta-7 receptors become incorporated into the viral
Dr Guzzo's team found
that virus-associated alpha-4 beta-7 is functionally active, just as it is on
the cell surface, and binds readily to MAdCAM1. They
then created engineered virus particles with or without alpha-4 beta-7, and found that only virus that carried alpha-4 beta-7
was captured by MAdCAM1 and infected target cells in the laboratory.
Looking at HIV-1 from
human patients, they found that circulating virus consistently incorporates
alpha-4 beta-7 during both acute and chronic infection. Looking at monkeys
experimentally infected with SIV, they found that alpha-4 beta-7 incorporation
was highest during early infection.
Finally, they showed that
HIV carrying alpha-4 beta-7 migrated to gut tissue in mice (which have
compatible MAdCAM1), while HIV without
alpha-4 beta-7 did not. The same alpha-4 beta-7
antibody used in the monkey remission study potently blocked this gut homing,
but a control antibody did not. And virus with and without alpha-4 beta-7 did
not migrate differentially to lymph node and spleen tissue – the effect was
seen only in the gut.
Based on these findings, the researchers concluded, "Incorporation
of alpha-4 beta-7 into HIV-1 virions can promote tropism and retention of virus in gut
tissues, which may impact transmission and pathogenesis."
While this research answers
some questions, much remains to be learned. Dr Fauci noted that in the
monkey study the virus did not rebound for such a long time that the infused antibodies were no longer present,
suggesting that the therapy "somehow induced some sort of immune
response that has continued to suppress the virus long after the antibody to alpha-4 beta-7 was gone."
One hypothesis is that since alpha-4 beta-7 is expressed on both virus particles and
susceptible cells, the antibody may capture both and present them to the
immune system in a way that induces a long-lasting immunological response. The
antibody therapy might "teach the immune system to recognize HIV in a way
it doesn’t recognize it if it just sees HIV alone," Dr Fauci said.
"Our job now is to find out just what the nature of that immune response
A small clinical trial is now underway to test the antibody
therapy in people with chronic HIV infection on suppressive ART (NCT02788175). They will receive vedolizumab infusions over
30 weeks, then will stop both their antiretrovirals and vedolizumab to see if
viral rebound occurs. Dr Fauci said that so far 12 people have received
infusions, starting in late August. Preliminary results are expected by the end