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Journal of Virology, August 2007, p. 8439-8450, Vol. 81, No. 16
0022-538X/07/$08.00+0     doi:10.1128/JVI.00199-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Decreased CXCR3+ CD8 T Cells in Advanced Human Immunodeficiency Virus Infection Suggest that a Homing Defect Contributes to Cytotoxic T-Lymphocyte Dysfunction{triangledown}

Diana M. Brainard,1,2 Andrew M. Tager,1 Joseph Misdraji,3 Nicole Frahm,2 Mathias Lichterfeld,2 Rika Draenert,4 Christian Brander,2 Bruce D. Walker,2 and Andrew D. Luster1*

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129,1 Partners AIDS Research Center, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Charlestown, Massachusetts 02129,2 Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114,3 Medizinische Poliklinik, Ludwig-Maximilians-Universitaet, Muenchen, Germany4

Received 29 January 2007/ Accepted 13 May 2007

To exert their cytotoxic function, cytotoxic T-lymphocytes (CTL) must be recruited into infected lymphoid tissue where the majority of human immunodeficiency virus (HIV) replication occurs. Normally, effector T cells exit lymph nodes (LNs) and home to peripheral sites of infection. How HIV-specific CTL migrate into lymphoid tissue from which they are normally excluded is unknown. We investigated which chemokines and receptors mediate this reverse homing and whether impairment of this homing could contribute to CTL dysfunction as HIV infection progresses. Analysis of CTL chemokine receptor expression in the blood and LNs of untreated HIV-infected individuals with stable, chronic infection or advanced disease demonstrated that LNs were enriched for CXCR3+ CD8 T cells in all subjects, suggesting a key role for this receptor in CTL homing to infected lymphoid tissue. Compared to subjects with chronic infection, however, subjects with advanced disease had fewer CXCR3+ CD8 T cells in blood and LNs. CXCR3 expression on bulk and HIV-specific CD8 T cells correlated positively with CD4 count and negatively with viral load. In advanced infection, there was an accumulation of HIV-specific CD8 T cells at the effector memory stage; however, decreased numbers of CXCR3+ CD8 T cells were seen across all maturation subsets. Plasma CXCL9 and CXCL10 were elevated in both infected groups in comparison to the levels in uninfected controls, whereas lower mRNA levels of CXCR3 ligands and CD8 in LNs were seen in advanced infection. These data suggest that both CXCR3+ CD8 T cells and LN CXCR3 ligands decrease as HIV infection progresses, resulting in reduced homing of CTL into LNs and contributing to immune dysfunction.

* Corresponding author. Mailing address: Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129. Phone: (617) 726-5710. Fax: (617) 726-5651. E-mail: aluster{at}partners.org

{triangledown} Published ahead of print on 6 June 2007.

Journal of Virology, August 2007, p. 8439-8450, Vol. 81, No. 16
0022-538X/07/$08.00+0     doi:10.1128/JVI.00199-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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