Abstract

T helper cells can support the functions of CD8⁺ T cells against persistently infecting viruses such as murine lymphocytic choriomeningitis virus (LCMV), cytomegalovirus, hepatitis C virus and HIV. These viruses often resist complete elimination and remain detectable at sanctuary sites, such as the kidneys and other extralymphatic organs. The mechanisms underlying this persistence are not well understood. Here we show that mice with potent virus-specific T-cell responses have reduced levels and delayed formation of neutralizing antibodies, and these mice fail to clear LCMV from extralymphatic epithelia. Transfer of virus-specific B cells but not virus-specific T cells augmented virus clearance from persistent sites. Virus elimination from the kidneys was associated with the formation of IgG deposits in the interstitial space, presumably from kidney-infiltrating B cells. CD8⁺ T cells in the kidneys of mice that did not clear virus from this site were activated but showed evidence of exhaustion. Thus, we conclude that in this model of infection, site-specific virus persistence develops as a consequence of potent immune activation coupled with reductions in virus-specific neutralizing antibodies. Our results suggest that sanctuary-site formation depends both on organ anatomy and on the induction of different adaptive immune effector mechanisms. Boosting T-cell responses alone may not reduce virus persistence.

1. Institute for Experimental Immunology, University Hospital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
2. Department for Internal Medicine, University Hospital Basel, 4031 Basel, Switzerland.
3. Department of Visceral and Transplantation Surgery, University Hospital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland.
4. German Rheumatology Research Center, Charité Platz 1, D-10117 Berlin, Germany.
5. Experimental Hematology, Department of Research, Basel University Hospital, 4031 Basel, Switzerland.
6. Pediatric Immunology, Center for Biomedicine, University of Basel and University Children's Hospital of Basel, Mattenstrasse 28, 4058 Basel, Switzerland and Transplantation Immunology and Nephrology, University Hospital Basel, 4031 Basel, Switzerland.
7. Department of Neuropathology, Georg August University, Goettingen, Germany.
8. Department of Pathology, University Hospital, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
9. Institute of Clinical Chemistry, University Hospital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland.
10. These authors contributed equally to this work.

Correspondence to: Mike Recher^1,10 e-mail: rechermike@bluewin.ch

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