Mechanisms of loss of HIV-1-specific T-cell responses

Virus-specific T-cell responses, important for the control of HIV-1 infection, are seen in HIV-1-infected subjects in the early stages of infection. A progressive variable decline in HIV-1-specific CD4 and CD8 T-cell responses during the course of the infection is not reversed by the administration of potent antiretroviral drugs. The mechanisms responsible for this HIV-1-inflicted loss are complex, involving processes ranging from T-cell ontogeny to the final stages of antigen presentation and T-cell differentiation. HIV-1-specific CD4 and CD8 T cells are present in most patients, but have been rendered anergic, either directly by HIV-1 or indirectly by clonal inactivation, exhaustion and/or suppression. The absence of functional HIV-1-specific T cells in chronic infection, even after the initiation of antiretroviral therapy, indicates that additional immunomodulatory therapy is required. To induce or maintain such cellular responses in an immunosuppressed environment of chronic infection is proving difficult to achieve. The induction of virus-specific CD4 T-cell and, subsequently, CD8 T-cell responses may require different novel approaches based on an appreciation of the complex mechanisms involved in the loss of these responses.