title: Vaccination against endogenous retrotransposable element consensus sequences does not protect rhesus macaques from SIVsmE660 infection and replication.
abstract: The enormous sequence diversity of HIV remains a major roadblock to the development of a prophylactic vaccine and new approaches to induce protective immunity are needed. Endogenous retrotransposable elements (ERE) such as endogenous retrovirus K (ERV)-K and long interspersed nuclear element-1 (LINE-1) are activated during HIV-1-infection and could represent stable, surrogate targets to eliminate HIV-1-infected cells. Here, we explored the hypothesis that vaccination against ERE would protect macaques from acquisition and replication of simian immunodeficiency virus (SIV). Following vaccination with antigens derived from LINE-1 and ERV-K consensus sequences, animals mounted immune responses that failed to delay acquisition of SIVsmE660. We observed no differences in acute or set point viral loads between ERE-vaccinated and control animals suggesting that ERE-specific responses were not protective. Indeed, ERE-specific T cells failed to expand anamnestically in vivo following infection with SIVsmE660 and did not recognize SIV-infected targets in vitro, in agreement with no significant induction of targeted ERE mRNA by SIV in macaque CD4+ T cells. Instead, lower infection rates and viral loads correlated significantly to protective TRIM5α alleles. Cumulatively, these data demonstrate that vaccination against the selected ERE consensus sequences in macaques did not lead to immune-mediated recognition and killing of SIV-infected cells, as has been shown for HIV-infected human cells using patient-derived HERV-K-specific T cells. Thus, further research is required to identify the specific nonhuman primate EREs and retroviruses that recapitulate the activity of HIV-1 in human cells. These results also highlight the complexity in translating observations of the interplay between HIV-1 and human EREs to animal models.
authors.affiliation: Vaccine Research, Worldwide R&D, Pfizer Inc., San Diego, California, United States of America.
authors.forename: Neil C
authors.initials: NC
authors.lastname: Sheppard
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON, Canada.
authors.forename: R Brad
authors.initials: RB
authors.lastname: Jones
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States of America; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, United States of America.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Burwitz
authors.affiliation: Wisconsin National Primate Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Francesca A
authors.initials: FA
authors.lastname: Nimityongskul
authors.affiliation: Wisconsin National Primate Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Laura P
authors.initials: LP
authors.lastname: Newman
authors.affiliation: Wisconsin National Primate Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Buechler
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States of America; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, United States of America.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Reed
authors.affiliation: Wisconsin National Primate Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Shari M
authors.initials: SM
authors.lastname: Piaskowski
authors.affiliation: Wisconsin National Primate Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Kim L
authors.initials: KL
authors.lastname: Weisgrau
authors.affiliation: Wisconsin National Primate Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Castrovinci
authors.affiliation: Wisconsin National Primate Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Wilson
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON, Canada.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
authors.affiliation: Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Byung
authors.initials: B
authors.lastname: Park
authors.affiliation: Division of Experiment Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.affiliation: Wisconsin National Primate Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Eva G
authors.initials: EG
authors.lastname: Rakasz
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States of America; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, United States of America; Department of Medical Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Jonah B
authors.initials: JB
authors.lastname: Sacha
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016384:Consensus Sequence; D015686:Gene Products, env / Q000276:immunology; D015683:Gene Products, gag / Q000276:immunology; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008253:Macaca mulatta / Q000276:immunology* / Q000821:virology; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018626:Retroelements / Q000276:immunology*; D018449:SAIDS Vaccines / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D044767:Ubiquitin-Protein Ligases; D014611:Vaccination; D014779:Virus Replication / Q000502:physiology*
chemical_list: D015686:Gene Products, env; D015683:Gene Products, gag; D011506:Proteins; D012333:RNA, Messenger; D018626:Retroelements; D018449:SAIDS Vaccines; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases