title: Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis.
abstract: Although in decline after successful anti-HIV therapy, B-cell lymphomas are still elevated in HIV-1-seropositive (HIV+) persons, and the mechanisms are obscure. The HIV-1 matrix protein p17 persists in germinal centers long after HIV-1 drug suppression, and some p17 variants (vp17s) activate Akt signaling and promote growth of transformed B cells. Here we show that vp17s derived from four of five non-Hodgkin lymphoma (NHL) tissues from HIV+ subjects display potent B-cell growth-promoting activity. They are characterized by amino acid insertions at position 117-118 (Ala-Ala) or 125-126 (Gly-Asn or Gly-Gln-Ala-Asn-Gln-Asn) among some other mutations throughout the sequence. Identical dominant vp17s are found in both tumor and plasma. Three of seven plasma samples from an independent set of NHL cases manifested multiple Ala insertions at position 117-118, and one with the Ala-Ala profile also promoted B-cell growth and activated Akt signaling. Ultradeep pyrosequencing showed that vp17s with C-terminal insertions are more frequently detected in plasma of HIV+ subjects with than without NHL. Insertion of Ala-Ala at position 117-118 into reference p17 (refp17) was sufficient to confer B-cell growth-promoting activity. In contrast, refp17 bearing the Gly-Asn insertion at position 125-126 did not, suggesting that mutations not restricted to the C terminus can also account for this activity. Biophysical analysis revealed that the Ala-Ala insertion mutant is destabilized compared with refp17, whereas the Gly-Asn form is stabilized. This finding provides an avenue for further exploration of structure function relationships and new treatment strategies in combating HIV-1-related NHL.
authors.affiliation: Centro di Riferimento Oncologico Instituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, 33081 Aviano, Pordenone, Italy;
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dolcetti
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy;
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giagulli
authors.affiliation: Center for Translational Medicine, Xi'an Jiaotong University School of Life Science and Technology, Xi'an, Shaanxi 710048, China;
authors.forename: Wangxiao
authors.initials: W
authors.lastname: He
authors.affiliation: National Institute for Infectious Diseases "L. Spallanzani," 00149 Rome, Italy;
authors.forename: Marina
authors.initials: M
authors.lastname: Selleri
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Caccuri
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Eyzaguirre
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy;
authors.forename: Pietro
authors.initials: P
authors.lastname: Mazzuca
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Corbellini
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy;
authors.forename: Federica
authors.initials: F
authors.lastname: Campilongo
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Cosenza, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Marsico
authors.affiliation: National Institute for Infectious Diseases "L. Spallanzani," 00149 Rome, Italy;
authors.forename: Emanuela
authors.initials: E
authors.lastname: Giombini
authors.affiliation: Centro di Riferimento Oncologico Instituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, 33081 Aviano, Pordenone, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Muraro
authors.affiliation: National Institute for Infectious Diseases "L. Spallanzani," 00149 Rome, Italy;
authors.forename: Gabriella
authors.initials: G
authors.lastname: Rozera
authors.affiliation: Centro di Riferimento Oncologico Instituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, 33081 Aviano, Pordenone, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: De Paoli
authors.affiliation: Centro di Riferimento Oncologico Instituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, 33081 Aviano, Pordenone, Italy;
authors.forename: Antonino
authors.initials: A
authors.lastname: Carbone
authors.affiliation: National Institute for Infectious Diseases "L. Spallanzani," 00149 Rome, Italy;
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Capobianchi
authors.affiliation: National Institute for Infectious Diseases "L. Spallanzani," 00149 Rome, Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ippolito
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy;
authors.forename: Simona
authors.initials: S
authors.lastname: Fiorentini
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: William A
authors.initials: WA
authors.lastname: Blattner
authors.affiliation: Center for Translational Medicine, Xi'an Jiaotong University School of Life Science and Technology, Xi'an, Shaanxi 710048, China; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Wuyuan
authors.initials: W
authors.lastname: Lu
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201; rgallo@ihv.umaryland.edu arnaldo.caruso@unibs.it.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gallo
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy; rgallo@ihv.umaryland.edu arnaldo.caruso@unibs.it.
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Caruso
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D005260:Female; D015488:HIV Antigens / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D015488:HIV Antigens; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; D051057:Proto-Oncogene Proteins c-akt
keywords: AIDS; B-cell clonogenicity; HIV-1 matrix protein p17; non-Hodgkin lymphoma; p17 variants