CD4+ T cell-mediated presentation of non-infectious HIV-1 virion antigens to HIV-specific CD8+ T cells

Abstract

The mechanism of chronic immune activation and impairment of HIV-specific immune responses during chronic infection is not fully understood. However, it is known that high immune activation leads to more rapid progression to AIDS. We hypothesize that CD4(+) T cell-mediated viral antigen presentation contributes to this pathologic immune activation in HIV-infected individuals. HIV-specific T cells, responding to noninfectious HIV-1 virions as antigen, were measured by flow cytometric assays. These experimental conditions reflect the in vivo condition where noninfectious HIV-1 represents more than 99% of the antigens. CD4(+) T cells purified from HIV-infected individuals were capable of cross presenting exogenous noninfectious HIV-1 virions to HIV-1-specific CD8(+) T cells. Cross presentation required the entry of HIV-1 to CD4(+) T cells and antigen translocation from endoplasmic reticulum to the Golgi complex. Blocking CD4(+) mediated activation of HIV-specific CD8(+) T cells and redirecting the viral antigens to antigen presenting cells improved HIV-specific T cell responses. One possible cause of chronic immune activation and impairment of HIV-1 specific T cell responses is represented by HIV-1 harboring CD4(+) T cells cross presenting HIV-1 antigen to activate CD8(+) T cells. This new mechanism provides the first evidence that cross presentation of noninfectious HIV-1 virions play a role in the immunopathogenesis of HIV-1 infection.