AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 17, Number 6, 2001, pp. 553–561 Mary Ann Liebert, Inc. Relationship between Antibody-Dependent Cellular Cytotoxicity, Plasma HIV Type 1 RNA, and CD4 1 Lymphocyte Count DONALD N. FORTHAL, GARY LANDUCCI, and BOBI KEENAN ABSTRACT To explore the role of antibody-dependent cellular cytotoxicity (ADCC) in controlling HIV-1 infection, ADCC was compared with plasma RNA and CD4 1 cell count in 40 patients not receiving antiretroviral therapy and in seven patients after the initiation of treatment. Among untreated patients, ADCC effector cell function of peripheral blood mononuclear cells, measured by 51 Cr release assay, correlated inversely with viral load (R 5 20.42, p 5 0.007) and directly with CD4 1 cell count (R 5 0.52, p 5 0.001). On the other hand, HIV-1-specific ADCC antibody level correlated directly with viral load, but only among patients with high CD4 1 cell counts. Therapy-induced changes in ADCC effector cell function correlated strongly with changes in CD4 1 cell count (R 5 0.86, p 5 0.014), whereas there was no consistent pattern of change in ADCC antibody with therapy. In a novel assay, ADCC reduced virus yield from CD4 1 lymphocytes infected with a primary HIV isolate. ADCC may contribute to control of viremia, and CD4 1 lymphocytes likely play a role in ADCC effector and anti- body functions. 553 INTRODUCTION H IV-1 VIREMIA is an important indicator of the immuno- logical and clinical course of HIV-1 infection. 1 The key determinants of the level of viremia during infection are likely to include host factors, such as coreceptor expression and HIV- 1-specific immune responses, virological factors, or both. 2–6 Antibody-dependent cellular cytotoxicity (ADCC) occurs when antibody forms a bridge between target cells bearing for- eign antigens and effector cells expressing Fc receptors. Like cytotoxic T lymphocyte (CTL) activity, ADCC leads to the death of cells infected with HIV-1 and should thereby lead to the elimination of cells producing virus. 7 Several human and animal studies suggest a role for ADCC in modulating HIV-1 infection. For example, Baum et al. have shown that patients with rapidly progressive disease have lower ADCC antibody titers than patients with more slowly progressive disease. 8 Fur- thermore, ADCC effector function predicts survival in severely immunocompromised AIDS patients, independently of viral load, CD4 1 cell count, and antiretroviral therapy (ART). 9 In SIV-infected rhesus macaques with rapidly progressivedisease, passively infusing plasma from animals with typical disease reduces plasma SIV levels in a manner most consistent with ADCC. 10 During acute SIV infection, a rapid increase in nat- ural killer (NK) activity and in the number of activated NK cells precedes the decline in viremia 11 ; since NK cells are a major effector cell for ADCC, it is possible that these activated NK cells are mediating ADCC. Finally, the demonstration that in- fusion of an anti-CD8 monoclonal antibody results in a tran- sient increase in plasma SIV viremia is consistent with a role for ADCC in the control of lentivirus infection, since macaque NK cells generally express CD8 and would likely be depleted along with CTLs. 12,13 If ADCC is important in the control of viremia during HIV- 1 infection,an inverse relationshipbetween ADCC antibody or effector cell functions and plasma HIV-1 RNA level would be expected at some time during the course of infection. Further- more, the components of ADCC, namely effector cells and an- tibody, should have a demonstrable effect on virus yield from infected cells in vitro. In this study, we compared plasma viremia level, as well as CD4 1 lymphocyte counts, with ADCC in HIV-1-infectedpatients prior to and after receiving ART. We also determined the ability of HIV-1-infected patient serum, combined with peripheral blood mononuclear cell (PBMC) ef- fector cells, to reduce viral yield from CD4 1 lymphocytes in- fected with a clinical strain of HIV-1. Division of Infectious Diseases, Department of Medicine, University of California, Irvine College of Medicine, Orange, California 92868.