Biology Reference
In-Depth Information
Other Mechanisms
Recombinant and synthetic peptides derived from the HIV-1 genome corre-
sponding to the protein envelope (Env) and internal core protein (Gag) were
examined for their e¨ect on NK from normal and AIDS. Normal lymphocytes
pretreated for 24±72 h with Env-Gag, Env 487±511, or Env 647±659 signi®-
cantly suppressed NK cytotoxicity but signi®cantly stimulated proliferation.
In target binding assays, lymphocytes precultured with Env-Gag speci®cally
suppressed the target binding capacity of e¨ector cells and decreased levels of
secreted NK cytotoxic factor ( NKCF ). The inhibition was found in both nor-
mal and AIDS-derived cells ( Nair and Schwartz, 1997).
Healthy controls show statistically signi®cantly higher NK cytotoxic activity
than either HIV-1-infected asymptomatic or AIDS groups of patients. Whereas
challenge of samples from normal with IL-2, INF-a, or mixture of TPA
ion-
ophore resulted in signi®cant enhancement in NK CMC. Challenge of HIV
,
asymptomatic, or AIDS resulted in an increase that was not statistically signif-
icant. This ®nding suggests alterations in the mechanisms responsible for NK
cells activity in HIV
individuals (Sepulveda et al., 1997).
NK cells mediate ADCC via activation of the CD16 FcR. The receptor is
linked to the zeta chain, which regulates the cells for activation. In one study,
the zeta chain level was examined and revealed signi®cantly lower levels in NK
from AIDS. The CD16 decreased ADCC cytolysis by NK cells correlated with
the levels of zeta chain expressed but did not with NK cell-mediated cyto-
toxicity (Geertsma et al., 1999).
ROLE OF NK CELLS IN THE PATHOGENESIS OF HIV INFECTION
Depletion of CD4
B
T Lymphocytes
It is not clear how NK cells become inactivated and depleted following HIV
infection. Further, it is not clear how NK cells may regulate the frequency of
circulating CD4
cells. NK cells lose their cytotoxic function and become in-
activated when cocultured overnight with K562 target cells (Jewett and Bona-
vida, 1995a). Inactivated NK cells release signi®cant levels of cytokines such as
TNF-a and IFN-g, which could up-regulate the replication and expression of
HIV and contribute to subsequent lysis of CD4
T cells. Signi®cant levels of
TNF-a and IFN-g are detected in AIDS patients (Jassoy et al., 1993).
Because the properties of the NK cells observed in vitro following interac-
tion with NK-sensitive or ADCC targets are similar to those observed in NK
cells from HIV-infected persons ( Hu et al., 1995), we reasoned that an in vivo
ADCC reaction might be responsible in part for the functional inactivation and
depletion of NK cells and destruction of CD4
T lymphocytes serving as tar-
gets for ADCC. In vivo, a signi®cant population of circulating T cells from
HIV-seropositive individuals express gp120 (Daniel et al., 1993) and antibodies
to gp120 have been detected in the serum of HIV-infected persons (Amadori et
