Biology Reference
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Picker, 1998; Picker and Maino, 2000; Sester et al., 2000); 2) the array of spe-
ci®c class I and II epitopes to which the individual responds ( Kern et al., 1998,
1999; Maecker et al., 2001) and 3) the number and relative hierarchy of
T-cell receptor ( TCR)-de®ned clonotypes involved in these pathogen-speci®c
responses (Bitmansour et al., 2001).
CD4 T-CELL CYTOKINE RESPONSES TO HIV ANTIGENS
Although viral-speci®c CD4
T cells have proven to be a critical component of
the immunologic control of chronic viral infections in a number of infectious
disease models (Asanuma et al., 2000; Li et al., 1998; Pitcher et al., 1999;
Rosenberg and Walker, 1998; Rosenberg et al., 1997; Waldrop et al., 1997), the
role, and even the existence of, HIV-1-speci®c CD4
T cells in human HIV-1
infection has been controversial. Recently, a number of studies have provided
new evidence for a signi®cant role of CD4
T cells in maintaining HIV immu-
nity. Pitcher and colleagues ( Pitcher et al., 1999) demonstrated that signi®cant
frequencies of CD4
T cells expressed IFN-g and TNF-a in response to HIV
antigens in the majority of subjects with active HIV-1 infection. It was further
demonstrated that overall frequencies of functional, HIV-1-speci®c CD4
memory T cells were considerably diminished in a cohort of long-term highly
active antiretroviral therapy ( HAART )-treated subjects with chronic HIV in-
fection, suggesting that prolonged viral suppression is associated with a decline
in HIV-1-speci®c CD4
T-cell memory. These observations were subsequently
con®rmed in a separate study (Maino et al., 2000) using similar methodology
that further demonstrated that vaccinations of such HAART-treated subjects
with a gp-120-depleted HIV-1 immunogen rapidly enhanced frequencies of HIV-
speci®c CD4
T cells expressing either TNF-a or IFN-g, either by expansion
of the remaining HIV-1-speci®c memory cells or by recruitment of new HIV-1-
speci®c memory cells. The inability to develop HIV-speci®c CD4
T-cell cyto-
kine responses in chronic HIV infection despite e¨ective suppression of viral
replication may suggest that memory T cells speci®c to the virus are preferen-
tially lost very early after seroconversion.
Alternatively, recent studies examining similar methodologies for measure-
ment of T helper immune responses suggest these data are consistent with the
model that the memory T-cell population is in constant ¯ux, with the size of
any given antigen-speci®c T-cell clonotype being continuously in¯uenced by the
local antigen concentrations in the tissues and, most signi®cantly, by competi-
tion with other clonotypes (Andersson et al., 1998; Cavert et al., 1997; Haase,
1999). Other reports have suggested that the immune repertoire against the
virus may decrease in response to potent antiviral drug therapy (as the antigenic
stimulus is removed) but memory HIV-speci®c immune function remains a
measurable parameter (Pitcher et al., 1999). Such ®ndings are consistent with
the concept that low-level HIV-speci®c memory T cells persist in chronic in-
fection. A major implication of these ®ndings is that in the absence of HAART
