HIV-1 protease inhibitors (PIs) are among the most effective antiretroviral medicines.

HIV-1 protease inhibitors (PIs) are among the most effective antiretroviral medicines. in current clinical tests for PI resistance, conferred PI resistance, providing an explanation for PI failure without resistance. Intro HIV-1 protease inhibitors (PIs) have played a critical role in the success of highly active antiretroviral therapy (HAART) (1C3). PIs are the important medicines in 2 of the 4 recommended initial HAART regimens and are also extremely important in salvage therapy for individuals who fail initial regimens (1). Among all HIV-1 medicines, PIs have the highest intrinsic antiviral activity (2, 4). PIs are the only antiretroviral medicines that have been successfully used in monotherapy (5). The high antiviral activity of this class results in large part from steep, highly cooperative dose-response curves (2, 4), the molecular basis LHX2 antibody of which is not KW-2478 fully recognized (6). KW-2478 The PIs are substrate or transition state analogues that inhibit the activity of HIV-1 protease. This enzyme cleaves viral polyproteins during disease maturation (7). Among the protein products of the HIV-1 genome are 3 polyproteins: the envelope (Env) precursor protein (gp160), the Gag precursor protein (Pr55Gag), and the Gag-Pol precursor protein (Pr160Gag-Pol). A cellular protease cleaves gp160 into the surface and transmembrane subunits, gp120 and gp41, respectively (8). These subunits remain connected, and trimers of gp120/gp41 complexes constitute the surface spikes that mediate viral access. In contrast, the Gag and Gag-Pol polyproteins are each cleaved into multiple adult virion proteins by HIV-1 protease. The cleavages carried out by HIV-1 protease happen within the nascent disease particle and create mature virions capable of infecting fresh cells. While the connection of PIs with the prospective enzyme is definitely well understood in the structural and biochemical level (9C12), it remains unclear where in the disease KW-2478 life cycle the inhibition of disease maturation becomes manifest. Virus maturation is generally considered to be important for early postentry methods including uncoating and reverse transcription (13C15). Both the RT and integrase (IN) enzymes are generated from Pr160Gag-Pol by cleavages carried out by HIV-1 protease. However, inhibition of the proteolytic cleavages necessary for maturation could in basic principle affect other methods as well. Studies of mutant viruses incapable of completing the necessary proteolytic cleavages suggest that immature particles are defective in access (16C18). Interactions between the cytoplasmic tail (CT) of gp41 and uncleaved Pr55Gag appear to inhibit the fusion of immature particles. Despite the importance of PIs in HIV-1 treatment, the precise step or methods in the disease life cycle clogged by these medicines under clinical conditions have not been clearly defined. Understanding where the PIs take action in the disease life cycle is also important for understanding the resistance that arises in some individuals on PI-based regimens. Resistance to PIs can occur through mutations in the protease gene (19), but the majority of individuals faltering PI-containing regimens do so without mutations in protease (20C23). This interesting and unpredicted observation appears to violate the basic evolutionary tenets that govern other types of HIV-1 KW-2478 drug resistance. It also poses an important clinical dilemma should treatment become changed for individuals with detectable viremia but no mutations in protease? One probability is that standard assays for resistance ignore parts of the HIV-1 genome that may contain mutations conferring resistance to PIs. To understand the molecular mechanisms responsible for the high antiviral activity of PIs and the unusual features of resistance to.

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