NEF-PATHOGENESIS · The importance of Nef effects on HIV-1 infectivity for viral pathogenesis
7РП — „Хора“ (Действия „Мария Кюри“)
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- 2009-07-01 → 2011-06-30
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Накратко на български
Протеинът Nef на вируса HIV-1 се изследва чрез неговото влияние върху заразността и устойчивостта на вируса към определени антитела. Разбирането на тези механизми помага да се разбере как протича заболяването и как вирусът се размножава в организма.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
The importance of Nef effects on HIV-1 infectivity for viral pathogenesis
The AIDS epidemic remains a worldwide emergency and the molecular mechanisms leading to the disease are not yet fully understood. Nef is a gene product of HIV crucial for virus replication in vivo and for AIDS progression. However, the mechanisms supporting its pathogenic role remain undefined. Among other activities, Nef enhances intrinsic virus infectivity, a feature which remains poorly understood. Our results now show that the activity of Nef is not an exclusive prerogative of primate lentiviruses, as previously thought, but is also exerted by glycogag, a pathogenic factor expressed by unrelated retroviruses which cause disease in other primates and rodents. This evidence highlights the fundamental importance of the Nef activity in the biology and pathogenesis of retroviruses (Pizzato, PNAS, 207, 9364-9, 2010). While most studies involving Nef have so far been conducted with laboratory adapted HIV-1 isolates, an effort was made to study HIV-1 found in the patient population , by investigating the activity of Nef on particles derived from primary HIV-1 isolates, including isolates from the subgroup C, the most predominant worldwide. We have found that the envelope glycoprotein derived from some primary isolates is not responsive to the Nef effect on virus infectivity, challenging the hypothesis that such activity is a fundamental feature in the natural infection. Our investigation further revealed that Nef renders HIV-1 10-50 fold more resistant specifically to two human antibodies (2F5 and 4E10) which belong to one of the most powerful classes of neutralizing agents, active against a wide range of HIV-1 isolates. We established that Nef decreases the recognition of the virus particles by these antibodies, which bind to a domain of the envelope glycoprotein adjacent to the retroviral membrane (MPER). Envelope glycoproteins dericed from diverse isolates of HIV-1 are equally sensitive to this activity, which is exerted by Nef proteins derived from both HIV-1 and SIV. Our results therefore indicate that such novel activity of Nef, by protecting lentiviruses from one of the most broadly-acting classes of neutralizing antibodies, contributes to AIDS pathogenesis, and could have direct implications for vaccine design.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The AIDS epidemic remains a worldwide emergency and the molecular mechanisms leading to the disease are not fully understood. Nef is a gene product of primate lentiviruses crucial for virus replication in vivo and for AIDS progression. The mechanisms supporting its pathogenic role remain undefined. Among other activities, Nef enhances intrinsic virus infectivity, a feature well conserved and under selective pressure during disease progression. While the significance of this activity in vivo is unknown, a recent finding from the applicant (Pizzato M. et al, PNAS, 104, 2007) shows that it requires the interaction of Nef with the cellular GTPase dynamin 2. In addition, preliminary results show that glycogag, encoded by gamma-retroviruses, exerts a similar enhancing activity on HIV infectivity, suggesting that this is a fundamental property of unrelated retroviruses. The aim of the research is to establish in vivo the role of the Nef-induced enhancement of HIV-1 infectivity, and to evaluate the importance of the interaction with dynamin 2. A recently developed humanized mouse will be used as model of HIV infection in vivo. Because Nef exerts several functions, the specific role of the enhancement of infectivity will be studied by separating this from other activities, following four objectives: 1) To establish in vivo the phenotype of HIV-1 carrying Nef mutations which selectively impair specific activities. 2) To study the requirement of Nef in vivo using a CD4-independent HIV whose infectivity cannot be affected by the Nef-induced CD4 downregulation activity. 3) To assess the role of glycogag-induced enhancement of infectivity for HIV replication and pathogenesis in vivo. 4) To study the importance in vivo of the Nef surface interacting with dynamin 2. This research will establish the significance of the Nef-induced enhancement of infectivity in vivo and will indicate whether the Nef-dynamin 2 interaction could be suitable as an antiretroviral target.
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITE DE GENEVE · GeneveКоординаторШвейцария
Връзки
Данни: CORDIS, © Европейски съюз