Certain CpG-containing DNA sequences from bacteria, viruses, or invertebrates elicit responses in the vertebrate innate immune system. These responses also account for many nonspecific effects of oligodeoxynucleotides used for antisense approaches. Here we describe a sequence from an acutely pathogenic simian immunodeficiency virus (SIV) that induces release of cytokines from macrophages and B lymphocyte proliferation. Furthermore, several similar sequences in other immunodeficiency viruses were found that also activate macrophages. These results led to the question if CpG-containing DNA, which is thought to play an immunostimulatory role in bacterial infections, has a similar role in infections by immunodeficiency viruses.