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Journal of Virology, November 2005, p. 13953-13962, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.13953-13962.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Sexual Transmission of Single Human Immunodeficiency Virus Type 1 Virions Encoding Highly Polymorphic Multisite Cytotoxic T-Lymphocyte Escape Variants

Anita Milicic,^1, Charles T. T. Edwards,^1, Stéphane Hué,¹ Julie Fox,² Helen Brown,¹ Tilly Pillay,¹ Jan W. Drijfhout,³ Jonathan N. Weber,² Edward C. Holmes,⁴ Sarah J. Fidler,² Hua-Tang Zhang,^1, and Rodney E. Phillips^1*,

The Peter Medawar Building for Pathogen Research and The James Martin 21st Century School, Nuffield Department of Clinical Medicine, University of Oxford, South Parks Road, Oxford OX1 3SY, United Kingdom,¹ Jefferiss Research Laboratories, Wright-Fleming Institute, Imperial College London, St. Mary's Hospital, Norfolk Place, London W2 1PG, United Kingdom,² Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, P.O. Box 9600, 2300 Leiden, The Netherlands,³ Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, United Kingdom⁴

Received 6 February 2005/ Accepted 7 August 2005

Antigenic variation inherent in human immunodeficiency virus type 1 (HIV-1) virions that successfully instigate new infections transferred by sex has not been well defined. Yet this is the viral "challenge" which any vaccine-induced immunity must deal with. Closely timed comparisons of the virus circulating in the "donor" and that which initiates new infection are difficult to carry out rigorously, as suitable samples are very hard to get in the face of ethical hurdles. Here we investigate HIV-1 variation in four homosexual couples where we sampled blood from both parties within several weeks of the estimated transmission event. We analyzed variation within highly immunogenic HIV-1 internal proteins encoding epitopes recognized by cytotoxic Tlymphocytes (CTLs). These responses are believed to be crucial as a means of containing viral replication. In the donors we detected virions capable of evading host CTL recognition at several linked epitopes of distinct HLA class I restriction. When a donor transmitted escape variants to a recipient with whom he had HLA class I molecules in common, the recipient's CTL response to those epitopes was prevented, thus impeding adequate viral control. In addition, we show that even when HLA class I alleles are disparate in the transmitting couple, a single polymorphism can abolish CTL recognition of an overlapping epitope of distinct restriction and so confer immune escape properties to the recipient's seroconversion virus. In donors who are themselves controlling an early, acute infection, the precise timing of onward transmission is a crucial determinant of the viral variants available to compose the inoculum.

A.M. and C.T.T.E. contributed equally to this study.

R.E.P. and H.-T.Z. share senior authorship.

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