%0 Journal Article
%T TRIM5 and the Regulation of HIV-1 Infectivity
%A Jeremy Luban
%J Molecular Biology International
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/426840
%X The past ten years have seen an explosion of information concerning host restriction factors that inhibit the replication of HIV-1 and other retroviruses. Among these factors is TRIM5, an innate immune signaling molecule that recognizes the capsid lattice as soon as the retrovirion core is released into the cytoplasm of otherwise susceptible target cells. Recognition of the capsid lattice has several consequences that include multimerization of TRIM5 into a complementary lattice, premature uncoating of the virion core, and activation of TRIM5 E3 ubiquitin ligase activity. Unattached, K63-linked ubiquitin chains are generated that activate the TAK1 kinase complex and downstream inflammatory mediators. Polymorphisms in the capsid recognition domain of TRIM5 explain the observed species-specific differences among orthologues and the relatively weak anti-HIV-1 activity of human TRIM5. Better understanding of the complex interaction between TRIM5 and the retrovirus capsid lattice may someday lead to exploitation of this interaction for the development of potent HIV-1 inhibitors. 1. Introduction HIV-1 was identified only two years after the first report of AIDS in 1981 [1]. The HIV-1 genome was cloned and sequenced, ORFs were identified, and functions of the gene products pinpointed. At a time when few antivirals were in clinical use, HIV-1 proteins were isolated, their activities were described, their structures were determined, and inhibitors were identified [2¨C5]. The first anti-HIV-1 drug, AZT, was approved for patients in 1987, and effective combinations of anti-HIV-1 drugs were in the clinic by the mid-1990s. Thanks to these anti-HIV-1 drugs, the number of AIDS cases plummeted in countries like the United States. HIV-1 infection became an outpatient disease. Yet, despite the impact of basic science on disease in individuals with HIV-1 infection, the AIDS pandemic has not gone away. 2. Ongoing Pandemic and the Need for More Basic Research Failure to control the AIDS pandemic may be attributable to a number of factors, including the need for improvement in drugs and more ready access to those drugs that already exist. Aside from one extraordinary case of a person who underwent bone marrow transplantation with cells from a CCR5-defective donor [6], there has been no documented cure of HIV-1 infection. Aside from a small effect in one vaccination trial [7], there is no evidence for prevention of HIV-1 infection in people by a vaccine. Without prospects for curative drugs or a preventive vaccine, the cost of HIV-1 infection to individuals and to society will
%U http://www.hindawi.com/journals/mbi/2012/426840/