Biology Reference
In-Depth Information
p24 subunit, which is raised substantially during early viral replication (Klein et
al., 1995). This region presents several clusters of class I restricted epitopes that
are recognizable by the CTL. HIV-speci®c CTL is also seen among the most
conserved of the HIV proteinsÐthe polymerase protein ( Pol). It is also found
to be HLA class I restricted and several epitopes have been described. HIV-
speci®c CTL against the regulatory Nef proteins has been described ( Bauer et
al., 1997). It is an early expressed protein and a factor involved in viral repli-
cation that is implicated as a cause of MHC class I down-regulation leading
to viral escape of CTL killing (Cohen et al., 1999; Collins et al., 1998). The
presence of Nef-speci®c CTL is seen as good sign for possible control of viral
replication by the CTL. Moreover, Nef-speci®c epitopes were found to be re-
stricted by several HLA molecules, making it a good target for a wide variety of
CTL from di¨erent individuals (Kalams and Walker, 1994).
HIV-speci®c CTL has also been implicated as a part of pathogenesis of HIV
disease and the development of AIDS. Most studies have shown that the de-
velopment of AIDS coincides with the time of deteriorating CTL responses in
HIV-infected individuals, giving a picture of a possible protective role being
played by the CTL in slowing down disease progression (Goulder et al., 1997).
In the same vein, some studies have implicated the CTLs as the cause of
pathology seen in some of the organs they in®ltrate, notably the lungs and the
brain (Krakauer and Nowak, 1999; Wodarz and Krakauer, 2000). HIV-speci®c
CTL has been isolated from both sites (Plata et al., 1990). Whereas interaction
between CD44
, non-ADCC-mediated, HIV-speci®c CTL and local alveolar
macrophages is thought to lead to localized in¯ammatory reactions and subse-
quent functional abnormalities of the lung parenchyma, the development of
AIDS dementia complex is more glaring ( Twigg et al., 1999). The cerebrospinal
¯uid (CSF ) and brain tissues of HIV-infected individuals with this disorder
are known to be in®ltrated by CD8
lymphocytes with CTL capabilities. This
suggests that CTL may have a role in the pathogenesis of AIDS dementia
complex through direct or indirect cytotoxicity (Kalams and Walker, 1994).
The HIV pathogenesis is a continuous spectrum that ends with the develop-
ment of AIDS and the death of the patient. The most marked feature of the
AIDS period is the presence of several opportunistic infections from pathogens
that are normally not a problem for a normal immune system. The decline
in health status is also accompanied by a decline in all immune parameters
including CTL. Several mechanisms have been advanced as the cause of the
decline in the HIV-speci®c CTL but no explanation is conclusive (Goulder and
Walker, 1999; Soudeyns and Pantaleo, 1997; Zerhouni et al., 1997). Some
studies have suggested that escape mutations, down-regulation of MHC class I,
decreased expression of surface markers such as leukocyte function-associated
antigen ( LFA-1), defects in APC and CTL clonal expansion/exhaustion leading
to anergy are responsible for this decline in e¨ective CTL response (Lewis et
al., 1994; Wodarz et al., 1998). Indeed, one study has shown that the slow
progressors, unlike the rapid progressors, accumulate far more nonsynonymous
mutations (involving amino acid changes) than synonymous mutations (Birk et
