August 1, 2006 (AIDSmeds)—A University of California research team has discovered
that HIV is able to survive the antiviral effects of treatment by
hiding out in the mucosal tissues of the intestine. Even when blood
tests show that viral load is undetectable and T-cell counts are responding well to HIV treatment, there is likely ongoing viral
replication and immune system damage occurring in the gut. While its
not entirely clear what these findings mean for HIV-positive people,
the researchers hint at the possible need for early HIV treatment,
intestinal biopsies, and the use of anti-inflammatory medications to
effectively manage HIV infection in the gut.
The study, reviewed in the August issue of the Journal of Virology,
was conducted by Satya Dandekar, PhD, and her colleagues with the UC
Davis Health System in Davis, California. According to Dr. Dandekar,
who is professor and chair of the Department of Medical Microbiology
and Immunology, "The real battle between the virus and exposed
individuals is happening in the gut immediately after viral infection.
We need to be focusing our efforts on improving treatment of gut mucosa
where massive destruction of immune cells is occurring."
Dr.
Dendekar explained that gut-associated lymphoid tissue (GALT) accounts
for 70% of the body's immune system. "Restoring its function is crucial
to ridding the body of the virus," she said.
Last year,
Dr. Dandekar published a study of HIV-infected patients who, despite
the lack of treatment, had survived over 10 years with healthy levels
of T-cells and suppressed viral loads. "We looked at their gut lymphoid
tissue and did not see loss of T-cells there. This correlated with
better clinical outcome," she explained.
Those results
prompted Dr. Dandekar and her team to undertake the current study
evaluating the effect of combination HIV treatment on viral suppression
and immune restoration in GALT. They followed 10 patients receiving HIV
treatment, taking blood samples and small biopsies of intestinal tissue
both before and after three years of treatment. Three of the patients
were treated within four to six weeks of first being infected with the
virus (patients with primary HIV infection). The other participants
were known to be HIV positive for more than one year (patients who
chronic HIV infection).
"We found a substantial delay in
the time that it takes to restore the gut mucosal immune system in
those with chronic infections," Dr. Dandekar said. "In these patients
the gut is acting as a viral reservoir that keeps us from ridding
patients of the virus."
Hoping to figure out why HIV
treatment does not work as well in the gut, Dr. Dandekar's group
further examined the GALT samples collected after at least three years
of therapy. They found evidence of inflammation, which disrupts tissue
function, promotes cell death, and upsets the normal balance of gut
flora. They also found that the activity of genes that control and
promote mucosal repair and regeneration was suppressed, while the genes
responsible for the inflammatory response were more active than in
normal tissue.
GALT samples collected from the three
patients with primary HIV infection – compared to those with chronic
HIV infection – suggested that they had fewer signs of inflammation at
the beginning of the study and experienced greater recovery of GALT
after three years of treatment.
Based on these findings,
Dr. Dandekar and the other authors suggest that anti-inflammatory drugs
may improve HIV treatment outcomes, although no specific
anti-inflammatory recommendations are made.
The
researchers also suggest that early treatment may be necessary to
maintain the health of GALT, before it is heavily damaged by HIV.
According to Thomas Prindiville, MD, a gastroenterologist and co-author
of the study, "What we continue to see is that restoration of immune
function is more likely when treatment is started early. Starting
treatment before T-cell counts fall below 350, would preserve immune
function and hasten its full recovery."
To measure the
effects of early treatment and anti-inflammatory therapy on the gut,
Dr. Dandekar's group indicates that intestinal biopsies may be
necessary. Blood measurements of viral load and T-cell counts, she
says, do not provide an accurate picture of what is going on in GALT.
Of
course, there is a lot more to learn about HIV replication in GALT
before treatment guidelines are revised or intestinal biopsies are
recommended to people living with HIV and their healthcare providers.
Is HIV replication in the gut, while someone is on HIV treatment, a
cause of drug resistance?
Would improved HIV treatment activity in the gut really provide the
immune system with greater protection against AIDS-related
opportunistic infections? Which HIV medications are most effective
against HIV in GALT? Will early treatment, the use of
anti-inflammatories, and intestinal biopsies actually help HIV-positive
people live longer, healthier lives? These are just some of the
questions that need to be addressed in clinical trials before the
suggestions of Dr. Dandekar's group are put into practice.
Dr.
Dandekar's group says that it plans to keep testing ways of improving
the efficacy of HIV therapy in GALT. This includes studies evaluating
the treatment of gut inflammation, starting treatment earlier, and
using gut biopsies to monitor treatment success.
"If we
are able to restore the gut's immune response, the patient will be more
likely to clear the virus," Dr. Prindiville said. He added: "You can't
treat any infectious disease without the help of the immune system."
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