113 Murder on the HIV Express: Insights into How CD4 T Cells Are Killed in Lymphoid Tissues

Abstract

The mechanism underlying CD4 T-cell depletion in HIV-infected hosts remains poorly understood. Loss of these cells underlies subsequent clinical development of AIDS. Both direct and indirect mechanisms of CD4 T cell killing have been proposed. In ex vivo cultures of primary human tonsil tissue, CD4 T cells undergo a dramatic cytopathic response following HIV infection. Strikingly, we find that 95% of these dying lymphoid cells are not productively infected with HIV but instead correspond to bystander cells that are abortively infected. Abortive infection reflects the non-permissive state of most resting CD4 T cells where the viral life cycle is arrested prior to the completion of reverse transcription. CD4 T cell killing is prevented by HIV entry and fusion inhibitors and by inhibitors that block the initiation of reverse transcription (NNRTI's including efavirenz and nevirapine). Conversely, RT inhibitors that act later in the reverse transcription process as chain terminators (NRTI's including AZT and 3TC) or inhibitors of viral integration (raltegravir) do not rescue CD4 T cells from this form of death. The accumulation of cytoplasmic viral DNA is sensed in these cells activating an innate immune reponse that ultimately culminates in death of the host cell. The nature of this innate response will be discussed. Together, these findings highlight how a protective host response centrally contributes to the demise of CD4 T cells during HIV infection ultimately culminating in AIDS.