Genetic variation of human immunodeficiency virus (HIV) over time is an important consideration in long-term antiretroviral therapy, in all likelihood affecting the course of HIV disease and its response to antiretroviral therapy. Viral replication persists throughout HIV disease, and viral burden is correlated with disease stage. CD4+ T-helper cells, a prime target for HIV, appear responsible for direct cellular and humoral responses to infection. HIV can be divided into three groups: nonsyncytium-inducing (NSI) isolates with low replicative capacity; high-replicative-capacity NSI isolates; and high-replicative-capacity, syncytium-inducing (SI) isolates. The SI phenotype also is associated with T-helper-cell tropism, rapid CD4+ cell count decline, and rapid HIV disease progression. In some HIV-infected individuals, SI variants evolve from NSI variants at approximate mean CD4+ cell counts of 400 to 500 cells/microliters. Appearance of SI variants may be a useful prognostic marker for decline in cell counts and more rapid progression to AIDS. However, SI variants are not required for HIV disease progression. Only about one-half of AIDS patients harbor SI variants, indicating that HIV that remains NSI can cause AIDS and death. Zidovudine resistance has been found (in ACTG 116B/117) to be an independent predictor of HIV disease progression. Zidovudine resistance and SI phenotype together are closely associated with rapid HIV disease progression.