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.