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Journal of Virology, October 2006, p. 10162-10172, Vol. 80, No. 20
0022-538X/06/$08.00+0     doi:10.1128/JVI.00249-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Infection of CD127+ (Interleukin-7 Receptor+) CD4+ Cells and Overexpression of CTLA-4 Are Linked to Loss of Antigen-Specific CD4 T Cells during Primary Human Immunodeficiency Virus Type 1 Infection

John J. Zaunders,1* Susanna Ip,1,2 Mee Ling Munier,1,2 Daniel E. Kaufmann,3 Kazuo Suzuki,1 Choechoe Brereton,1 Sarah C. Sasson,1,2 Nabila Seddiki,4 Kersten Koelsch,1,2 Alan Landay,5 Pat Grey,2 Robert Finlayson,6 John Kaldor,2 Eric S. Rosenberg,3 Bruce D. Walker,3 Barbara Fazekas de St. Groth,4 David A. Cooper,1,2 Anthony D. Kelleher,1,2 on Behalf of the PHAEDRA Study Team,{dagger}

Centre for Immunology, St. Vincent's Hospital, Sydney, NSW, Australia,1 National Centre in HIV Epidemiology and Clinical Research, University of NSW, Sydney, NSW, Australia,2 Partners AIDS Research Center, Massachusetts General Hospital, Boston, Massachusetts,3 Centenary Institute of Cancer Medicine and Cell Biology, Sydney, NSW, Australia,4 Rush University, Chicago, Illinois,5 Taylor Square Private Clinic, Sydney, NSW, Australia6

Received 3 February 2006/ Accepted 6 July 2006

We recently found that human immunodeficiency virus (HIV)-specific CD4+ T cells express coreceptor CCR5 and activation antigen CD38 during early primary HIV-1 infection (PHI) but then rapidly disappear from the circulation. This cell loss may be due to susceptibility to infection with HIV-1 but could also be due to inappropriate apoptosis, an expansion of T regulatory cells, trafficking out of the circulation, or dysfunction. We purified CD38+++CD4+ T cells from peripheral blood mononuclear cells, measured their level of HIV-1 DNA by PCR, and found that about 10% of this population was infected. However, a small subset of HIV-specific CD4+ T cells also expressed CD127, a marker of long-term memory cells. Purified CD127+CD4+ lymphocytes contained fivefold more copies of HIV-1 DNA per cell than did CD127-negative CD4+ cells, suggesting preferential infection of long-term memory cells. We observed no apoptosis of antigen-specific CD4+ T cells in vitro and only a small increase in CD45RO+CD25+CD127dimCD4+ T regulatory cells during PHI. However, 40% of CCR5+CD38+++ CD4+ T cells expressed gut-homing integrins, suggesting trafficking through gut-associated lymphoid tissue (GALT). Furthermore, 80% of HIV-specific CD4+ T cells expressed high levels of the negative regulator CTLA-4 in response to antigen stimulation in vitro, which was probably contributing to their inability to produce interleukin-2 and proliferate. Taken together, the loss of HIV-specific CD4+ T cells is associated with a combination of an infection of CCR5+ CD127+ memory CD4+ T cells, possibly in GALT, and a high expression of the inhibitory receptor CTLA-4.

* Corresponding author. Mailing address: Centre for Immunology, St. Vincent's Hospital, Victoria St., Darlinghurst, NSW 2010, Australia. Phone: 61-2-8382-3700. Fax: 61-2-8382-2391. E-mail: j.zaunders{at}cfi.unsw.edu.au.

{dagger} Members of the PHAEDRA Study Team are P. Grey, J. Kaldor, D. A. Cooper, T. Ramacciotti, K. Petoumenos, D. Smith, M. Bloch, N. Medland, R. Finlayson, A. McFarlane, N. J. Roth, C. Workman, A. Carr, A. D. Kelleher, J. Zaunders, and P. Cunningham.

Journal of Virology, October 2006, p. 10162-10172, Vol. 80, No. 20
0022-538X/06/$08.00+0     doi:10.1128/JVI.00249-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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