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Journal of Virology, September 2004, p. 9862-9871, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.9862-9871.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

High Levels of Human Immunodeficiency Virus Infection of CD8 Lymphocytes Expressing CD4 In Vivo

Alexandra Cochrane,1* Stuart Imlach,1,{dagger} Clifford Leen,2 Gordon Scott,3 Dermot Kennedy,4 and Peter Simmonds1

Laboratory for Clinical and Molecular Virology, University of Edinburgh,1 Regional Infectious Diseases Unit, Western General Hospital,2 Department of Genitourinary Medicine, Royal Infirmary of Edinburgh, Edinburgh,3 The Brownlee Centre, Gartnavel General Hospital, Glasgow, United Kingdom4

Received 17 March 2004/ Accepted 17 May 2004

Human immunodeficiency virus (HIV)-infected CD8 lymphocytes have been reported in vivo, but the mechanism of infection remains unclear. Experiments using the thy/hu mouse model support export of intrathymically infected CD8 precursors, while recent in vitro data suggest that mature CD8 lymphocytes upregulate CD4 upon activation (generating a CD8bright CD4dim phenotype) and are susceptible to HIV infection. To determine whether these mechanisms operate in vivo and to assess their relative importance in the generation of circulating HIV-infected CD8 lymphocytes, we quantified HIV long terminal repeat (LTR) DNA in CD8+ CD4– and CD8bright CD4dim lymphocytes isolated from HIV-infected individuals by fluorescence-activated cell sorting. HIV infection of CD8 lymphocytes was demonstrated in 17 of 19 subjects, with a significant inverse relationship between level of infection and CD4 lymphocyte count (R = –0.73; P < 0.001). The level of HIV infection of CD8bright CD4dim lymphocytes was significantly higher (median, 1,730 HIV LTR copies/106 cells; n = 9) than that of CD8+ CD4– lymphocytes (undetectable in seven of nine individuals; P < 0.01) and approached that of CD4 lymphocytes from the same individuals (median, 3,660 HIV LTR copies/106 cells). CD8bright CD4dim lymphocytes represented 0.8 to 3.3% of total CD8 lymphocytes and were most prevalent in the memory subset. Thus, HIV-infected CD8 lymphocytes commonly circulate in HIV-infected individuals and are generated through infection of activated CD8 lymphocytes rather than through export of intrathymically infected precursors. The high level of infection of CD8bright CD4dim lymphocytes could have a direct role in the decline in CD8 lymphocyte function that accompanies HIV disease progression.

* Corresponding author. Mailing address: Laboratory for Clinical and Molecular Virology, University of Edinburgh, Edinburgh EH9 1QH, United Kingdom. Phone: 44 (0)131 650 7945. Fax: 44 (0)131 650 7965. E-mail: alex.cochrane{at}ed.ac.uk.

{dagger} Present address: Moredun Research Institute, Pentlands Science Park, Bush Loan, Penicuik EH26 0PZ, United Kingdom.

Journal of Virology, September 2004, p. 9862-9871, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.9862-9871.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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