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CTL Fail to Accumulate at Sites of HIV-1 Replication in Lymphoid Tissue^1,2

Elizabeth Connick^3,*, Teresa Mattila, Joy M. Folkvord^*, Rick Schlichtemeier^*, Amie L. Meditz^*, M. Graham Ray^*, Martin D. McCarter, Samantha MaWhinney, Aaron Hage, Cara White and Pamela J. Skinner

^* Division of Infectious Diseases, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262; Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN 55108; Department of Surgery, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262; and Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262

The inability of HIV-1-specific CTL to fully suppress virus replication as well as the failure of administration of exogenous CTL to lower viral loads are not understood. To evaluate the hypothesis that these phenomena are due to a failure of CTL to localize at sites of HIV-1 replication, we assessed the distribution of HIV-1 RNA and HIV-1-specific CTL identified by HIV-1 peptide/HLA class I tetrameric complexes (tetramers) within lymph nodes of 14 HIV-1-infected individuals who were not receiving antiretroviral therapy. A median of 0.04% of follicular compared with 0.001% of extrafollicular CD4⁺ cells were estimated to be producing HIV-1 RNA, a 40-fold difference (p = 0.0001). Tetramer-stained cells were detected by flow cytometry in disaggregated lymph node cells from 11 subjects and constituted a significantly higher fraction of CD8⁺ cells in lymph node (mean, 2.15%) than in PBMC (mean, 1.52%; p = 0.02). In situ tetramer staining in three subjects’ lymph nodes, in which high frequencies of tetramer-stained cells were detected, revealed that tetramer-stained cells were primarily concentrated in extrafollicular regions of lymph node and were largely absent within lymphoid follicles. These data confirm that HIV-1-specific CTL are abundant within lymphoid tissues, but fail to accumulate within lymphoid follicles where HIV-1 replication is concentrated, suggesting that lymphoid follicles may be immune-privileged sites. Mechanisms underlying the exclusion of CTL from lymphoid follicles as well as the role of lymphoid follicles in perpetuating other chronic pathogens merit further investigation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Public Health Services Grants R29AI-42499, UO1AI-41536, PO1-AI-55356, and P30-AI-054907 from the National Institutes of Health.

² These data were presented in part at the 12th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 22–25, 2005 (Abstract 464).

³ Address correspondence and reprint requests to Dr. Elizabeth Connick, Division of Infectious Diseases, University of Colorado at Denver and Health Sciences Center, Box B168, 4200 East 9th Avenue, Denver, CO 80262. E-mail address: liz.connick{at}uchsc.edu

⁴ Abbreviations used in this paper: PBS-H, PBS supplemented with heparin; NGS, normal goat serum; B-LCL, B-lymphoblastoid cell line; CI, confidence interval; KSHV, Kaposi’s sarcoma herpes virus.