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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.

SUBMITTER: Almodovar S

PROVIDER: S-EPMC3358101 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Human Immunodeficiency Virus nef signature sequences are associated with pulmonary hypertension.

Almodovar Sharilyn S Knight Rob R Allshouse Amanda A AA Roemer Sarah S Lozupone Catherine C McDonald Daniel D Widmann Jeremy J Voelkel Norbert F NF Shelton Robert J RJ Suarez Edu B EB Hammer Kenneth W KW Goujard Cecile C Petrosillo Nicola N Simonneau Gerald G Hsue Priscilla Y PY Humbert Marc M Flores Sonia C SC

AIDS research and human retroviruses 20120117 6

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 change ...[more]

PMID: 22066947

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Project description:Abstract Background Data characterizing risk factors and long-term outcome studies on human immunodeficiency virus (HIV)-associated pulmonary hypertension (PH) in Africa are lacking. Methods The Pan African Pulmonary Hypertension Cohort, a multinational registry of 254 consecutive patients diagnosed with PH (97% of African descent) from 9 centers in 4 African countries was implemented. We compared baseline characteristics and 3-year survival of an HIV-infected cohort newly diagnosed with PH (PH/HIV+) to an HIV-uninfected cohort with PH (PH/HIV−). Results One hundred thirty-four participants with PH completed follow up (47 PH/HIV+ and 87 PH/HIV−; age median, 36 versus 44 years; P = .0004). Cardiovascular risk factors and comorbidities were similar except for previous tuberculosis (62% versus 18%, P < .0001). Six-minute walk distance (6MWD) <300 meters was common in PH/HIV− (P = .0030), but PH/HIV+ had higher heart (P = .0160) and respiratory (P = .0374) rates. Thirty-six percent of PH/HIV+ and 15% of PH/HIV− presented with pulmonary arterial hypertension (PAH) (P = .0084), whereas 36% of PH/HIV+ and 72% of PH/HIV− exhibited PH due to left heart disease (PHLHD) (P = .0009). Pulmonary hypertension due to lung diseases and hypoxia (PHLD) was frequent in PH/HIV+ (36% versus 15%) but did not reach statistical significance. Human immunodeficiency virus-associated PAH tended to have a poorer survival rate compared with PHLHD/PHLD in HIV-infected patients. Conclusions The PH/HIV + patients were younger and commonly had previous tuberculosis compared to PH/HIV− patients. Despite a better 6MWD at presentation, they had more signs and symptoms of early onset heart failure and a worse survival rate. Early echocardiography assessment should be performed in HIV-infected patients with history of tuberculosis who present with signs and symptoms of heart failure or posttuberculosis lung disease. The HIV cohort within the Pan African Pulmonary Hypertension Cohort is particularly relevant given the colliding epidemics of HIV/tuberculosis in Africa. Due to immunosuppression, young people living with HIV/AIDS contract tuberculosis several times, increasing their risk of post-tuberculosis lung diseases and HIV-associated pulmonary hypertension in particular.

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Human Immunodeficiency Virus nef signature sequences are associated with pulmonary hypertension.

Publications

Human Immunodeficiency Virus nef signature sequences are associated with pulmonary hypertension.

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