Role of Antibody-Dependent Cellular Cytotoxicity and Lymphokine-Activated Killer Cells in AIDS and Related Diseases

Abstract

This overview summarizes current knowledge on the overall efficacy and potential contribution of antibody-dependent cellular cytotoxicity (ADCC) and lymphokine-activated killer cell (LAK) activities in evoking non-major histocompatibility complex (non-MHC) cytolytic responses to human immunodeficiency virus-1 (HIV-1)-infected targets. High titers of ADCC antibodies to the HIV-1 virion are present in HIV-1-seropositive populations at all stages of disease. These antibodies are broadly reactive with a large number of HIV-1 strains and are predominantly directed against envelope determinants spanning both gp120 and gp41. However, the relative ability of natural killer (NK) effectors, derived from HIV-seropositive individuals, to evoke ADCC responses becomes increasingly impaired with disease progression. HIV-1-seropositive individuals also show marked decreases in both production of and responsiveness to interleukin-2 (IL-2). HIV-1-seropositive individuals generally have the ability to generate ex vivo propagated LAK cells; however, these cytolytic effectors are less effective than their counterparts derived from healthy controls. Increased understanding and control of non-MHC-restricted cytotoxic-responses to HIV, and their induction by lymphokines, may lead to improved treatment strategies for the management of AIDS and related diseases.

Anti-HIV Antibody–Dependent Activation of NK Cells Impairs NKp46 Expression

“…Furthermore, SPs have ADCC responses against a broader array of HIV Ags than do nonSPs (5). Several groups also published data suggesting the ability of NK cells to mediate ADCC decreases during HIV infection (11,14,17,22). The association of ADCC with slower disease progression was observed in the rhesus macaque SIV model: maintenance of ADCC activity was observed in slow progressing macaques, and lower plasma ADCC activity was observed in macaques with more rapidly progressing infections (6).…”

“…Chronic HIV infection that induces ongoing activation of NK cells due to ADCC would be expected to elicit in vivo phenotypic and functional changes in NK cells similar to those observed after in vitro activation (i.e., reduced CD16 expression, hyporesponsiveness, and reduced NKp46 expression) (26)(27)(28)(29)39). Indeed, HIV infection results in a set of dysfunctional NK cell changes similar to that observed after CD16-mediated activation in vitro (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Thus, we speculate that continued activation of NK cells as a result of ADCC during untreated chronic viral infections could explain the reduced functionality of NK cells observed during HIV infection.…”

“…Perhaps coinciding with this subset redistribution, NK cells from viremic individuals mediate reduced levels of cytolysis against target cells devoid of the MHC class I ligands of NK cell inhibitory receptors (20). Similarly, several studies (11,14,17,22) reported decreased NK cell-mediated ADCC by HIV-infected patients. Lastly, HIV infection is associated with a decreased expression of the activating natural cytotoxicity receptors (e.g., NKp30, NKp44, NKp46) and CD16, as well as an increased expression of inhibitory killer cell Iglike receptors (KIRs) (13,(15)(16)(17)(18)(19)(20).…”

“…Furthermore, the recently completed RV144 vaccine trial, which was modestly protective in the absence of strong broadly neutralizing Ab or cytotoxic T cell responses, induced Abs capable of mediating ADCC that may have been related to the observed protection (8)(9)(10). Despite the immense interest in using ADCC for therapeutic purposes, it should be noted that NK cells exhibit extensive phenotypic alterations and dysfunction during HIV infection (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). However, it is unclear whether chronic activation of NK cells via ADCC could contribute to this disease-related dysfunction.…”

“…Upon ex vivo analyses, NK cells from HIV-infected individuals exhibit altered phenotype, function, and subset distribution (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Infection with HIV was observed to coincide with the appearance of a hypofunctional CD16 + CD56 2 subset and a decrease in the highly functional CD16 + CD56 dim subset (12,21).…”