Preferential Cytolysis of Peripheral Memory CD4 + T Cells by In Vitro X4-Tropic Human Immunodeficiency Virus Type 1 Infection before the Completion of Reverse Transcription

Abstract

CD4+ T-cell depletion is the hallmark of AIDS pathogenesis. Multiple mechanisms may contribute to the death of productively infected CD4+ T cells and innocent-bystander cells. In this study, we characterize a novel mechanism in which human immunodeficiency virus type 1 (HIV-1) infection preferentially depletes peripheral memory CD4+ T cells before the completion of reverse transcription. Using a recombinant HIV-1 carrying the green fluorescent protein reporter gene, we demonstrate that memory CD4+ T cells were susceptible to infection-induced cell death at a low multiplicity of infection. Infected memory CD4+ T cells underwent rapid necrotic cell death. Killing of host cells was dependent on X4 envelope-mediated viral fusion, but not on virion-associated Vpr or Nef. In contrast to peripheral resting CD4+ T cells, CD4+ T cells stimulated by mitogen or certain cytokines were resistant to HIV-1-induced early cell death. These results demonstrate that early steps in HIV-1 infection have a detrimental effect on certain subsets of CD4+ T cells. The early cell death may serve as a selective disadvantage for X4-tropic HIV-1 in acute infection but may play a role in accelerated disease progression, which is associated with the emergence of X4-tropic HIV-1 in the late stage of AIDS.