title: Human Immunodeficiency Virus nef signature sequences are associated with pulmonary hypertension.
abstract: Severe pulmonary hypertension (PH) associated with vascular remodeling is a long-term complication of HIV infection (HIV-PH) affecting 1/200 infected individuals vs. 1/200,000 frequency in the uninfected population. Factors accounting for increased PH susceptibility in HIV-infected individuals are unknown. Rhesus macaques infected with chimeric SHIVnef virions but not with SIV display PH-like pulmonary vascular remodeling suggesting that HIV-Nef is associated with PH; these monkeys showed changes in nef sequences that correlated with pathogenesis after passage in vivo. We further examined whether HIV-nef alleles in HIV-PH subjects have signature sequences associated with the disease phenotype. We evaluated specimens from participants with and without HIV-PH from European Registries and validated results with samples collected as part of the Lung-HIV Studies in San Francisco. We found that 10 polymorphisms in nef were overrepresented in blood cells or lung tissue specimens from European HIV-PH individuals but significantly less frequent in HIV-infected individuals without PH. These polymorphisms mapped to known functional domains in Nef. In the validation cohort, 7/10 polymorphisms in the HIV-nef gene were confirmed; these polymorphisms arose independently from viral load, CD4(+) T cell counts, length of infection, and antiretroviral therapy status. Two out of 10 polymorphisms were previously reported in macaques with PH-like pulmonary vascular remodeling. Cloned recombinant Nef proteins from clinical samples down-regulated CD4, suggesting that these primary isolates are functional. This study offers new insights into the association between Nef polymorphisms in functional domains and the HIV-PH phenotype. The utility of these polymorphisms as predictors of PH should be examined in a larger population.
authors: Cardiovascular Pulmonary Research Laboratory, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado 80045, USA. sharilyn.almodovar@ucdenver.edu
authors: Sharilyn
authors: S
authors: Almodovar
authors: Rob
authors: R
authors: Knight
authors: Amanda A
authors: AA
authors: Allshouse
authors: Sarah
authors: S
authors: Roemer
authors: Catherine
authors: C
authors: Lozupone
authors: Daniel
authors: D
authors: McDonald
authors: Jeremy
authors: J
authors: Widmann
authors: Norbert F
authors: NF
authors: Voelkel
authors: Robert J
authors: RJ
authors: Shelton
authors: Edu B
authors: EB
authors: Suarez
authors: Kenneth W
authors: KW
authors: Hammer
authors: Cecile
authors: C
authors: Goujard
authors: Nicola
authors: N
authors: Petrosillo
authors: Gerald
authors: G
authors: Simonneau
authors: Priscilla Y
authors: PY
authors: Hsue
authors: Marc
authors: M
authors: Humbert
authors: Sonia C
authors: SC
authors: Flores
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000235:genetics* / Q000276:immunology; D000328:Adult; D000818:Animals; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D015497:HIV-1 / Q000302:isolation & purification / Q000472:pathogenicity*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D012495:San Francisco; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications / Q000235:genetics* / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000302:isolation & purification / Q000472:pathogenicity*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics; D014779:Virus Replication / Q000235:genetics; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: C429284:NEF protein, SIV; D054334:Viral Regulatory and Accessory Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus