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Journal of Virology, September 2008, p. 9154-9163, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00773-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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{triangledown} ,{dagger}

Yan Zhou,1 Lin Shen,1 Hung-Chih Yang,1 and Robert F. Siliciano1,2*

Department of Medicine, Johns Hopkins University School of Medicine,1 Howard Hughes Medical Institute, Baltimore, Maryland2

Received 9 April 2008/ Accepted 25 June 2008

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.

* Corresponding author. Mailing address: Department of Medicine, Johns Hopkins University School of Medicine, Ross 1049, 720 Rutland Ave., Baltimore, MD 21205. Phone: (410) 955-2958. Fax: (410) 955-0964. E-mail: rsiliciano{at}jhmi.edu

{triangledown} Published ahead of print on 2 July 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, September 2008, p. 9154-9163, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00773-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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