|
(page 2 of 2)
Failure of the immune system leads to any number of infections
collectively known as AIDS-related illnesses.
In AIDS, fungi, parasites, bacteria, and viruses can rage
unchecked through the bloodstream. Many of these pathogens
are commonly found in the environment and are normally contained
by our immune systems. They are, however, poorly controlled
in HIV-infected people. These infections are called opportunistic
because they arise when enough of the T cells that would normally
fight them off have been killed.
Mosier studies the viral dynamics of several opportunistic
viruses that are common co-infections and he has found ways
of controlling some of them.
Epstein–Barr virus (EBV), Kaposi’s sarcoma herpesvirus,
and cytomegalavirus can be controlled by transplanting CTLs
that are specific for these viruses into patients. Transplanting
EBV-specific CTLs, for instance, will prevent them from causing
lymphomas and will clear the EBV from the system.
"They last for many months and are very effective at eradicating
infection," says Mosier.
However, the same sustained and effective response is not
found with HIV-specific CTLs. Infusing them into a patient
does have an immediate antiviral impact, but the effect is
short-term and is lost within about three days.
The Biology of a Coreceptor
Besides studying the basic viral dynamics of HIV, Mosier
is actively involved in searching for novel compounds to use
as antiviral therapeutics. His target is the C–C chemokine
receptor 5 (CCR5).
CCR5 is a seven trans-membrane spanning protein of 332 amino
acids that inserts into the cell membranes of human CD4+ T
helper cells with the N-terminus and three external loops
exposed to the outside and the C-terminus and three internal
loops, which are responsible for signaling, on the inside.
The idea to explore CCR5 as a possible target for therapy
and vaccines came shortly after the molecule was recognized
as a co-receptor for HIV entry. This recognition came from
studies with cells of certain individuals who seemed to be
protected from infection despite having had multiple high-risk
exposures to the virus.
It turned out that CCR5 is a coreceptor to which HIV virions
need to bind after they bind to CD4 receptors on a cell, and
the expression of this coreceptor is rate limiting for transmission
of the virus and its expansion from cell to cell.
The resistant individuals all had a 32-base pair knockout
mutation in CCR5 gene that left their CD4+ T cells with no
coreceptors. Later data showed that individuals who were heterozygous
for the mutation had lower CCR5 expression levels, less cell-to-cell
infection, and brighter clinical prognoses.
"Since the virus has to use this receptor," says Mosier,
"one might be able to block the interaction and prevent infection."
Possible agents would either bind to CCR5 and prevent it
from functioning as a coreceptor, interfere with the folding
of CCR5, or downregulate the expression of the CCR5 gene.
Mosier believes that the most effective therapy in the short-term
will be the chemokine receptor blockers—molecules like
the natural CCR5 human peptide ligand RANTES, which binds
to the same loops of CCR5 as HIV.
Mosier calls RANTES a good lead candidate for a therapeutic
blocking agent, and he has already seen that some of its synthetic
analogues are 1,000-fold more potent at blocking HIV cell
entry. As a drug, RANTES or a RANTES-like compound would probably
be added to the current regiments of drugs rather than used
as a single agent. "They will be part of a larger cocktail,"
says Mosier.
However, these RANTES compounds would be unlike current
regimens, which are largely available in pill form. RANTES
is a 68-amino acid long peptide, so it would not be orally
bioavailable because enzymes in the stomach would digest it.
Drugs based on RANTES would have to be injected in the same
way people with Type 1 diabetes inject insulin.
He also says that he has obtained some encouraging data
about the slow recovery of CCR5 when challenged with these
agents. A large dose of the coreceptor blocking agents can
"strip" the CCR5 receptors off the cell walls completely for
over 24 hours.
"You might be able to get away with once-a-day dosing,"
he says.
As with any antiretroviral therapy, though, the greatest
danger is that HIV will mutate. Since HIV has no proofreading
mechanism, it copies itself with such notoriously low fidelity
that it makes a mistake every time it makes a copy of itself.
Because of the large number of copies it makes, the chances
of spontaneous mutants with drug resistant properties are
great—perhaps even guaranteed.
Mosier’s basic research has provided an effective model
to test out HIV’s response to possible agents. He can
grow human T cells with a mutant form of CCR5 that has the
C-terminal end chopped off. These mutants can still bind to
the HIV virions, but they cannot signal inside the cells and
do not get internalized. Then, by comparing wild type to mutant
viral constructs, he can observe what changes in the HIV genome
allow it to enter the cell through another route.
1 | 2 |
|
