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New View Of HIV Entry Could Lead To Next Generation Of Inhibitors

May 1st, 2009 by Valerie Chavez

Scientists may need to rethink the design of drugs meant to block HIV
from infecting human cells, according to a study that appears in the
May 1st issue of the journal Cell, a Cell Press publication. That's
because the new report shows that HIV doesn't enter cells in the way
that experts had generally assumed it did.

Rather than fusing
directly with the plasma membrane at cells' outer surfaces to release
its contents, HIV fusion primarily occurs via smaller, membrane-bound
compartments inside of cells known as endosomes, the new research
shows. The discovery implies that anti-HIV drugs known as fusion
inhibitors might be more effective in blocking HIV if they too can do
their work inside of cells, where fusion takes place.

"We show
that HIV fusion occurs virtually exclusively from endosomes," said
Gregory Melikian of the University of Maryland School of Medicine. "It
appears that it is this path to entry that leads to infection."

"In
order to efficiently block intracellular fusion events, the next
generation of HIV entry inhibitors must be able to permeate the cell
membrane," he continued. Drugs that act on the endocytic machinery
itself might also prove useful in limiting HIV infection.

Endosomes
form in a process known as endocytosis by which cells take in material
by engulfing and pinching off a portion of the cell membrane to form a
smaller vesicle

. Enveloped viruses that depend on low pH for entry are known to
initiate infection by fusion with acidic endosomes. However, entry
sites for pH-independent viruses, including HIV, had not yet been
clearly defined.

In
the new study, Melikian and his colleagues relied on a series of
imaging studies to literally watch as HIV-1, the virus that normally
infects humans, enters cells. Those experiments showed that complete
viral fusion occurs not on the cell surface, but in endosomes. While
HIV's envelope sometimes did mix with the cell's plasma membrane, in
those cases delivery of the viral contents did not occur.

"Time-resolved
imaging of single viruses and differential blocking of fusion by
site-specific and universal inhibitors revealed that HIV-1 co-opts the
endocytic machinery to enter into and fuse with target cells," the
researchers wrote. "By contrast, fusion with the plasma membrane did
not progress beyond the lipid mixing step, suggesting that endosomal
entry is the pathway that leads to productive infection."

HIV-1
interacted with receptors on the cell surface leading to its
internalization long before endosomal fusion, they show. That process
minimized the surface exposure of conserved viral epitopes – portions
of macromolecules that are recognized by the immune system -- during
fusion and reducing the efficacy of inhibitors targeting these epitopes.

The
researchers also found that HIV-1's release from endosomes depend on
dynamins, enzymes that are important to the formation of new endosomes
and their fusion with other membranes. Melikian said that dynamins may
provide an additional driving force to expand pores and permit the
release of the HIV-1 core out into the cell.

While Melikian said
he hopes the findings will have practical implications, it does deliver
some bad news for those on a mission to fight HIV. That's because the
endosomal path to entry would offer the virus several advantages,
including sheltering HIV from antibodies and inhibitors that target key
portions of the virus during the unusually slow fusion reaction.

The
new result may also have relevance for other so-called pH-independent
viruses, all of which were assumed to enter via fusion with the plasma
membrane, Melikian said. After all, he noted, HIV has been a "poster
child" for that group. "This may be a universal trend. Endosomes may be
universally more conducive to viral entry."

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