Biology Reference
In-Depth Information
``rescue'' during acute infection, the majority of HIV-1
subjects (i.e., those
destined to become progressors) exhibit very low to undetectable frequencies of
HIV-1-speci®c CD4
T cells (determined by the intracellular cytokine assay)
very early in the course of infection, presumably due to the developing CD4
memory/e¨ector T cells being killed by direct HIV-1 infection and/or HIV-1-
associated apoptosis.
CD4 T-CELL CYTOKINE RESPONSES TO CMV IN HIV DISEASE
Cytomegalovirus (CMV ) infections are often associated with opportunisitic in-
fection in HIV disease, especially in untreated individuals. Studies by Waldrop
and co-workers (Waldrop et al., 1997) demonstrated that HIV-seropositive
subjects averaged over threefold higher frequencies of polarized, predomin-
ately IFN-g- and TNF-a-producing, CMV-speci®c CD4
T cells. Signi®cantly,
these seropositive subjects demonstrated diminished e¨ector frequencies for
heterologous, nonubiquitous viruses such as mumps. Taken together, these
data suggested the existence of homeostatic mechanisms capable of selectively
preserving memory T-cell populations reactive with ubiquitous, opportunistic
pathogens such as CMV at the expense of memory populations reactive with
more sporadically encountered infectious agents. An important conclusion of
this study was that, in HIV disease, protective immunity to particularly com-
mon pathogens may be maintained in a setting of decreasing overall CD4
T
cells by increasing the relative clonal representation of T cells reactive with such
pathogens (Mittler et al., 1996; Selin et al., 1996).
Komanduri and colleagues (Komanduri et al., 1998, 2001) used similar in-
tracellular cytokine detection methodology for enumeration of antigen-speci®c
memory T cells in a later study and provided evidence that the presence of
active CMV-associated end organ disease ( EOD) strongly correlated with loss
of CMV-speci®c CD4
T-cell responses. Patients with no history of EOD or
patients with quiescent EOD following HAART demonstrated strong CMV
cytokine responses. These studies highlight the signi®cance of this assay for the
understanding of the homeostatic mechanisms involved in disease and suggest
additional applications for monitoring immune reconstitution in other clinical
conditions where the immune system is compromised.
CD8
B
T-CELL CYTOKINE RESPONSES TO HIV ANTIGENS
In response to infection, CD8
T cells expand and di¨erentiate into e¨ector
cells, which mediate pathogen clearance through perforin-dependent cytolytic
activity or expression of IFN-g or TNF-a (Harty et al., 2000). CD8
T-cell
responses have been strongly implicated in the maintenance of immunity to
HIV. In normal immune responses, following pathogen clearance, the majority
of antigen-speci®c CD8
T cells undergo cell death (apoptosis) in which 80±
90% of the expanded population are eliminated, irrespective of the magnitude
