Proposed mechanisms of NF-κB activation in HIV-1–infected cells. Several mechanisms may regulate NF-κB activity in HIV-1–infected cells. Binding of HIV-1 to CD4 leads to NF-κB activation via Lck/Raf and PI-3K/Akt. CD4 crosslinking induces Ras activation, which also leads to NF-κB activation. PKR, induced by low level IFN and HIV-1 transcripts, may induce IKK activation. Autocrine release of cytokines such as TNF-α and IL-1 may constitutively stimulate the signaling pathways leading to NF-κB activation. Activation of the IKK complex either directly by HIV-1 regulatory proteins or by cytokine release leads to the phosphorylation and degradation of IκBα and IκBβ, thus releasing NF-κB to translocate to the nucleus and transactivate responsive genes. Newly synthesized IκBβ enters the nucleus and prevents IκBα-mediated termination of the NF-κB response, thus maintaining constitutive NF-κB activity at the protein-DNA level and creating an intracellular environment conducive to viral replication.