9th Conference on Retroviruses and Opportunistic Infections Seattle, Washington - February 24 -February 28, 2002

Conf Retroviruses Opportunistic Infect 2002 Feb 24-28;9:abstract no. L8
Hans-Georg Kraeusslich
Univ. of Heidelberg, Germany

BACKGROUND: Human immunodeficiency virus (HIV-1) assembles at the plasma membrane of the infected cell and is released by budding of an immature non-infectious virus, whose inner structure consists mainly of uncleaved Gag polyproteins. Gag alone is sufficient for the formation of virus-like particles closely resembling the immature virus. Proteolysis of Gag into the domains matrix (MA), capsid (CA), nucleocapsid (NC), and p6, as well as several small peptides, occurs by action of the viral protease (PR) inside the virion and causes morphological rearrangements of the inner structure (maturation) which are essential for infectivity. PR inhibitors, which are commonly used in HIV therapy, block this conversion. The shell of the mature capsid corresponds to a homomultimer of the viral CA protein and encases a ribonucleoprotein complex consisting of the genomic RNA complexed with the viral NC and replication proteins as well as other viral and cellular proteins. The last step of HIV-1 release involves severing of the viral bud from the cell membrane and requires the viral p6 domain. 3-dimensional structures of several HIV structural proteins or domains thereof have been solved, but the molecular organization and structure of the immature and mature capsid are not known. Cleavage at individual sites within the Gag polyprotein appears to occur in an ordered manner suggesting that maturation proceeds through unstable intermediate stages. Sequential cleavages at the N- and C-terminus of CA appear to cause consecutive structural rearrangements governing the reorganization of the core and the 14 amino acid peptide, which is cleaved from the C-terminus of CA as a last step of maturation plays a decisive role in this process. In vitro assembly studies revealed that HIV-1 Gag segments are sufficient to form particles closely resembling the immature and mature core. However, other viral and cellular proteins are likely to modulate this process and the concerted regulation of virus assembly, budding and induction of proteolysis, as well as the role of individual cleavages is not completely understood.

CONCLUSIONS: This issue is of particular importance for understanding PR-inhibitor resistance, which appears to involve a mixture of alterations conferring resistance and those restoring viral fitness. Furthermore, virus assembly and reorganisation may also provide attractive targets for novel antiretrovirals, since capsid stability is maintained by multiple, weak, non-covalent interactions.

020224
L8

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