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Journal of Virology, May 2002, p. 4222-4232, Vol. 76, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.9.4222-4232.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Effect of the V3 Loop Deletion of Envelope Glycoprotein on Cellular Responses and Protection against Challenge with Recombinant Vaccinia Virus Expressing gp160 of Primary Human Immunodeficiency Virus Type 1 Isolates

Irena Kiszka,¹ Dariusz Kmieciak,^1, Jaroslaw Gzyl,¹ Toshio Naito,¹ Elizabeth Bolesta,¹ Aleksander Sieron,² Satya P. Singh,³ Alagarsamy Srinivasan,³ Giorgio Trinchieri,⁴ Yutaro Kaneko,⁵ and Danuta Kozbor^1*

Center for Neurovirology and Cancer Biology, Temple University, Philadelphia, Pennsylvania 19122,¹ Department of Pathology and Laboratory Medicine, School of Medicine, MCP Hahnemann, Philadelphia, Pennsylvania 19102,² Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107,³ The Wistar Institute, Philadelphia, Pennsylvania 19104,⁴ Pharmaceutical Division, Ajinomoto Co., Inc., Tokyo 104, Japan⁵

Received 3 December 2001/ Accepted 30 January 2002

The magnitude and breadth of cytotoxic-T-lymphocyte (CTL) responses induced by human immunodeficiency virus type 1 (HIV-1) envelope protein from which the hypervariable V3 loop had been deleted (V3) were evaluated in the HLA-A2/K^b transgenic mice. It was demonstrated that vaccines expressing the V3 mutant of either HIV-1_IIIB or HIV-1_89.6 envelope glycoprotein induced broader CD8⁺ T-cell activities than those elicited by the wild-type (WT) counterparts. Specifically, the differences were associated with higher responses to conserved HLA-A2-restricted CTL epitopes of the envelope glycoprotein and could be correlated with an increased cell surface occupancy by the epitope-HLA-A2 complexes in target cells expressing the V3 mutant. Using recombinant vaccinia virus expressing heterologous gp160 of primary HIV-1 isolates in a murine challenge system, we observed that the extent of resistance to viral transmission was higher in animals immunized with the V3 than the WT envelope vaccine. The protection was linked to the presence of envelope-specific CD8⁺ T cells, since depletion of these cells by anti-CD8 antibody treatment at the time of challenge abolished the vaccine-induced protection. The results from our studies provide insights into approaches for boosting the breadth of envelope-specific CTL responses.

Present address: Department of Biochemistry and Molecular Biology, University of Medical Sciences, Poznan, Poland.

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