![]() ![]() Crystal structures obtained from the CA-CTD-SP1 region of Gag were also shown to form an identical ordered structure to the lattice observed in immature HIV virions. In vitro (absent the cell context), the full length HIV Gag does not assemble into spherical particles with sizes similar to HIV, however partial deletion of the MA domain and p6 along with addition of RNA results in assembly of fully spherical structures resembling the immature lattice of HIV as observed in cryotomography. This points to Gag-Gag interactions having a major role in assembly of the immature lattice. These particles have similar sizes and appear identical to immature HIV virions in thin section TEM imaging. HIV Gag expressed within mammalian cells is sufficient for the release of Gag virus- like particles (VLPs). In addition to the identified Gag-Gag interactions, it has been shown that IP6, which makes ionic contacts with residues within the Gag hexamer, further stabilizes the immature Gag lattice. ![]() These interactions suggest significant Gag avidity within the immature lattice. Further, Gag interacts through a dimeric interaction at its CA-CTD domain, followed by interactions within the folded SP1 six helix bundle. Specifically each Gag molecule is stabilized within the lattice through interactions in its CA-NTD domain which forms the basis of the Gag hexagonal structure. Tomogram averaging cryotomography has resolved major interactions between Gag molecules within the lattice, which shows each molecule having interactions with at least 5 other Gag molecules. Binding of maturation inhibitors within the immature lattice suggests that the observed order within the Gag lattice plays a crucial role during the proteolysis of Gag which leads to the formation of HIV mature cores. To become infectious, HIV protease needs to access and cleave the junctions between MA and CA as well as CA and SP1 regions, among other cleavage sites. The Gag polyprotein has a series of folded domains which include MA, CA with separate CA-NTD and CA-CTD regions as well as SP1 and NC. Immature HIV virions released from infected cells, package ~2000 copies of Gag. It is a common view that the immature HIV Gag lattice is a critical starting point for maturation and therefore interactions which result in stabilization of the immature lattice, including the cellular cofactor IP6 have been of great interest. ![]() A detailed molecular understanding of the maturation process is a primary focus of significant current research. Specifically, protease inhibitors result in lack of proteolysis trapping the lattice in the immature form and maturation inhibitors result in formation of aberrant cores. ![]() Not surprisingly, most of the antivirals available for treatment result in abnormalities in the formation of the mature core. The action of the protease, leads to formation of a fullerene cone structure that encapsulates the genomic RNA creating the mature core within the infectious virion. During maturation, this lattice is transformed by successive actions of the 22 kD HIV protease dimer. HIV-1 virions are released from infected cells as immature virions, mainly characterized by a lattice of HIV Gag proteins anchored to the inner leaflet of the virion membrane. HIV-1 developing resistance to antivirals is an increasingly significant problem which highlights the need for continued development of new antivirals that exploit novel targets to inhibit HIV-1 replication. AIDS has claimed upward of 30 million lives over the past 30 years and while the disease can be kept in check using potent antivirals, there remains no cure for AIDS. Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). ![]()
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