Three Johns Hopkins researchers propose, for the first
time, that HIV and other retroviruses can use a Trojan
horse style of infection, taking advantage of a cloak of
human proteins to sneak into cells.
The hypothesis explains 20 years of perplexing
observations and suggests new ways to reduce HIV
transmission and treat HIV infection, but it also implies
that existing approaches to developing vaccines against HIV
won't work. A description of the hypothesis and its
supporting evidence appear in the Proceedings of the
National Academy of Sciences, published online Aug.
"Most researchers have focused on viral proteins when
trying to understand HIV's mechanisms or develop vaccines,"
said James Hildreth, professor of
pharmacology and molecular sciences in Hopkins'
Institute for Basic Biomedical Sciences. "But so many
aspects of retroviral biology have not been reconciled,
including HIV, that we have to take a broader view. If our
hypothesis is true and retroviruses can rely on human
proteins, vaccines based solely on a few key viral proteins
will never be able to completely prevent infection. There
needs to be serious attention to this hypothesis."
Even if a vaccine against the viral proteins
physically blocks a retrovirus's primary way of infecting
cells, the retrovirus's ability to enter new cells by way
of its cover of human proteins — the Trojan horse
— provides previously unrecognized ways to escape the
vaccine's effects, said Stephen Gould, professor of
chemistry in the Institute for Basic Biomedical
To go from cell to cell, all retroviruses are packaged
in "envelopes" made from viral proteins and proteins from
human cell membranes. The prevailing view is that the viral
proteins do all the work to enter new cells, and the human
proteins are just along for the ride. But the Hopkins team
suggests that sometimes the viral proteins take the back
seat, and the retrovirus relies instead on the cells' own
mechanism for shuttling molecules from one cell to
"New hypotheses are frequently huge jumps from current
thinking that then occasionally turn out to be true. This
is not one of those times," Gould said. "This hypothesis
links what is known about how molecules are transported
within and between cells and a great deal of what is known
about HIV and other retroviruses. When the pieces are put
together, it's such an obvious connection. The biggest
surprise is that the idea hasn't been widely discussed
Researchers elsewhere, for example, have shown that a
version of HIV completely missing its key envelope protein
can still infect cells in the laboratory, strong support
for the Trojan horse effect.
"Despite that observation being 'impossible' under the
prevailing view of how HIV gets into cells, people have
said that this little bit of infection can't be important,"
said Gould, an expert on cellular transport vehicles. "But
just because something isn't big doesn't mean it's not
important--this little bit of infection offers the
retrovirus a chance to survive, mutate and thrive in
infected people. In general, our hypothesis makes HIV
appear nastier than we think it is, and we already think
it's a pretty nasty virus."
But all is not lost, the Hopkins team said. The new
hypothesis, and some quirky observations from the past,
highlight the potential of targeting immune responses
against the human proteins in the virus's envelope, instead
of the viral proteins, as a way to prevent infection.
Each person's immune system innately "knows" to attack
and destroy tissue from other people, a characteristic
reflected in the need to have appropriate blood and organ
"matches" in transfusions and transplants. The human
proteins that elicit these immune responses are among those
found in the viral envelope.
The researchers suggest that heightening this immune
response by vaccinating people with small amounts of these
human proteins (called "alloimmunization") could be a very
cost-effective way to reduce the rate of new HIV
infections, especially in developing countries. The immune
system would immediately attack the viral envelope, and the
virus would be degraded before the person's own cells could
"Unlike current vaccine approaches, which target
particular viral proteins, this new vaccination strategy
has the decided advantage of working against all strains of
HIV as well as against other retroviruses," Gould said.
"Harnessing this immune response may be the only
near-term prospect we have to reduce the rate of new HIV
infections," Hildreth said. "There's lots of evidence
supporting the idea of alloimmunization to fight HIV
transmission. We need to push for it and push hard,
especially since this could be done in developing countries
Already, some clinical reports indicate that people
whose tissue and blood types don't match are less likely to
infect one another with HIV or other retroviruses. However,
a person who is a "good" tissue match for his or her
infected partner is more likely to become infected.
Unfortunately, the proposed vaccine strategy might not help
protect people from their rare "good" matches.
The proposed Trojan horse mode of infection stemmed
from trying to explain a number of observations in the
researchers' respective labs that couldn't be explained by
existing models of HIV biology. However, these findings can
easily be explained if HIV can act like an exosome, tiny
pockets made from cell membranes that are used to send
molecules between cells.
Gould, an expert in the basic biology of the cell;
Hildreth, an expert on HIV's biology; and graduate student
Amy Booth also reviewed decades of scientific reports about
the viral envelope or "particle" — the way
retroviruses package themselves — and more recent
discoveries about exosomes.
The retroviral particles and exosomes contain the same
human proteins, are built by the same machinery and have
the same job — transferring payloads from one cell to
another. With these and other striking similarities, the
researchers suggest retroviral particles are treated like
regular exosomes. In this way, the retroviral particle is
protected from immune attack and able to enter cells
throughout the body.
"This 'Trojan exosome hypothesis' explains why
retroviruses carry the human proteins they do, why they are
able to survive even in people with healthy immune systems
and why traditional approaches have failed to generate an
effective HIV vaccine," Gould said. "The evolutionary
implications are similarly revealing, both for how
retroviruses evolved and why animals possess intense tissue
Added Hildreth: "Reexamining previous experiments and
analyzing new results in the context of this hypothesis
have the potential to revolutionize what we know about
retroviruses and what we can do to fight the spread of HIV
and other retroviruses."
The researchers note that the immunization method
suggested by their hypothesis and others' observations is
already performed safely to alleviate some instances of
infertility, reducing the hurdles to testing its
applicability in HIV prevention.
The work was supported by the National Institutes of
Health and the Johns Hopkins Fund for Medical Discovery.