Co-dependence of HTLV-1 p12 and p8 functions in virus persistence.
HTLV-1 orf-I is linked to immune evasion, viral replication and persistence. Examining the orf-I sequence of 160 HTLV-1-infected individuals; we found polymorphism of orf-I that alters the relative amounts of p12 and its cleavage product p8. Three groups were identified on the basis of p12 and p8 expression: predominantly p12, predominantly p8 and balanced expression of p12 and p8. We found a significant association between balanced expression of p12 and p8 with high viral DNA loads, a correlate of disease development. To determine the individual roles of p12 and p8 in viral persistence, we constructed infectious molecular clones expressing p12 and p8 (D26), predominantly p12 (G29S) or predominantly p8 (N26). As we previously showed, cells expressing N26 had a higher level of virus transmission in vitro. However, when inoculated into Rhesus macaques, cells producing N26 virus caused only a partial seroconversion in 3 of 4 animals and only 1 of those animals was HTLV-1 DNA positive by PCR. None of the animals exposed to G29S virus seroconverted or had detectable viral DNA. In contrast, 3 of 4 animals exposed to D26 virus seroconverted and were HTLV-1 positive by PCR. In vitro studies in THP-1 cells suggested that expression of p8 was sufficient for productive infection of monocytes. Since orf-I plays a role in T-cell activation and recognition; we compared the CTL response elicited by CD4+ T-cells infected with the different HTLV-1 clones. Although supernatant p19 levels and viral DNA loads for all four infected lines were similar, a significant difference in Tax-specific HLA.A2-restricted killing was observed. Cells infected with Orf-I-knockout virus (12KO), G29S or N26 were killed by CTLs, whereas cells infected with D26 virus were resistant to CTL killing. These results indicate that efficient viral persistence and spread require the combined functions of p12 and p8.
Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, Maryland, United States of America.
Cynthia A
CA
Pise-Masison
Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, Maryland, United States of America.
Maria Fernanda
MF
de Castro-Amarante
Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, United States of America.
Yoshimi
Y
Enose-Akahata
Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, Maryland, United States of America.
R Cody
RC
Buchmann
Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, Maryland, United States of America.
Claudio
C
Fenizia
Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, Maryland, United States of America.
Robyn
R
Washington Parks
Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, Maryland, United States of America.
Dustin
D
Edwards
Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, Maryland, United States of America.
Martina
M
Fiocchi
Oswaldo Cruz Foundation Salvador, Bahia, Brazil.
Luiz Carlos
LC
Alcantara
Department of General and Experimental Pathology, Medical University in Białystok, Białystok, Poland.
Izabela
I
Bialuk
Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, United States of America.
Jhanelle
J
Graham
Evolutionary Biology, Genetic Diversity Centre, University of Basel, Basel, Switzerland.
Jean-Claude
JC
Walser
Vaccine Branch Flow Cytometry Core Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Katherine
K
McKinnon
Oswaldo Cruz Foundation Salvador, Bahia, Brazil.
Bernardo
B
Galvão-Castro
Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Batiment Lwoff, Institut Pasteur, Paris, France.
Antoine
A
Gessain
Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland, United States of America.
David
D
Venzon
Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, United States of America.
Steven
S
Jacobson
Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, Maryland, United States of America.
Genoveffa
G
Franchini
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D004279:DNA, Viral / Q000097:blood / Q000235:genetics / Q000276:immunology; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000235:genetics / Q000276:immunology*; D055785:Gene Knockdown Techniques; D015490:HTLV-I Infections / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D004279:DNA, Viral; D054334:Viral Regulatory and Accessory Proteins; C084305:p12I protein, Human T-lymphotropic virus 1