Pathogenicity of human immunodeficiency virus (HIV) is determined by the level of viral gene expression, biologic features of the infecting virus strain, and the immune response to infection. HIV gene expression is regulated by cellular and viral factors. The nuclear factor kappa B protein is a potentially important cellular protein involved in HIV gene expression, whereas TAT is a viral protein critical for viral RNA synthesis. Differences in biologic features of HIV-1 strains that affect pathogenicity include differences in cell-specific tropism and cytopathogenicity. These properties are regulated primarily by the envelope protein. Variation in virus strains during the progression of HIV infection results in alterations in both of these characteristics, with an outgrowth of HIV species unable to infect macrophages, and with enhanced replication rate and syncytium formation in primary lymphocytes.