Immunoglobulin class switching from immunoglobulin M (IgM) to IgG and IgA is central to immunity against viruses and requires the activation of B cells by T cells via CD154 (CD40 ligand) and cytokines. These molecules limit their signaling activity in immune cells by turning on negative feedback proteins, including IκB and SOCS. We show here that negative factor (Nef) protein, an immunosuppressive human immunodeficiency virus 1 protein expressed and released by infected cells, penetrates B cells both in vivo and in vitro. Nef suppressed immunoglobulin class-switch DNA recombination by inducing IκBα and SOCS proteins, which blocked CD154 and cytokine signaling via NF-κB and STAT transcription factors. Thus, human immunodeficiency virus 1 may evade protective T cell-dependent IgG and IgA responses by 'hijacking' physiological feedback inhibitors in B cells via Nef.