The paradox of the immune response in HIV infection: when inflammation becomes harmful.

HIV-infection is associated with ongoing activation of the immune system and persistent inflammation. These are key driving forces in the loss of CD4+ T cells, progression to AIDS and development of non-HIV-related complications such as cardiovascular disease and certain cancers. Diseases associated with accelerated aging are increasing in incidence despite good anti-retroviral therapy (ART). The common underlying mechanism appears to be chronic inflammation. HIV-specific mechanisms as well as non-specific generalized responses to infection contribute to the chronic and aberrant activation of the immune system. An early loss of gut mucosal integrity, the pro-inflammatory cytokine milieu, co-infections and later, marked destruction of lymph node architecture are all factors contributing to the ongoing activation of both the innate and adaptive immune systems. These factors paradoxically promote CD4+ T cell loss, both by providing additional substrate for viral infection in the form of activated CD4+ T cells, as well as by priming non-infected 'bystander' CD4+ T cells for death by apoptosis. However, the relative contributions of each of these mechanisms to ongoing immune activation remain to be determined. Cost-effective markers of inflammation and selective anti-inflammatory agents are important fields of current and future research.