title: T cell responses to human endogenous retroviruses in HIV-1 infection.
abstract: 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.
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America. keith.garrison@ucsf.edu
authors.forename: Keith E
authors.initials: KE
authors.lastname: Garrison
authors.forename: R Brad
authors.initials: RB
authors.lastname: Jones
authors.forename: Duncan A
authors.initials: DA
authors.lastname: Meiklejohn
authors.forename: Naveed
authors.initials: N
authors.lastname: Anwar
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
authors.forename: Joan M
authors.initials: JM
authors.lastname: Chapman
authors.forename: Ann L
authors.initials: AL
authors.lastname: Erickson
authors.forename: Ashish
authors.initials: A
authors.lastname: Agrawal
authors.forename: Gerald
authors.initials: G
authors.lastname: Spotts
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.forename: Seth
authors.initials: S
authors.lastname: Rakoff-Nahoum
authors.forename: Jack
authors.initials: J
authors.lastname: Lenz
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
mesh_terms: D000956:Antigens, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D020077:Endogenous Retroviruses / Q000276:immunology*; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1; D006801:Humans; D012367:RNA, Viral / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019562:Viral Load
chemical_list: D000956:Antigens, Viral; D012367:RNA, Viral