T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection

PLoS Pathogens

Seth Rakoff-Nahoum¹  R. Brad Jones²  Mario A Ostrowski²  Naveed Anwar²  Jack Lenz³  Joan M Chapman⁴  Ann L Erickson⁴  Keith E Garrison⁴  Lishomwa C Ndhlovu⁴  Ashish Agrawal⁵  Duncan A Meiklejohn⁵  Frederick M Hecht⁶  Gerald Spotts⁶  Douglas F Nixon⁷ 

[1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America;Department of Immunology, University of Toronto, Toronto, Ontario, Canada;Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America;Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America;Gladstone Institute of Virology and Immunology, University of California San Francisco, San Francisco, California, United States of America;Positive Health Program, Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America;St. Michael's Hospital, Toronto, Ontario, Canada

关键词: T cells;    HIV-1;    Cytotoxic T cells;    Amino acid sequence analysis;    Viral load;    Immune response;    HIV;    Retroviruses;   

DOI  :  10.1371/journal.ppat.0030165

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Human endogenous retroviruses (HERVs) are remnants of ancient infectious agents that have integrated into the human genome. Under normal circumstances, HERVs are functionally defective or controlled by host factors. In HIV-1-infected individuals, intracellular defense mechanisms are compromised. We hypothesized that HIV-1 infection would remove or alter controls on HERV activity. Expression of HERV could potentially stimulate a T cell response to HERV antigens, and in regions of HIV-1/HERV similarity, these T cells could be cross-reactive. We determined that the levels of HERV production in HIV-1-positive individuals exceed those of HIV-1-negative controls. To investigate the impact of HERV activity on specific immunity, we examined T cell responses to HERV peptides in 29 HIV-1-positive and 13 HIV-1-negative study participants. We report T cell responses to peptides derived from regions of HERV detected by ELISPOT analysis in the HIV-1-positive study participants. We show an inverse correlation between anti-HERV T cell responses and HIV-1 plasma viral load. In HIV-1-positive individuals, we demonstrate that HERV-specific T cells are capable of killing cells presenting their cognate peptide. These data indicate that HIV-1 infection leads to HERV expression and stimulation of a HERV-specific CD8+ T cell response. HERV-specific CD8+ T cells have characteristics consistent with an important role in the response to HIV-1 infection: a phenotype similar to that of T cells responding to an effectively controlled virus (cytomegalovirus), an inverse correlation with HIV-1 plasma viral load, and the ability to lyse cells presenting their target peptide. These characteristics suggest that elicitation of anti-HERV-specific immune responses is a novel approach to immunotherapeutic vaccination. As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant. HERV-specific immunity is an important new avenue for investigation in HIV-1 pathogenesis and vaccine design.

【 授权许可】

CC BY