Attenuated Retrovirus Vaccines and AIDS Koen K. A. van Rompay; Spinner, Abbie; Otsyula, Moses ...
Science (American Association for the Advancement of Science),
11/1995, Letnik:
270, Številka:
5239
Journal Article
Recenzirano
Research on macaques found that a deletion mutant of simian immunodeficiency virus used as a vaccine in adults caused AIDS in newborn macaques. Other research on simian AIDS and the implications of ...the research for human AIDS vaccination are discussed.
The HTLV-I trans-activator protein, Tax, was found to down-regulate the expression of human beta-polymerase, a cellular enzyme involved in host cell DNA repair.
Human T cell leukemia virus type I (HTLV-I) is the etiological agent for adult T cell leukemia (ATL). The HTLV-I trans-activator protein Tax can activate the expression of its own long terminal ...repeat (LTR) and many cellular and viral genes. Tax down-regulated the expression of human β-polymerase (huβ-pol), a cellular enzyme involved in host cell DNA repair. This finding suggests a possible correlation between HTLV-I infection and host chromosomal damage, which is often seen in ATL cells.
Human T-cell leukemia virus type I (HTLV-I) is the etiological agent for adult T-cell leukemia (ATL) and various human myopathies/neuropathies. HTLV-I encodes a 40 kDa phosphoprotein, Tax, which has ...been implicated in cellular transformation. In similarity with several other oncoproteins such as Myc, Jun, and Fos, Tax is a transcriptional activator. How Tax mechanistically dysregulates the cell cycle remains unclear. Recent findings from us and others have shown that Tax targets key regulators of G1/S and M progression such as p16INK4a, cyclin D1, cyclin D3-cdk, and the mitotic spindle checkpoint apparatus. Thus, Tax influences the progression of cells in various phases of the cell cycle. In this regard, we will discuss three distinct mechanisms through which Tax affects cell-cycling: a) through direct association Tax can abrogate the inhibitory function of p16INK4a on the G1-cdks, b) Tax can also directly influence cyclin D-cdk activities by a protein-protein interaction, and c) Tax targets the HsMAD1 mitotic spindle-assembly checkpoint protein. Through these varied routes, the HTLV-I oncoprotein dysregulates cellular growth controls and engenders a proclivity of cells toward a loss of DNA-damage surveillance.
Control of cytomegalovirus (CMV) gene expression is a poorly understood process. The size and complexity of the virus suggest that a myriad of factors are involved. Some of these factors are ...undoubtedly viral, while others are likely host cell derived. To understand the regulation of the CMV life cycle, I have examined three separate areas: (1) characterization of the "immediate-early" gene and gene product of CMV Colburn; (2) elucidation of sequence homologies between CMV Colburn and host cell DNAs; and (3) description of genome conservation between divergent strains of CMVs toward an understanding of evolutionally preserved "house-keeping" functions. The major "immediate-early" gene of Colburn has a protein molecular weight of 94,000 daltons (IE94). The IE94 gene has been mapped and cloned. Using permissive and nonpermissive infections and gene transfections, pertinent observations as to the regulated expression and function of the IE94 gene are as follows: (1) The IE94 protein is phosphorylated at multiple amino acid (serine) residues. The protein is apparently phosphorylated by a host cell kinase with the phosphorylation pattern changing during the course of permissive infections. (2) The IE94 protein is feedback regulated by later viral polypeptides. Absence of these later viral proteins causes IE protein overproduction. (3) Nucleotide sequencing has revealed that the IE94 promoter upstream region is punctuated by repetitive palindromes, and that progressive deletions of 5' sequences upstream have significant influence on IE94 gene expression. CMV, like HSV, has significant cross-homology with uninfected cellular DNA. In Colburn, this homology is contained wholly within a single 880 base-pair region. Within this region there are 3 tracts of repetitive CA dinucleotides. I have found that these simple sequences are highly conserved across mammalian species and are discretely and abundantly distributed in cellular genomes. Unique sequences flanking the viral CA repeats are also preserved in the cells. CMV Colburn was isolated from the brain of a child with encephalitis, but is apparently of simian origin. To explore evolutionally conserved functions in cytomegalovirus genomes I have found sequence homology in two highly divergent strains, human CMV(Towne) and simian CMV (Colburn). These conserved homologies are well defined but limited in size.
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