"Our data strongly suggest that the immunologic factors at
work during this early period of infection, as much or more than
virologic factors, are the critical determinants of the ultimate outcome
of HIV disease," says Anthony S. Fauci, M.D., NIAID director and
chief of the NIAID Laboratory of Immunoregulation. "The growing
understanding of the initial interaction between HIV and the immune
system, and of the immune responses to HIV during primary infection,
both favorable and unfavorable, is important to the development of
effective HIV vaccines."
Drs. Fauci, Giuseppe Pantaleo, formerly of NIAID's Laboratory
of Immunoregulation and now with the Centre Hospitalier Vadois in
Lausanne, Switzerland, and their coworkers report their findings in the
January 1997 Proceedings of the National Academy of Sciences.
Once it enters the body, HIV infects a large number of CD4+ T
cells and replicates rapidly. During this acute, or primary phase of
infection, the blood contains many viral particles that spread
throughout the body, seeding various organs, particularly the
lymphoid organs such as the lymph nodes, spleen, tonsils and
adenoids. Two to four weeks after initial infection with the virus, up
70 percent of HIV-infected persons suffer flu-like symptoms. The
patient's immune system fights back with killer T cells (CD8+ T cells)
and B-cell-produced antibodies.
"One important way in which a person's immune system
responds to primary HIV infection is by mobilizing different subsets of
certain white blood cells -- CD8+ T cells -- that can destroy cells
have been infected with HIV," says Dr. Fauci. "We found a clear
correlation between the patterns of CD8+ T cell expansion during
primary infection and how well a patient did clinically during the
subsequent year or 18 months. Regardless of the amount of HIV in
the blood during primary infection, patients who mobilized a broad
repertoire of CD8+ T cells had slower progression of disease than
individuals who showed a pronounced expansion of only a single
subset of CD8+ T cells."
Scientists currently do not know the reasons for the qualitative
differences in the immune responses of different individuals during
primary HIV infection, Dr. Fauci notes, but they probably include
factors intrinsic to the HIV-infected person, such as the genes that
encode specific markers called human leukocyte antigens (HLAs) on
immune system cells.
The current report is the latest from an ongoing series of
experiments begun several years ago in the Laboratory of
Immunoregulation. In their research, Dr. Fauci and his team have
carefully analyzed CD8+ T cells taken from patients during primary
HIV infection, classifying the cells according to the variable (V)
regions of their receptors. All T cells have receptors with alpha and
beta chains, and on the beta chain is a region known as V-beta that
varies among T cells. Humans have 24 different V-beta families.
Previously, the NIAID team demonstrated that during primary
infection, some HIV-infected patients have a marked expansion of a
limited variety of T cells, representing very few V-beta families.
patients mobilize a wider array of T cells, with many different V-beta
In the current study, the investigators studied 21 individuals
with documented primary HIV infection at clinics in the United States,
Canada, Switzerland and Italy. Blood samples from these patients
were analyzed in NIAID's Laboratory of Immunoregulation.
Four of these 21 patients had major expansions of a single
V-beta subset during primary infection. Approximately one year later,
each of these four individuals had developed AIDS, as indicated by
CD4+ T cell counts below 200 cells per cubic millimeter (mm3) of
blood. The mean CD4+ T cell count among these patients was 101
cells/mm3; a healthy person without HIV infection usually has a CD4+
T cell count of 600-1500 cells/mm3.
Four other patients had moderate expansions of one or two V-beta
subsets. At approximately one year, this group of patients had a
mean CD4+ T cell count of 456/mm3.
Thirteen patients had expansions of multiple V-beta families or
no expansion at all. The mean CD4+ T cell count in this group of
patients was 651/mm3 after approximately one year.
Previous studies have shown that levels of HIV in a person's
bloodstream six to 12 months following primary infection are highly
predictive of that person's clinical course, with more virus generally
correlating with more rapid disease progression. The current findings
add a new level of complexity to the understanding of the relationship
between "viral load" and a person's clinical outcome.
"In the current analysis, we studied an earlier stage of disease
-- the primary infection -- and found that the initial level of HIV in
blood does not predict clinical outcome. At this early stage of
disease, the qualitative nature of a person's immune response, rather
than plasma viremia, proved to be the best prognostic indicator,"
notes Dr. Pantaleo.
"Individuals with an effective primary immune response --
those with a broad expansion of CD8+ T cell subsets -- appear to be
the same people who will have low levels of virus six or 12 months
later, levels which in turn are predictive of relatively slow disease
progression. In contrast, individuals with an ineffective primary
immune response (i.e., expansion of only a single subset of CD8+ T
cells) may have less success in controlling the virus over time, and
therefore, have high levels of virus six to 12 months later," says Dr.
NIAID is a component of the National Institutes of Health
(NIH). NIAID conducts and supports research to prevent, diagnose
and treat illnesses such as HIV disease and other sexually
transmitted diseases, tuberculosis, asthma and allergies. NIH is an
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