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.
SUMMARY The role of natural killer (NK) and lymphokine‐activated killer (LAK) cell‐mediated cytotoxiciry in AIDS has yet to be established. The objective of this study was to determine inducible LAK cell responses at different stages of HIV‐1 infection, and specifically to establish the participation of CD8 lymphocytes in these responses. Peripheral blood lymphocytes (PBL) were isolated from healthy seronegative (CDC‐0) subjects and HIV‐1 individuals who were clinically asymptomatic (Centre for Disease Control group 2, CDC‐2) or symptomatic (CDC‐4) with regard to secondary opportunistic infection (OI). LAK cells were generated upon incubation of PBL with IL‐2 and their cytolysis of K562 and U‐937 targets was determined using chromium release assays. The role of CD8+ lymphocytes as progenitors and effectors of these LAK cell responses was determined by immunomagnetic depletion of CD8+ cells from precursor PBL and LAK cells, respectively. LAK cell‐mediated cytotoxicities in HIV‐1‐infected individuals were reduced compared with scronegativc controls without any corresponding changes in the relative proportions of CD56+ (NK) cells among groups. Depletions of CD8+ subsets from either PBL or LAK cells dramatically reduced total LAK cytotoxic responses and LAK activities per unit CD56+ cell in the OI‐CDC‐2 scropositive population. No corresponding changes in LAK activities in seronegative control or HIV+/OI+ CDC‐4 groups were observed. Levels of LAK activity against K562 targets in CDC‐0/HIV and CDC‐4/HIV+ groups correlated with the percentage of CD56+ LAK cells; corresponding LAK activity in the CDC‐2/HIV+ group correlated with the percentage of both CD56+ and CD8+ subsets. These findings suggest that adaptive changes in non‐MHC restricted cytotoxic responses occur in HIV‐1 individuals at early stages post‐HIV infection, before the onset of opportunistic infection.
SUMMARYThe role of natural killer (NK) cells and their inducibie counterparts, lymphokine-activated killer (LAK) cells in AIDS with regard to HIV-I viral immunosurveillance and the control of secondary opportunistic disease has yet to be established. In this study, we have demonstrated that LAK cells derived from all HIV-I + groups showed striking increases in their capacity to lyse HIV-1-infected U-937 cells relative to their uninfected U-937 counterparts. Surprisingly, similarly derived LAK cells from healthy seronegative controls showed no differences in their lysis of HIV-1-infected versus uninfected U-937 cells. The differential ability of LAK effectors from seropositive donors to lyse HIV-1-infected targets was demonstrable using a number of U-937 subclones and their HIV-1-infected counterparts. Again, no differences in LAK cell-mediated lysis of HIV-l-infectcd and uninfected U-937 subclones were observed in seronegative individuals. Our findings that H1V-1 + individuals show selective expansion of non-MHC restricted. HIV-1-directed cytotoxic LAK cells indicate that natural immunity may indeed play a role in HIV-1 viral immunosurveillance.
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