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HIV Conquers Immune System Faster than Previously Realized

HIV Conquers Immune System Faster than Previously Realized
HIV Conquers Immune System Faster than Previously Realized


Duke Health News Duke Health News

DURHAM, N.C. – New research into the earliest events
occurring immediately upon infection with HIV-I shows that the
virus deals a stunning blow to the immune system earlier than
was previously understood. According to scientists at Duke
University Medical Center, this suggests the window of
opportunity for successful intervention may be only a matter of
days – not weeks – after transmission, as researchers had
previously believed.

Appearing in the August issue of the Journal of Virology,
the finding may make the challenge of designing an effective
HIV/AIDS vaccine appear daunting. But researchers say the study
has also yielded a blueprint for what a successful vaccine
should look like, and moreover, when such a vaccine would need
to work.

Until now, scientists believed that the window of
opportunity to intervene in the process of HIV-1 infection lay
in the three to four weeks between transmission and the
development of an established pool of infected CD4 T cells.
HIV-1 cripples the immune system by invading and killing CD4 T
cells, key infection-fighters in the body.

"But this new study shows that HIV-I does a lot of damage to
the immune system very early in that time frame, and now we
feel that the opportunity to intervene most effectively may
range from about five to seven days after infection," said
Barton Haynes, M.D., the senior author of the study and
director of the Center for HIV/AIDS Vaccine Immunology (CHAVI)
at Duke University Medical Center.

Haynes said the findings suggest that an optimal vaccine
strategy would have to pack a double punch: First, establishing
as much immunity as possible before infection, much as classic
vaccines do, and then following a few days later with a
mechanism to provoke a strong, secondary, broad-based antibody
response. "Vaccine candidates to date have pretty much followed
a single strategy. Now we know that we need to activate
multiple arms of the immune system and we have a better idea of
when to do it."

The conclusion comes from the study of 30 people who were
newly-infected with HIV-1. Plasma from these individuals was
sampled every three days for several months – before, during,
and after the "ramp-up" phase of infection, when HIV-1 is
multiplying rapidly and heading toward its peak viral load. In
measuring the levels of four products of CD4 T cell death
during this period in these samples, they were able to track
and establish a timetable of the virus's destructive path.

The four byproducts of CD4 T cell death include TRAIL (tumor
necrosis factor-related apoptosis-inducing ligand), Fas ligand,
TNF receptor type 2 and plasma microparticles, tiny bits of
cell membrane that are broken up and left floating around in
the plasma when the cell dies and breaks apart.

The researchers found that TRAIL levels increased
significantly a full week (7.2. days) before peak viral load,
which is approximately 17 days after HIV-1 transmission,
suggesting that during the earliest period of infection, called
the eclipse phase, TRAIL may actually initiate or hasten
HIV-1's destruction of CD4 T cells. In contrast, they found
that the levels of the other three cell death products were
most significantly elevated during peak viral load.

"What this demonstrates is that significant T cell death is
occurring much earlier during this period than we previously
believed, and that TRAIL itself may be a co-conspirator in
enhancing cell death," Haynes said. "This leads us to believe
that the time frame for successful intervention has to move
even close to the point of infection."

Researchers also examined the effects of cell death products
upon B cells, another arm of the immune system responsible for
the creation of antibodies. Previous studies have shown that
the antibody response to HIV-1 is "too little, too late" –
appearing after the virus has peaked and after the reservoir of
infected T cells has already been established.

Through a series of in vitro laboratory experiments with
peripheral blood cells, scientists found that microparticles
suppressed levels of IgG and IgA, two classes of antibodies
that normally would protect a person against infection. "This
is important because many scientists believe that a fast-acting
memory B cell response as well as a T cell response will be
necessary to fight HIV-1" said Nancy Gasper-Smith, PhD, the
lead author of the study.

Daniel Douek, M.D., PhD, chief of the Human Immunology
Section of the National Institutes of Health, said the study
sheds new light on key events in the earliest phase of
infection. "The cohort is a gem. It is clear from the raised
levels of TRAIL that the body senses the virus before plasma
viral loads have peaked. This suggests that the virus begins to
cause damage in ways that may be unrelated to the
well-described massive depletion of gut CD4 T cells that
becomes apparent around peak viral load. For clinical practice,
this means the window of opportunity in which antiviral
therapies and vaccines must act is becoming ever narrower."

"These and other studies that recently revealed more about
the singular nature of HIV-1 have given us valuable information
that is helping us move closer to establishing a basic science
foundation that can lead to novel technologies for vaccine
design, Haynes said. Haynes. "It is becoming clearer why we
have failed in our efforts to date, and what we need to
confront to succeed in the future."

The study was supported by grants from the National
Institutes of Health

Colleagues from Duke who contributed to the research include
Deanna Crossman, John Whitesides, Nadia Mensali, Janet
Ottinger, Steven Plonk, M. Anthony Moody, Guido Ferrari, Kent
Weinhold, Sara Miller and Thomas Denny. Additional co-authors
are David Pisetsky and Charles Reich, from the Durham Veterans
Administration Hospital; Li Qin and Stephen Self, from Fred
Hutchinson Cancer Research Center and the Statistical Center
for HIV-AIDS Research and Prevention; George Shaw from the
University of Alabama: and Laura Jones, from Cornell.

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