Vaccines: Could Vaccine Alter Course of HIV Disease?
Plus, April 29, 1996 issue; Published by Charles
Henderson, Publisher. Editorial & Publishing Office: P.O.
Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931;
Subscription Office: P.O. Box 830409, Birmingham, AL
35283-0409 / FAX: (205) 995-1588
J. DeNoon, Senior Editor
HIV disease will rapidly progress or remain relatively stable
is established very early in the course of infection, new
new data identify stage-independent predictors of disease
progression. Examination of these predictors in AIDS- vaccine
recipients with breakthrough HIV infection should indicate
whether the vaccine can change the course of disease.
ability to more carefully define the stage and rate of
progression of HIV-1 disease could potentially assist
preventive and therapeutic vaccine trial design by allowing
balanced stratification of subjects," suggested
researcher Michael T. Wong of Wilford Hall Medical Center,
Lackland Air Force Base, Texas, and colleagues.
et al. reported their findings in The Journal of Infectious
Diseases ("Patterns of Virus Burden and T Cell Phenotype
Are Established Early and Are Correlated with the Rate of
Disease Progression in Human Immunodeficiency Virus Type
1-Infected Persons," J Inf Dis, 1996;173(4):877-887).
et al. studied a cohort of 1,200 patients enrolled in the U.S.
Air Force arm of the prospective Tri-Service Natural History
Program. This program follows HIV infected patients in the
U.S. military health-care system and periodically collects
samples of plasma, serum, and peripheral blood mononuclear
researchers identified 32 patients with rapid progression of
HIV disease (defined as rapid decline in CD4(+) T-cell counts
with progression to clinical AIDS) and 25 patients with stable
disease (defined as constant or rising CD4(+) T-cell counts
with no clinical disease).
of these patients received intensive virological and
immunological evaluations of samples collected over a four-
year period. Evaluations included virus load in serum and PBMC,
(beta)-microglobulin, delayed-type hypersensitivity (DT
960429H) to recall antigens, HIV p24 antigen, and
determination of CD4(+), CD8(+), natural killer (NK) cell, and
gamma-delta T-cell subsets.
resulting data were subjected to various univariate and
multivariate statistical analyses.
contrast of rapid-progression and stable-progression
populations indicates that regardless of progression rate or
the compartment assessed, the pattern and magnitude of virus
load is established early in HIV disease," Wong et al.
found. "The magnitude is the single virologic feature
that distinguishes the more rapid from the slower course of
findings support the "steady-state" hypothesis: that
soon after HIV infection the virus and the immune system
establish a dynamic equilibrium characterized by a plateau
level of viral burden. Higher plateau levels are associated
with more rapid progression to disease and death. Moreover,
animal and human studies suggest that there is a certain
threshold level for this plateau below which the immune system
is able to eliminate the virus.
the current study is among the first to systematically
evaluate phenotypic features of the cellular immune
compartment over time.
analysis showed that the major phenotypic predictors of the
rate of disease progression were the markers
CD3(+)CD4(+)CD28(+) and gamma-delta T-cell-receptor-bearing
early HIV-1 infection, a constellation of high virus burden
and in vivo costimulatory antigen and lymphocyte activation
abnormalities is predictive of rapid disease course,"
Wong et al. concluded.
proportion of CD4(+) and CD8(+) T cells lacking the CD28
costimulatory molecule predicted the rate of HIV progression
but did not change during the course of infection.
CD28(-) cells, when stimulated via the T-cell receptor, would
be expected to respond with anergy or apoptosis, ascribing a
functional deficit to this phenotypically characterized
determinant of rate," Wong et al. wrote.
cells might be induced to become CD28(-) as a result of direct
viral infection of the cell or contact of the cell membrane
with suppressive viral products or as a consequence of
HIV-influenced cytokine patterns or deranged regulatory cell
findings confirm previous observations that the loss of
"naive" unstimulated T-cell precursors is the
hallmark of HIV disease.
loss of naive cells, through inadequate production, excessive
stimulatin and conversion to memory cells, or both, could
theoretically decrease the ability of CD4(+) cells to respond
to new antigens or to broaden existing responses," Wong
et al. suggested.
T-cell phenotype that did not change over time but which
discriminated rapid from stable progressors (and both groups
from normal controls) was the percentage of
(dipeptidyl peptidase IV) is physically associated with CD45
on T cells, has been associated with T-cell activation and CD3
phosphorylation, and identifies a T-cell subset reacting to
soluble and recall antigens," Wong et al. noted.
"Cross-sectional studies have found CD26 is decreased on
T cells of HIV positive patients and suggest that
CD4(+)CD26(-) cells are the main reservoir for HIV-1."
there is an increase in the percentage of T cells bearing the
gamma-delta receptor soon after HIV infection - even before
CD4(+) lymphocyte counts begin to decline. This proportion
does not change over time, but its magnitude differentiates
between rapid and stable disease.
most of the phenotypic subsets tested, those showing slow as
well as rapid progression were significantly different from
normal controls, demonstrating distinctive changes in immune
subsets compared with uninfected subjects," Wong et al.
concluded. "These observations suggest that those showing
slow and rapid progression represent the ends of a continuous
spectrum of severity of disease progression rather than
researchers concluded that the optimal time to intervene in
HIV disease would be soon after infection, before
establishment of steady-state equilibrium.
stressed the importance of determining whether the
disease-stage-independent predictors of progression are
altered in recipients of experimental HIV vaccines who suffer
breakthrough HIV infections.
constancy of many of these markers over time, used as
surrogates of outcome, could provide a greater power to
identify treatment effects for a given sample size," Wong
et al. suggested.
corresponding author for this study is Michael T. Wong,
Department of Infectious Diseases, Wilford Hall Medical
Center, 2200 Bergquist Dr., Suite 1, Lackland Air Force Base,
(c) 1995 - Charles Henderson, Publisher. All rights Reserved.
Permission to reproduce granted to AEGIS by Charles W.
Henderson. Authorization to reproduce for personal use granted
granted by C. W. Henderson, Publisher, provided that the fee
of US$4.50 per copy, per page is paid directly to the
Copyright Clearance Center, 27 Congress Street, Salem,
Massachusetts 01970, USA.