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Journal of Virology, January 2002, p. 688-696, Vol. 76, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.2.688-696.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Simian Immunodeficiency Virus {Delta}nef Vaccine, after Application to the Tonsils of Rhesus Macaques, Replicates Primarily within CD4+ T Cells and Elicits a Local Perforin-Positive CD8+ T-Cell Response

Christiane Stahl-Hennig,1 Ralph M. Steinman,2 Peter Ten Haaft,3 Klaus Überla,4 Nicole Stolte,1 Sem Saeland,5 Klara Tenner-Racz,6 and Paul Racz6*

German Primate Center, 37077 Göttingen, Germany,1 Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York 10021-6399,2 Department of Virology, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands,3 Department of Molecular and Medical Virology, Ruhr University, Bochum 44780, Germany,4 Laboratory for Immunological Research, Schering-Plough, 69571 Dardilly, France,5 Department of Pathology and Körber Laboratory for AIDS Research, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany6

Received 2 August 2001/ Accepted 9 October 2001

Deletion of the nef gene from simian immunodeficiency virus (SIV) strain SIVmac239 yields a virus that undergoes attenuated growth in rhesus macaques and offers substantial protection against a subsequent challenge with some SIV wild-type viruses. We used a recently described model to identify sites in which the SIV{Delta}nef vaccine strain replicates and elicits immunity in vivo. A high dose of SIV{Delta}nef was applied to the palatine and lingual tonsils, where it replicated vigorously in this portal of entry at 7 days. Within 2 weeks, the virus had spread and was replicating actively in axillary lymph nodes, primarily in extrafollicular T-cell-rich regions but also in germinal centers. At this time, large numbers of perforin-positive cells, both CD8+ T cells and CD3-negative presumptive natural killer cells, were found in the tonsil and axillary lymph nodes. The number of infected cells and perforin-positive cells then fell. When autopsy studies were carried out at 26 weeks, only 1 to 3 cells hybridized for viral RNA per section of lymphoid tissue. Nevertheless, infected cells were detected chronically in most lymphoid organs, where the titers of infectious virus could exceed by a log or more the titers in blood. Immunocytochemical labeling at the early active stages of infection showed that cells expressing SIV{Delta}nef RNA were CD4+ T lymphocytes. A majority of infected cells were not in the active cell cycle, since 60 to 70% of the RNA-positive cells in tissue sections lacked the Ki-67 cell cycle antigen, and both Ki-67-positive and -negative cells had similar grain counts for viral RNA. Macrophages and dendritic cells, identified with a panel of monoclonal antibodies to these cells, were rarely infected. We conclude that the attenuated growth and protection observed with the SIV{Delta}nef vaccine strain does not require that the virus shift its characteristic site of replication, the CD4+ T lymphocyte. In fact, this immunodeficiency virus can replicate actively in CD4+ T cells prior to being contained by the host, at least in part by a strong killer cell response that is generated acutely in the infected lymph nodes.

* Corresponding author. Mailing address: Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 77, 20359 Hamburg, Germany. Phone: 49 40 42818 499. Fax: 49 40 42818 544. E-mail: racz{at}bni.uni-hamburg.de.

Journal of Virology, January 2002, p. 688-696, Vol. 76, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.2.688-696.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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