Human immunodeficiency virus nef signature sequences are associated with pulmonary hypertension

Sharilyn Almodovar, Rob Knight, Amanda A. Allshouse, Sarah Roemer, Catherine Lozupone, Daniel McDonald, Jeremy Widmann, Norbert F. Voelkel, Robert J. Shelton, Edu B. Suarez, Kenneth W. Hammer, Cecile Goujard, Nicola Petrosillo, Gerald Simonneau, Priscilla Y. Hsue, Marc Humbert, Sonia C. Flores

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)607-618
Number of pages12
JournalAIDS Research and Human Retroviruses
Issue number6
Publication statusPublished - Jun 1 2012

ASJC Scopus subject areas

  • Immunology
  • Virology
  • Infectious Diseases


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