Science：对HIV人类易感性的研究新进展

生物谷

生物谷报道：灵长类的基因组中包含有大量的内源性逆转录病毒片段，同时可以随着进化编码出对逆转录病毒提供免疫反应的功能蛋白。最近，研究者发现，对HIV有抵抗力的黑猩猩和其他一些灵长类的基因组中存在一种名为 "PtERV1"的病毒易感。PtERV1病毒已存在了四百万年之久，是一个内源性逆转录病毒，也就是说它能将自身插入其宿主的生殖系从而能从一代传给下一代。黑猩猩和大猩猩的基因组中有100多个 PtERV1的拷贝，但是人类的基因组中没有。

Shari Kaiser和同事用黑猩猩的基因组重建了该病毒的核心蛋白质，发现一个名为TRIM5-α的蛋白质的人类版本防止该病毒插入细胞。人类的TRIM5-α 对HIV的防御比较差，而其他灵长类该蛋白的版本提供对HIV的防御。这些作者提出，早期人类进化出对PtERV1的抵抗力，但是代价是对其他逆转录病毒比如HIV的抵抗力降低了。这项新研究提出，人类对HIV的易感性也许在我们的祖先对一个古老病毒产生抵抗力的进化交易的结果。该结果发表在最新一期的《科学》杂志上。

Fig. 1. Reconstruction of PtERV1 p12 and CA and infectivity of PtERV1/MLV chimeric virus. (A) An alignment of the p12 and CA sequences of the consensus PtERV1 from chimpanzee (top line) and MLV (bottom line) is shown. A late domain (PPPY) characteristic for retroviruses is in p12 and the Major Homology Region (MHR) conserved in all retroviruses is present in CA are indicated by shaded boxes. (B) An unrooted phylogenetic NJ tree was generated with nucleotide sequences of PtERV1 (MA through PRO) from chimpanzee, rhesus, and gorilla genomes. Branches are color coded: gorilla, orange; chimpanzee, blue; and rhesus, green. Fifteen amino acid changes were introduced into one extant copy of PtERV1 p12-CA from chimpanzees to generate the "ancestral" clone (fig. S1). The derived consensus sequence from chimpanzee is denoted by a black branch. The nucleotide consensus is slightly displaced from the node of the monophyletic clade containing chimp and gorilla sequences because synonymous changes were not introduced during the reconstruction process. (C) Schematic representation of the chimeric virus between MLV and PtERV1 is shown. The Gag-Pol expression vector used to make virus contains the MA, NC, and the entire POL coding sequence of MLV and the p12 and CA from PtERV1. Protease cleavage sites between MLV MA and PtERV1 p12, as well as between PtERV1 CA and MLV NC, were generated to match cleavage sites recognized by MLV protease. (D) Green fluorescent protein (GFP)–encoding virus was used to infect Crandell-Rees feline kidney (CRFK) cells with PtERV1 chimeric virions. Fluorescence-activated cell sorting (FACS) plots of virus-challenged cells are shown. The y axis indicates cell size, and the x axis denotes GFP positivity, which is an indicator of transduction. The initial PtERV1 clone used to reconstruct this consensus was tested in the chimeric context and was noninfectious (left). After 15 mutations were introduced to reconstruct the consensus p12 and CA sequence, infectious virus particles were generated (right).

原文出处：

Science 22 June 2007 Vol 316, Issue 5832

Restriction of an Extinct Retrovirus by the Human TRIM5 Antiviral Protein

Shari M. Kaiser, Harmit S. Malik, and Michael Emerman
Science 22 June 2007: 1756-1758.
Resistance that humans acquired 4 million years ago to a now extinct virus that infected chimpanzees and gorillas may have left us more sensitive to HIV infection today.
Abstract »| Full Text »| PDF »| Supporting Online Material »|

相关基因：

TRIM5

Official Symbol TRIM5 and Name: tripartite motif-containing 5 [Homo sapiens]
Other Aliases: RNF88, TRIM5alpha
Other Designations: tripartite motif protein TRIM5
Chromosome: 11; Location: 11p15
Annotation: Chromosome 11, NC_000011.8 (5662868..5641363, complement)
MIM: 608487
GeneID: 85363

