"Our findings argue for treatment early in disease, before elements of
the immune system are
significantly depleted," says senior author H. Clifford Lane, M.D.,
NIAID's clinical director.
"Our data also suggest that drugs to prevent opportunistic infections
may remain important even
for patients with CD4+ T cell counts that are rapidly increasing in
response to therapy, because
these individuals may be missing part of their CD4+ T cell repertoires."
Adds co-lead author Mark Connors, M.D., of the NIAID Laboratory of
loss of CD4+ T cells is a qualitative phenomenon as well as a
quantitative one. In other words, a
CD4+ T cell count of 200 per cubic millimeter (mm3) of blood during the
natural history of HIV
infection may be very different from a CD4+ T cell count of 200/mm3 in
the context of therapy.
Depletions in the CD4+ T cell repertoires of HIV-infected people and
hence the reduced ability
of their immune systems to recognize certain antigens are probably key
to the development of
immunodeficiency in these people."
The current findings shed light on an observation reported by Dr. Lane
and his colleagues in the
mid-1980s: HIV-infected people often lose their ability to respond to
"remote recall antigens":
substances to which one was exposed in the past, such as the antigens in
a tetanus vaccine. The
new data suggest that this decreased responsiveness is due to a loss of
specific CD4+ T cell
types, which scientists refer to as "clones."
"A loss of CD4+ T cell clones, and the resulting "holes" in a person's
CD4+ T cell repertoire,
rather than an active immunosuppressive phenomenon, may explain why an
becomes unresponsive to remote recall antigens," says co-lead author
Joseph A. Kovacs, M.D.
Using molecular techniques, the NIAID researchers have demonstrated that
CD4+ T cell
diversity begins to decline when an HIV-infected person's CD4+ T cell
count falls to
approximately 150 to 200 cells/mm3 of blood. This decline accelerates
when a person's count
falls to 50 cells/mm3. A healthy person without HIV infection typically
has a CD4+ T cell count
in the range of 600 to 1500 cells/mm3.
Even when therapies boosted a person's CD4+ T cell counts to 200/mm3 or
higher, CD4+ T cell
diversity was not restored, the researchers observed.
However, Dr. Lane suggests that even patients with advanced disease may
be able to mount
adequate immune responses if antiretroviral therapy reduces HIV
replication to very low levels.
With potent suppression of HIV, other clones may be able to proliferate
to sufficient levels to
perform the job normally done by the missing clones.
"Think of a person's CD4+ T cell clones as tiles in a scrabble game,"
explains Dr. Lane. "As
disease progresses, not only does an HIV-infected person have fewer
tiles, but also fewer
different tiles. If a person loses the letter "z," they will be unable
to spell out the word "zebra."
However, if they have enough other tiles, they still may be able to
describe a zebra by spelling
a"horse-like animal with black and white stripes."
CD4+ T cells have on their surfaces a molecule called a T-cell receptor
(TCR) which recognizes
and binds to foreign invaders that have been ingested and processed by
other specialized immune
cells -- antigen-presenting cells (APC) -- and displayed on the
Each CD4+ T cell's TCR has an alpha and beta chain. Each beta chain
contains a variable region
that is derived from one of at least 22 V-beta subfamilies. These
V-beta subfamilies are often
used by immunologists to classify T cells.
In their studies, Drs. Lane, Connors, Kovacs and their colleagues used a
chain reaction (PCR) technique to examine differences in size patterns
in the V-beta subfamilies
of CD4+ T cells taken from both HIV-infected and HIV-uninfected people.
Among these subjects were five sets of twins in which one twin was
HIV-seropositive, the other
HIV-seronegative. The five healthy, HIV-seronegative twins had TCR
V-beta families that were
virtually all normal. Their infected twins had disruptions in as many
as 11 different V-beta
The researchers applied the same PCR technique to samples taken from
HIV-infected people at
different stages of HIV infection, and found that disruptions in the
CD4+ T cell repertoire
became more pronounced as disease progressed. In a group of eight
control patients without
HIV infection, fewer than 5 percent of all V-beta families had
disruptions. In a group of five
HIV-infected people with CD4+ T cell counts above 200 cells/mm3,
approximately 15 percent of
all V-beta families had disruptions. However, among six patients with
CD4+ T cell counts lower
than 200/mm3, nearly 40 percent of V-beta families had disruptions. In
most cases these were
associated with depletions within these V-beta families.
Therapy with antiretroviral drugs or interleukin-2 plus antiretroviral
therapy led to only minor
changes in previously disrupted V-beta repertoires, and in the relative
percentages of naive and
memory CD4+ T cell subsets, the researchers found.
"Most likely, the increase in a patient's CD4+ T cell count after
initiating therapy represents
expansion of the existing repertoire in a patient's bloodstream and
lymph nodes rather than the
generation of "new" CD4+ T cells by the thymus," says Dr. Kovacs. "This
view is fortified by
our observation that many of the patients in the study had minimal
"In the future, modifications of the techniques used in this study may
prove useful clinically for
better defining the predictive value of a CD4+ T cell count," he adds.
"Knowing a person's
specific T cell repertoire might allow one to better predict the
susceptibility of a person to
opportunistic infections, and may one day help guide treatment
In addition to Drs. Lane, Connors and Kovacs, co-authors of the paper
include Seth Krevat, Juan
C. Gea-Banacloche, M.D., Michael C. Sneller, M.D., Mark Flanigan, Julia
A. Metcalf, R.N.,
Robert E. Walker, M.D., Judith Falloon, M.D., Michael Baseler, Ph.D.,
Randy Stevens, Irwin Feuerstein, M.D., and Henry Masur, M.D. The
techniques used for
precisely analyzing CD4+ T cell repertoires were developed at the
Pasteur Institute in France by
Drs. Christophe Pannetier and Philippe Kourlisky.
NIAID, a component of the National Institutes of Health, conducts and
supports research aimed
at preventing, diagnosing and treating illnesses such as AIDS and other
diseases, tuberculosis, asthma and allergies. NIH is an agency of the
U.S. Department of Health
and Human Services.
Connors M, et al. "HIV infection induces changes in CD4+ T-cell
phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by
antiviral or immune-based therapies." Nature Medicine 1997; 3(5): 533-540.
NIAID press releases, fact sheets and other materials are available on
the Internet via the NIAID home page at http://www.niaid.nih.gov.