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.
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.
Zhou
Yan
Y
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Shen
Lin
L
Yang
Hung-Chih
HC
Siliciano
Robert F
RF
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D016923:Cell Death; D016207:Cytokines / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000503:physiopathology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000378:metabolism*; D048348:Reverse Transcription; D013997:Time Factors; D014774:Virulence
D016207:Cytokines; D019718:Receptors, CXCR4; D049452:Green Fluorescent Proteins