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Journal of Virology, December 2005, p. 15368-15375, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15368-15375.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Genetic and Stochastic Influences on the Interaction of Human Immunodeficiency Virus Type 1 and Cytotoxic T Lymphocytes in Identical Twins{dagger}

Otto O. Yang,1,2*,{ddagger} Joseph Church,3 Christina M. R. Kitchen,4 Ryan Kilpatrick,1 Ayub Ali,1 Yongzhi Geng,5 M. Scott Killian,1 Rachel Lubong Sabado,1 Hwee Ng,1 Jeffrey Suen,5 Yvonne Bryson,5 Beth D. Jamieson,1 and Paul Krogstad5,6,{ddagger}

UCLA AIDS Institute and Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California,1 Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, California,2 Childrens Hospital Los Angeles and the Keck School of Medicine of the University of Southern California, Los Angeles, California,3 Department of Biostatistics, School of Public Health, University of California, Los Angeles, California,4 Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California,5 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California6

Received 22 July 2005/ Accepted 27 September 2005

Human immunodeficiency virus type 1 (HIV-1) evolves in vivo under selective pressure from CD8+ T-lymphocyte (CTL) responses, which are in turn determined by host and viral genetic factors, such as restricting major histocompatibility complex molecules and the available viral epitope sequences. However, CTL are derived stochastically through the random gene rearrangements to produce T-cell receptors (TCR), and the relative impact of genetic versus stochastic processes on CTL targeting of HIV and immune-driven viral evolution is unclear. Here we evaluate identical twins infected with HIV-1 as neonates from a common blood transfusion, with subsequently similar environmental exposures, thereby allowing controlled comparisons of CTL targeting and viral evolution. Seventeen years after infection, their CTL targeting of HIV-1 was remarkably similar. In contrast, their overall TCR profiles were highly dissimilar, and a dominant epitope was recognized by distinctly different TCR in each twin. Furthermore, their viral epitopes had diverged, and there was ongoing viral phylogenetic divergence between the twins between 12 and 17 years after infection. These results indicate that while CTL targeting is predominately genetically determined, stochastic influences render the interaction of HIV-1 and host immunity, and therefore viral escape and CTL efficacy, unpredictable.

* Corresponding author. Mailing address: Division of Infectious Diseases, 37-121 CHS, UCLA Medical Center, 10833 LeConte Ave., Los Angeles, CA 90095. Phone: (310) 794-9491. Fax: (310) 825-3632. E-mail: oyang{at}mednet.ucla.edu.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} P.K. and O.O.Y. contributed equally to this work.

Journal of Virology, December 2005, p. 15368-15375, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15368-15375.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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