Final Report Summary - NEF-PATHOGENESIS (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.
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.
