Apoptotic peptides derived from HIV-1 Nef induce lymphocyte depletion in mice.

INTRODUCTION We have developed a mouse model to examine the effects of host exposure (ie, hematopoietic system) to secreted HIV-1 Nef or peptides derived from Nef. METHODS We used a combination of terminal uridine deoxynucleotidyl transferase (dUTP) nick end labeling (TUNEL) assays and CD4+ cell counts to assess the status of circulating immune cells in mice treated with Nef-derived proteins. RESULTS Mice treated with peptides derived from HIV-1 Nef protein displayed significant increases in apoptotic CD4+ lymphocytes and thymus cells and significant decreases in the numbers of circulating CD4+ lymphocytes. No effects were observed in mice treated with controls. There was a clear dose- and time-response relationship between cell changes and the amount of protein or peptide. induction of multiple markers of apoptosis such as DNA laddering and caspase 3 activation was observed during dose- or time-response experiments. Cell death and lymphocyte depletion were blocked by induction of a humoral response to the HIV Nef apoptotic epitope. CONCLUSIONS Extracellular Nef can induce apoptosis and lymphocyte depletion in vivo. Appropriate antibody response can block these effects, but the apoptotic motifs in Nef are thought to be poorly immunogenic.