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.
| Original language | English |
|---|---|
| Pages (from-to) | 607-618 |
| Number of pages | 12 |
| Journal | AIDS Research and Human Retroviruses |
| Volume | 28 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 1 2012 |
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ASJC Scopus subject areas
- Immunology
- Virology
- Infectious Diseases
Cite this
Human immunodeficiency virus nef signature sequences are associated with pulmonary hypertension. / Almodovar, Sharilyn; Knight, Rob; Allshouse, Amanda A.; Roemer, Sarah; Lozupone, Catherine; McDonald, Daniel; Widmann, Jeremy; Voelkel, Norbert F.; Shelton, Robert J.; Suarez, Edu B.; Hammer, Kenneth W.; Goujard, Cecile; Petrosillo, Nicola; Simonneau, Gerald; Hsue, Priscilla Y.; Humbert, Marc; Flores, Sonia C.
In: AIDS Research and Human Retroviruses, Vol. 28, No. 6, 01.06.2012, p. 607-618.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Human immunodeficiency virus nef signature sequences are associated with pulmonary hypertension
AU - Almodovar, Sharilyn
AU - Knight, Rob
AU - Allshouse, Amanda A.
AU - Roemer, Sarah
AU - Lozupone, Catherine
AU - McDonald, Daniel
AU - Widmann, Jeremy
AU - Voelkel, Norbert F.
AU - Shelton, Robert J.
AU - Suarez, Edu B.
AU - Hammer, Kenneth W.
AU - Goujard, Cecile
AU - Petrosillo, Nicola
AU - Simonneau, Gerald
AU - Hsue, Priscilla Y.
AU - Humbert, Marc
AU - Flores, Sonia C.
PY - 2012/6/1
Y1 - 2012/6/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84861855413&partnerID=8YFLogxK
U2 - 10.1089/aid.2011.0021
DO - 10.1089/aid.2011.0021
M3 - Article
C2 - 22066947
AN - SCOPUS:84861855413
VL - 28
SP - 607
EP - 618
JO - AIDS Research and Human Retroviruses
JF - AIDS Research and Human Retroviruses
SN - 0889-2229
IS - 6
ER -