3 During or just after budding, the Gag and Gag–Pol polyproteins in the immature particle are cleaved by the viral protease resident in Gag–Pol, which is self-activated via transient dimerization with an adjacent Gag–Pol protease domain. Viral assembly begins at the plasma membrane where the viral structural proteins, primarily the Gag and Gag–Pol polyproteins, condense to form nascent immature particles that bud through the plasma membrane and release from the cell. Produced by a frameshift at the NC/p6 junction that occurs in ~5% of Gag translations, the Gag–Pol polyprotein encodes all retroviral enzymes: integrase (IN), protease (PR), and reverse transcriptase (RT). Gag polyproteins selectively package the HIV genomic RNA dimer through two strictly conserved Cys–Cys–His–Cys zinc knuckles of the NC protein. 1, 2 Therefore, new HIV inhibitor targets and mechanisms are needed, especially those that pose a significant obstacle for the fitness of viral resistance mutants.Īssembly of the virion in infected cells is a critical step in HIV replication and is driven by the Gag polyprotein, consisting of the matrix (MA), capsid (CA), nucleocapsid (NC), and p6 proteins linked together via peptide spacer sequences. Disturbingly, increased HIV resistance to frontline treatments has been detected in newly diagnosed infections. Long-term cART treatment results in drug-induced toxic effects as well as emergence of HIV drug resistance due to failure of patients to adhere to treatment regimens. Therefore, strict adherence to, as well as lifelong treatment with, antiretroviral medication is needed for HIV-infected patients to prevent the development of AIDS symptoms. However, even in patients with no detectable viremia upon treatment with state-of-the-art combined antiretroviral therapy (cART), the virus rapidly recrudesces after withdrawal of therapy. Antiretroviral drugs targeting HIV enzymes (namely, protease, reverse transcriptase, and integrase) effectively reduce detectable viremia and promote long-term survival in patients.
0 kommentar(er)
