Natural Killer Cells in HIV Infection and Role in the Pathogenesis of AIDS - Cellular Aspects of HIV Infection - page 187

with the CD16 CD56 phenotype decreases concomitantly with an increase in
the frequency of NK cells with the CD16 dim=ÿ CD56 dim=ÿ phenotypes (Hu et
al., 1995). These ®ndings established that the reported decrease in the frequency
of NK cells in the HIV infection may be partially accounted for by the down-
regulation of these NK phenotypic markers.
We hypothesized, based on the presence of an inverse relationship between
the frequency of circulating CD16 dim=ÿ CD56 dim=ÿ NK cells and the cytotoxic
function of NK cells, that the loss of NK functional activity was concomi-
tant with the loss of the CD16 and CD56 markers. Indeed, we demonstrated
that the cell-sorted CD16 CD56 NK subpopulation from the peripheral
blood of HIV persons retained its cytotoxic activity, whereas the cell-sorted
CD16 dim=ÿ CD56 dim=ÿ subset was poorly cytotoxic, as assessed by both the
direct and ADCC systems ( Hu et al., 1995).
The number and percentage of CD16 CD56 NK cells that comprise 90%
of the NK cells in normal adults is profoundly decreased in HIV-seropositive
individuals, whereas the number of CD16 dim CD56 ÿ and CD16 dim CD56 NK
cells is increased. Some CD56 cells and virtually all CD56 ÿ cells were CD16 dim .
By analogy to our in vitro results, these in vivo studies suggest that NK cells
in HIV-infected subjects interact with target cells, possibly HIV-infected cells.
Although functional and phenotypic analyses of the CD16 dim CD56 ÿ NK sub-
set in HIV individuals show depressed NK and ADCC (Jewett et al., 1990), the
surface expression of CD69 is elevated in the CD16 dim CD56 ÿ cells relative
to the CD16 CD56 cells. Secretion of IFN-g and TNF-a was signi®cantly
depressed in the presence of phorbol myristate acetate (PMA) and calcium
ionophore in the CD16 dim CD56 ÿ NK subset when compared with the
CD16 CD56 NK subset. Furthermore, unlike the CD16 CD56 NK sub-
set, the CD16 dim CD56 ÿ NK subset did not proliferate in the presence of
IL-2. The CD16 dim CD56 ÿ subset was found to have a higher percentage of
fragmented DNA in the presence and absence of dexamethasone when com-
pared with the CD16 CD56 NK cells (Jewett et al., 1997). Furthermore, the
CD16 dim CD56 ÿ subpopulation had higher levels of Fas mRNA as determined
by reverse-transcriptase polymerase chain reaction ( RT-PCR). Altogether,
these studies indicate that the CD16 CD56 NK subset undergoes a series of
functional and phenotypic di¨erentiation in the presence of K562 or HIV target
cells that results in loss of cytotoxic function, proliferation, cytokine secretion,
and death of the NK cells. Table 9.2 summarizes the properties of NK subsets
from HIV-infected individuals.
Expression of NKRS
The discovery of novel inhibitory receptors (also called killer inhibitory re-
ceptors, KIRs) speci®c for MHC class I molecules ( NKRs) has stimulated
considerable interest in their possible involvement in the impairment of cyto-
toxic function of T cells and NK cells during HIV infection. Inhibitory NKRs
do not display variability and deliver inhibitory, rather than triggering, signals.