HIV LESSONS FROM THE MISSISSIPPI BABY
The news in July that
HIV had returned in a Mississippi toddler after a two-year treatment-free
remission dashed the hopes of clinicians, HIV researchers and the public at
large tantalized by the possibility of a cure.
But
a new commentary by two leading HIV experts at Johns Hopkins argues that
despite its disappointing outcome, the Mississippi case and two other recent
HIV "rebounds" in adults, have yielded critical lessons about the
virus' most perplexing -- and maddening -- feature: its ability to form
cure-defying viral hideouts.
Writing
in the Aug. 28 issue of the journal Science, HIV research
duo Robert Siliciano, M.D., Ph.D., and Janet Siliciano, Ph.D., note that such
"failures" are in fact stepping stones to new understanding of what
"cure" may look like and new therapies that tame the virus into
long-term remission.
"Heartbreaking
as these three cases are clinically, they provide a dramatic illustration of
the real barrier to an HIV cure and illuminate important therapeutic
strategies," says Robert Siliciano. "This is not the end of the story
but the beginning of a new chapter."
The
27-month off-treatment remission experienced by the Mississippi toddler is, in
and of itself, a laudable therapeutic goal, the Silicianos write, and is what
cure of HIV may look like in the foreseeable future. Finding ways to induce
long-term remission and to closely monitor its course will be the next frontier
in HIV treatment, they write.
The
ability to put the virus in remission and go off treatment for months or years
at a time is an important goal, because it can spare HIV-infected people from a
lifetime of daily antiviral regimens, which can be difficult to tolerate and
hard to follow. Failure to comply with the strict treatment protocol, which
occurs often, can lead to viral mutations that make HIV resistant to drugs.
All
three cases, the Silicianos write, also reaffirm that the single most important
hurdle to eradicating HIV is a tiny but extremely stable pool of virus tucked
away in a handful of immune cells known as memory CD4+ T cells.
Memory
T cells are the immune system's combat-trained sentinels, responsible for
fighting invaders they have encountered in the past. Much of the time, memory T
cells lie dormant and become active only when the body is invaded by old foes
they are specifically trained to recognize. HIV invades memory T cells early in
the infection, and as long as the T cells lie quiet, so does HIV inside
them.However, as soon as memory T cells get stirred up by an invader, the HIV
DNA inside them wakes up, cranks out new virus and reignites infection. Because
antiviral drugs work only against actively replicating virus, such silent viral
hideouts remain out of therapy's reach. Thus, reducing the number of latently infected
cells or precluding their formation altogether is an important and -- as the
three recent cases suggest -- realistic strategy, the Silicianos say.
"These
cases paint several clinical scenarios where a substantial reduction of viral
reservoirs would allow some patients to come off treatment for prolonged yet
uncertain periods of time, but they also raise the critical question of how to
best monitor them for relapse so they can resume therapy swiftly when the virus
rebounds," says Janet Siliciano.
In
the widely reported case of the Mississippi baby, a child born to an
HIV-infected mother received a full-treatment regimen of antiviral drugs within
hours of birth, instead of the customary prophylactic regimen typically used in
suspected but unconfirmed newborn infections. The baby's HIV infection was
subsequently confirmed. The child was lost to follow-up and went off treatment
but later returned to clinic. A series of standard and ultrasensitive tests
failed to detect HIV in the child's blood. In total, the child remained free of
HIV infection -- with undetectable viral loads and free of HIV antibodies --
for 27 months despite receiving no treatment. By contrast, most HIV-infected
people experience dramatic viral rebound within a few weeks of treatment cessation.
Described
as the first documented instance of HIV remission in a child, the Mississippi
case suggested that very early treatment with antiretroviral drugs quashed the
formation of viral reservoirs. The child was followed by a University of
Mississippi pediatrician, a University of Massachusetts immunologist and a
Johns Hopkins pediatric HIV expert, Deborah Persaud, M.D., who was also the
lead author on case report published Nov. 7, 2013, in The New England Journal
of Medicine.
In
two other "remission" cases reported in 2013, HIV ultimately
rebounded in two adults after months without antiviral therapy and following
bone marrow transplantation for cancer. Both patients received antiviral drugs
while undergoing transplantation to prevent the donors' immune cells from
becoming infected with HIV. The patients' own HIV-infected immune cells were
killed off by chemotherapy and by graft-versus-host disease, a common
post-transplant phenomenon in which the donor's immune cells attack and destroy
the recipient's organs, tissues and cells. When antiretroviral treatment was
stopped, the patients went into remission for several months, but the virus
came roaring back later on, according to published reports.
"Clearly,
neither approach managed to eradicate all latently infected cells, and what
these cases underscore is the ability of even a few such cells to rekindle
infection after prolonged remission," Robert Siliciano says.
The
three cases also lend urgency to the search for better ways to monitor the
presence of and measure the number of such dormant HIV reservoirs, which could
be used as a rough gauge of how long remission might last. Latently infected
cells can evade detection by even the most sophisticated tests, which are so
exquisitely sensitive that they can sniff the presence of a single HIV-infected
cell. The problem is not lack of test sensitivity, the Silicianos explain, but
the size of the blood sample tested. Latent HIV reservoirs exist in a few out
of millions of immune cells, but a mere 2 percent of memory T cells that harbor
such reservoirs are circulating in the blood at any given time. Thus, even
large blood samples may not capture the few infected cells harboring dormant
virus -- a feat that becomes even more challenging as the number of reservoirs
is reduced.
Even
though research indicates that remission duration is linked to the amount of
latently infected cells, the Silicianos caution remission time is bound to vary
widely from patient to patient. Its length would depend on individual biologic
factors and the occurrence of other infections that might coax latently
infected immune cells out of dormancy and trigger a rebound.
A
few patients may never relapse, the Silicianos say, but no patient is safe from
rebound as long as he or she harbors even a single latently infected T cell.
The unpredictable nature of remission and rebound will therefore require
frequent blood monitoring to detect the earliest signs of viral reactivation.
"It
is not too soon to begin planning for this type of 'cure' scenario," the
authors conclude.
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