Multi-step pathogenesis of AIDS - role of cytomegalovirus

Human immunodeficiency virus (HIV) has been shown to be the initial aetiological agent of the acquired immune deficiency syndrome (AIDS). The recent clinical, epidemiologic, pathological, immunological and molecular data presented in this review point to a multi-step pathogenesis of AIDS involving HIV as an initial cause leading to reactivation of cytomegalovirus (CMV), human herpsevirus-6 (HH-6) and other immunosuppressive organisms. Although the onset of CMV reactivation is not precisely known, it may be related to the transition from AIDS-related complex to AIDS. The molecular interactions between CMV and HIV occur in both directions. Although transcriptional activation of HIV by CMV infection (possibly via induction of NFxB) is better known, the enhancement of CMV repication by HIV is clinically as important. The interactions between HIV or simian immunodeficiency virus (SIV) and CMV appear to be more specific than between HIV or SIV and other herpes viruses, and are also cell-type-dependent. CMV-induced immune suppression (possibly of variable magnitude with different strains) may be an additional co-factor in AIDS. In a rhesus monkey model, the interaction of SIV with rhesus CMV appears contributory to the reproduction of the full-blown simian AIDS. Patients with AIDS and disseminated CMV infection display the maximum activation of HIV p24 antigenaenmia and the greatest deficiency of CD8⁺ T lymphocytes. Defects in CD4⁺ and CD8⁺ T cells, including HIV- and CMV-specific cytotoxic T cells, are crucially important in the progression to terminal AIDS and are related not only to HIV but also to CMV and HH-6 infections of lymphocytes. CMV-HIV coinfection of the bone marrow, the nervous system and the adrenal gland may provide explanation of puzzling complications of AIDS, such as leukopenia, pancytopenia, hypotension and rapidly progressive encephalopathy. Besides the known antiretrovial effects, anti-HIV and immunomodulatory therapies may be controlling CMV reactivation.