Activated Peripheral CD8 Lymphocytes Express CD4 In Vivo and Are Targets for Infection by Human Immunodeficiency Virus Type 1

doi:10.1128/JVI.75.23.11555-11564.2001

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Journal of Virology, December 2001, p. 11555-11564, Vol. 75, No. 23
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.23.11555-11564.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Activated Peripheral CD8 Lymphocytes Express CD4 In Vivo and Are Targets for Infection by Human Immunodeficiency Virus Type 1

S. Imlach,¹ S. McBreen,¹ T. Shirafuji,¹ C. Leen,² J. E. Bell,³ and P. Simmonds¹^,^*

Laboratory for Clinical and Molecular Virology, University of Edinburgh, Summerhall, Edinburgh EH9 1QH,¹ and Regional Infectious Diseases Unit² and Department of Neuropathology,³ Western General Hospital, Edinburgh EH4 2XU, United Kingdom.

Received 2 May 2001/Accepted 20 August 2001

There is increasing evidence that CD8 lymphocytes may represent targets for infection by human immunodeficiency virus type1 (HIV-1) in vivo whose destruction may contribute to the lossof immune function underlying AIDS. HIV-1 may infect thymic precursorcells destined to become CD4 and CD8 lymphocytes and contributeto the numerical decline in both subsets on disease progression.There is also evidence for the induction of CD4 expression andsusceptibility to infection by HIV-1 of CD8 lymphocytes activatedin vitro. To investigate the relationship between CD8 activationand infection by HIV-1 in vivo, activated subsets of CD8 lymphocytesin peripheral blood mononuclear cells (PBMCs) of HIV-seropositiveindividuals were investigated for CD4 expression and HIV infection.Activated CD8 lymphocytes were identified by expression of CD69,CD71, and the human leukocyte antigen (HLA) class II, the $beta$ -chainof CD8, and the RO isoform of CD45. CD4⁺ and CD4 CD8 lymphocytes, CD4 lymphocytes, other T cells, and non-T cellswere purified using paramagnetic beads, and proviral sequenceswere quantified by PCR using primers from the long terminal repeatregion. Frequencies of activated CD8 lymphocytes were higher inHIV-infected study subjects than in seronegative controls, andthey frequently coexpressed CD4 (mean frequencies on CD69⁺, CD71⁺, and HLA class II⁺ cells of 23, 37, and 8%, respectively, compared with 1 to 2%for nonactivated CD8 lymphocytes). The level of CD4 expressionof the double-positive population approached that of mature CD4lymphocytes. That CD4 expression renders CD8 cell susceptibleto infection was indicated by their high frequency of infectionin vivo; infected CD4⁺ CD8 lymphocytes accounted for between 3 and 72% of the totalproviral load in PBMCs from five of the eight study subjects investigated,despite these cells representing a small component of the PBMCpopulation (<3%). Combined, these findings provide evidence thatantigenic stimulation of CD8 lymphocytes in vivo induces CD4 expressionthat renders them susceptible to HIV infection and destruction.The specific targeting of responding CD8 lymphocytes may providea functional explanation for the previously observed impairmentof cytotoxic T-lymphocyte (CTL) function disproportionate to theirnumerical decline in AIDS and for the deletion of specific clonesof CTLs responding to HIVantigens.

^* Corresponding author. Mailing address: Laboratory for Clinical and Molecular Virology, University of Edinburgh, Summerhall,Edinburgh EH9 1QH, United Kingdom. Phone: 44 131 650 7927. Fax:44 131 650 7965. E-mail: Peter.Simmonds{at}ed.ac.uk.

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