AIDSWEEKLY Plus, Monday, December 8, 1997
Daniel J. DeNoon, Senior Editor
New evidence offers hope of an immune therapy that could strengthen the ability of killer cells to fight HIV.
As part of the immune system's extensive series of checks and balances, a minor subset of CD8(+) T cells expresses inhibitory natural-killer-cell receptors (NKRs) that bind human leukocyte antigen (HLA) class I molecules. These NKRs inhibit T-cell functions, including the killing of virus-infected cells by cytotoxic lymphocytes (CTLs) and the production of lymphokines.
Now an Italian research team (which included U.S. NIAID Director Anthony S. Fauci as co-author) reports that HIV infected individuals apparently have NKRs that down-regulate HIV specific CTL activity. The studies also show that when monoclonal antibodies (MAbs) are used to mask NKRs, in vitro anti-HIV CTL function is restored.
"We show that MAb-mediated masking of inhibitory NKRs may result in the de novo appearance or in a significant increase of HIV specific cytolysis," reported University of Genoa researcher Andrea De Maria and colleagues in the Proceedings of the National Academy of Sciences ("Expression of HLA Class I-Specific Inhibitory Natural Killer Cell Receptors in HIV-Specific Cytolytic T Lymphocytes: Impairment of Specific Cytolytic Functions," PNAS, 1997;94:10285-8).
During the course of HIV disease there is a progressive loss of CTL function. De Maria et al. found it remarkable that despite this loss of function, CD8(+) CTLs retain their potential cytotoxicity (as demonstrated by redirected killing induced by anti-CD3 MAbs).
Building on their earlier finding that expression of the HLA-C- specific NKR p58.2 is increased in HIV-1 infected patients (Cauda, R. et al., Clin Immunol Immunopathol, 1994;70:198-205), their present study shows that all known NKRs can be expressed in T cells from HIV infected individuals.
"Whereas in normal donors the antigen specificity of these T cells could not be determined, we provide here direct evidence that NKR(+) CTLs [from HIV(+) patients] include cells with defined antigen specificity," De Maria et al. wrote. "Perhaps more importantly, we demonstrate that the engagement of inhibitory NKRs with self-HLA class I molecules may down-regulate antigen-specific CTL function."
When the researchers blocked NKR receptors in T-cell cultures using NKR-specific IgM MAbs, they saw either increased cytolytic activity or de novo appearance of HIV specific cell killing.
"It will be of particular interest to determine whether the expression of inhibitory NKRs by HIV specific CTLs may play a role in the pathogenesis of HIV disease by inhibiting the destruction of HIV infected cells and thus accelerating disease progression," they concluded.
If this is so, it will be even more interesting to see whether immunotherapy targeted at NKRs can increase HIV specific CTL responses in vivo.
This study was supported in part by grants awarded by the Istituto Superiore di Sanita AIDS Project.
The corresponding author for this study is Lorenzo Moretta, Istituto Nazionale per la Ricerca sul Cancro, c/o Advanced Biotechnology Center, Laboratory of Immunopathology, L.go R.Benzi 10, Genova, 16132 Italy.
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