The typical course of HIV infection is characterized by multiple phases that occur over a period of eight to ten years. A critical event in the initial establishment of HIV infection is the localization of HIV in lymphoid organs that serve as major reservoirs for HIV and as primary sites for virus replication. Despite the fact that the majority of HIV-infected individuals do not show any clinical signs of disease activity for extended periods of time, HIV disease is active and progressive in lymphoid organs during this clinically latent period. Persistence of virus in lymphoid organs causes a chronic stimulation of the immune system that ultimately leads to destruction of the lymphoid tissue and loss of the ability to respond to HIV and/or other pathogens. Major expansions of restricted subsets of CD8+ T cells determined by the usage of certain variable domains (V) of the beta (beta) chain of the T cell receptor (TCR) occur in certain patients during primary HIV infection. These restricted expansions of CD8+ V beta subsets are oligoclonal and represent HIV-specific immune responses with cytolytic T cell activity. Although only limited numbers of patients were studied thus far, certain patterns have emerged that appear to correlate with the subsequent clinical outcome. It is conceivable that immunologic and virologic events associated with primary infection have a major impact on the ultimate course of HIV disease. Histopathologic, virologic, and immunologic studies of long-term nonprogressors (LTNP) indicate that a small proportion of patients who have been HIV-infected for approximately 10 years have normal lymph node architecture, brisk HIV-specific humoral and cellular immune responses, and high and stable CD4+ T cell counts serially determined over years. Viral burden and expression are low in these patients; however, low levels of viremia are present, and virus derived from mononuclear cells is replication competent and infectious in most patients. Studies of events associated with primary HIV infection, examination of lymphoid tissue at various stages of disease, and dissection of the immunologic and virologic components of LTNP should contribute substantially to our understanding of the pathogenesis of HIV disease.