NEWENTRY

Record to support submission of GeneRIFs for a gene not in Entrez Gene (Human immundeficiency virus type 1; Human immunodeficiencey virus type 1; Human immunodeficiency virus type 1; human immunodeficiency virus 1 HIV-1; human immunodeficiency virus HIV-1; human immunodeficiency virus type 1 ,HIV-1; human immunodeficiency virus type 1 HIV 1; human immunodeficiency virus type 1 HIV-1; human immunodeficiency virus type 1 HIV1; human immunodeficiency virus type 1, HIV-1; human immunodeficiency virus type I HIV-1; human immunodeficiency virus type-1 HIV-1; human immunodeficiency virus-1 HIV-1). [Human immunodeficiency virus 1]
GeneID: 2828719

作者简介：

Michael Emerman, Ph.D.
Member, Division of Human Biology,
Fred Hutchinson Cancer Research Center

CONTACT INFORMATION
Fred Hutch Cancer Research Center
1100 Fairview Ave N., C2-023
Seattle, WA 98109-1024

Phone: (206) 667-5058
Fax: (206) 667-6523
e-mail: memerman@fhcrc.org

LINK TO MICHAEL EMERMAN'S COMMUNITY OF SCIENCE WEB PAGE

CURRENT RESEARCH INTERESTS

This laboratory studies the regulatory and structural genes of the human immunodeficiency virus (HIV) in order to understand the molecular basis for its pathogenicity. Because the virus requires host cell proteins to complete nearly every step of its life cycle, much of our focus is on identifying and characterizing host cell functions that are modified or utilized by viral proteins to serve specific functions for viral replication.

HIV infection of non-dividing cells: A unique property of HIV is its ability to infect non-dividing cells such as terminally differentiated macrophages. With most retroviruses, the cell must pass through mitosis for the viral DNA to enter the nucleus. HIV, however, has evolved such that there are multiple genetically separate elements that allow nuclear entry independent of the cell cycle. We are trying to determine how these different elements act to target sub-viral particles through the nuclear membrane, and how they affect viral tropism in macrophages. This work involves understanding the events that occur immediately after the virus has entered the cell in order to enter the nucleus.

HIV spread: HIV-1 grows with very rapid kinetics in vivo. We are characterizing the mechanisms that allow such rapid growth. In particular we had developed assays that mimic the rapid kinetics in vivo and have established that cell-to-to transmission is necessary for rapid viral spread. This transmission depends on the attachment of virus to dendritic cells that subsequently present viral complexes to T cells. We are studying the ways in which dendritic cells interact with HIV and the specific molecules that lead to virus adsorption on cell surfaces and cell adhesions.

HIV and the cell cycle: HIV differs from other retroviruses in its interaction with the host cell. Unlike other retroviruses, which have little effect on cell growth, HIV encodes a protein that prevents infected cells from proliferating. This protein, called Vpr, prevents infected cells from entering mitosis by preventing the activation of the mitotic cyclin dependent kinase causing cells to arrest in G2 of the cell cycle. We are studying the molecular basis of Vpr action to understand how and why HIV interferes with the host cell cycle. We hope to understand the basis for the evolution of viral functions that impair the function of normal host T cells.

HIV population genetics: HIV evolves rapidly both on a global scale and in individual infected people. The frequency of different variants in a population of viral species is dependent on both selective forces and random drift. We have developed tissue culture assays to measure the contribution of random drift on the evolution of HIV populations and compare it to the contributions of selective forces.

PUBLICATIONS

Gummuluru S, KewalRamani VN, Emerman M. Dendritic cell mediated viral transfer to T cells is required for HIV-1 persistence in the face of rapid cell turnover. J Virol 76:10692-701, 2002.

Dvorin JD, Bell P, Maul GG, Yamashita M, Emerman M, Malim MH. Reassessment of the roles of integrase and the central DNA flap in human immunodeficiency virus type-1 nuclear import. J Virol 76:12087-96, 2002.

McDonald D, Vodicka M, Lucero G, Svitkina TM, Borisy GG, Emerman M, Hope TJ. Visualization of the intracellular behavior of HIV in living cells. J Cell Biol 159:441-52, 2002.

Malim MH, Emerman M. HIV-1 sequence variation: drift, shift, and attenuation. Cell 104:469-72, 2001.