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The human immunodeficiency virus type 1 p6 protein represents a docking site for several cellular and viral binding factors and fulfills major roles in the formation of infectious viruses. To date, however, the structure of this 52-amino acid protein, by far the smallest lentiviral protein known, either in its mature form as free p6 or as the C-terminal part of the Pr55 Gag polyprotein has not been unraveled. We have explored the high resolution structure and folding of p6 by CD and NMR spectroscopy. Under membranous solution conditions, p6 can adopt a helix-flexible helix structure; a short helix-1 (amino acids 14 -18) is connected to a pronounced helix-2 (amino acids 33-44) by a flexible hinge region. Thus, p6 can be subdivided into two distinct structural and functional domains; helix-2 perfectly defines the region that binds to the virus budding factor AIP-1/ALIX, indicating that this structure is required for interaction with the endosomal sorting complex required for transport. The PTAP motif at the N terminus, comprising the primary late assembly domain, which is crucial for interaction with another cellular budding factor, Tsg101, does not exhibit secondary structure. However, the adjacent helix-1 may play an indirect role in the specific complex formation between p6 and the binding groove in Tsg101. Moreover, binding studies by NMR demonstrate that helix-2, which also comprises the LXXLF motif required for incorporation of the human immunodeficiency virus type 1 accessory protein Vpr into budding virions, specifically interacts with the Vpr binding region, indicating that under the specific solution conditions used for structure analysis, p6 adopted a functional conformation.The main structural components of retrovirus particles are synthesized as three polyproteins that produce either the virion interior (Gag), the viral enzymes (Pol), or the glycoproteins of the virion envelope (Env). The Gag polyprotein is required and sufficient for virus particle assembly and budding, although genomic RNA and envelope proteins are obligatory for production of infectious progeny virions. The processing of the HIV-1 Gag polyprotein Pr55 by the viral protease generates the matrix, capsid, nucleocapsid (NC), and p6 proteins. Matrix mediates the plasma membrane targeting of Gag and lines the inner shell of the mature virus particle, capsid forms the conical core shell encasing NC, and NC regulates packaging and condensation of the viral genome (1-6). The role of p6 during virus entry and its location in mature HIV-1 2 virus particles are not known, although it appears not to be associated with the virus core (7,8). Several functions, however, have been ascribed to p6. It facilitates virus budding (9 -11) and is required for the incorporation of the viral accessory protein Vpr into the virus particle (12-15). It has also been implicated in the incorporation of the viral Pol and Env proteins (16,17) and in the control of particle size (18,19). Recently, p6 was reported to be the major phosphoprotein of HIV-1 particles (20...

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer that is derived from hepatocytes and is characterised by high mortality rate and poor prognosis. While HCC is driven by cumulative changes in the hepatocyte genome, it is increasingly recognised that the liver microenvironment plays a pivotal role in HCC propensity, progression and treatment response. The microenvironmental stimuli that have been recognised as being involved in HCC pathogenesis are diverse and include intrahepatic cell subpopulations, such as immune and stellate cells, pathogens, such as hepatitis viruses, and non-cellular factors, such as abnormal extracellular matrix (ECM) and tissue hypoxia. Recently, a number of novel environmental influences have been shown to have an equally dramatic, but previously unrecognized, role in HCC progression. Novel aspects, including diet, gastrointestinal tract (GIT) microflora and circulating microvesicles, are now being recognized as increasingly important in HCC pathogenesis. This review will outline aspects of the HCC microenvironment, including the potential role of GIT microflora and microvesicles, in providing new insights into tumourigenesis and identifying potential novel targets in the treatment of HCC.