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Category: Viruses and Viral Pathogenesis; Microbial Genetics and Molecular Biology
Human Retroviruses in the Second Decade: Some Pathogenic Mechanisms and Approaches to Their Control, Page 1 of 2
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This chapter summarizes some current concepts on human retroviruses, and focuses on three topics: human T-cell lymphotrophic leukemia virus types I (HTLV-I), some approaches to the inhibition of human immunodeficiency virus (HIV) replication, and the pathogenesis of AIDS-associated Kaposi's sarcoma (KS). HTLV-I is now known to cause some adult Tcell leukemias (ATLs)/lymphomas, tropical spastic paraparesis/ HTLV-I-associated myelopathy (TSP/HAM) (a neurological disease resembling multiple sclerosis), and several apparently autoimmune disorders, including some polymyositis, rheumatoid arthritis-like disorders, uveitis, bronchitis, and mild immune impairment associated with bacterial dermatitis in infants. Most studies favor the concept of an autoimmune mechanism for the demyelinating neurological disorder TSP/HAM. Steadily (even if slowly) accumulating knowledge about the pathogenic mechanisms by which HIV causes AIDS and abundant information on the replication cycle of HIV provide new ideas for different therapeutic and preventive approaches which some believe have not yet been fully exploited or sufficiently pursued. Most testing for new anti-HIV therapy today is based on targeting the enzymes of HIV (RT, protease, integrase, and RNase H). KS remains the most important tumor associated with HIV-1 infection in terms of both frequency and the suffering it produces.
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Phylogenetic tree of simian T-cell leukemia/lymphotropic virus type I (STLV-I), HTLV-I, and HTLV-II envelope nucleotide ( 30 ) DNA sequences (positions 6046 to 6567) are constructed on the outgroup HTLV-IIMO as calculated by the DNA Boot program (Phylip V.3:41), which implements the bootstrap method for placing confidence intervals, using parsimony for DNA sequences. The numbers located at the forks indicate the frequency of association of the various virus groups in the bootstrap analysis after 100 replications of the data. Agm, African green monkey.
Phylogenetic tree of simian T-cell leukemia/lymphotropic virus type I (STLV-I), HTLV-I, and HTLV-II envelope nucleotide ( 30 ) DNA sequences (positions 6046 to 6567) are constructed on the outgroup HTLV-IIMO as calculated by the DNA Boot program (Phylip V.3:41), which implements the bootstrap method for placing confidence intervals, using parsimony for DNA sequences. The numbers located at the forks indicate the frequency of association of the various virus groups in the bootstrap analysis after 100 replications of the data. Agm, African green monkey.
Schematic representation of HTLV-I genomic organization. The open boxes in the pX region (located between the end of the envelope gene and the 3' viral LTR) include the open reading frames for the p27rex/p21rex proteins, p40tax and the proteins pl2I, pl3II, and p30II, recently demonstrated to be produced through alternative splicing ( 31 , 32 ). aa, amino acids.
Schematic representation of HTLV-I genomic organization. The open boxes in the pX region (located between the end of the envelope gene and the 3' viral LTR) include the open reading frames for the p27rex/p21rex proteins, p40tax and the proteins pl2I, pl3II, and p30II, recently demonstrated to be produced through alternative splicing ( 31 , 32 ). aa, amino acids.
Comparison of the putative amino acid sequences of the bovine papillomavirus type 1 (BPV-1) E5 and HTLV-I pl2I proteins. Single amino acid codes are used, and the lower part of the figure represents the hydrophage profile of both proteins ( 17 ).
Comparison of the putative amino acid sequences of the bovine papillomavirus type 1 (BPV-1) E5 and HTLV-I pl2I proteins. Single amino acid codes are used, and the lower part of the figure represents the hydrophage profile of both proteins ( 17 ).
Genome structure of HIV-1 with reading frames indicated. Gag and Pol products are translated from unspliced RNA, and Env is translated from singly spliced RNA. More complex, multiple splicing events lead to formation of mRNA for the regulatory proteins.
Genome structure of HIV-1 with reading frames indicated. Gag and Pol products are translated from unspliced RNA, and Env is translated from singly spliced RNA. More complex, multiple splicing events lead to formation of mRNA for the regulatory proteins.
Experimental evidence indicating that HHV-7 uses CD4 as a component of its receptor: monoclonal antibodies (mAbs) to human CD4, the soluble form of human CD4 (sCD4), and the soluble form of HIV-1 gpl20 all inhibit infection of human CD4+ T cells by HHV-7.
Experimental evidence indicating that HHV-7 uses CD4 as a component of its receptor: monoclonal antibodies (mAbs) to human CD4, the soluble form of human CD4 (sCD4), and the soluble form of HIV-1 gpl20 all inhibit infection of human CD4+ T cells by HHV-7.
Infection of primary human CD4+ T lymphocytes by different HIV-1 isolates is inhibited by preexposure of the cells to HHV-7 for 48 h. Isolates 571, 573, and BO are primary isolates passaged only in primary human peripheral blood mononuclear cells.
Infection of primary human CD4+ T lymphocytes by different HIV-1 isolates is inhibited by preexposure of the cells to HHV-7 for 48 h. Isolates 571, 573, and BO are primary isolates passaged only in primary human peripheral blood mononuclear cells.
Time course of HIV-1 inhibition by hydroxyurea (HU) and/or by ddl in activated lymphocytes. Lymphocytes were obtained from an HIV-1-infected patient, isolated, and stimulated for 2 days with phytohemagglutinin and IL-2. Subsequently, hydroxyurea and ddl were added at the concentrations illustrated, and replication was analyzed as follows: every 3 to 4 days, supernatants were harvested for p24 analysis, and fresh supernatant and drugs were added. Partial inhibition was obtained when the drugs were used separately, and complete block of HIV-1 replication was achieved when hydroxyurea and ddl were used in combination. Hydroxyurea concentrations necessary to block HIV-1 (in combination with ddl) were not toxic and corresponded to the lower concentrations measured in the sera of cancer patients treated with hydroxyurea ( 4 ). (Reprinted with permission from Lori et al., Science 266:801-805, 1994.)
Time course of HIV-1 inhibition by hydroxyurea (HU) and/or by ddl in activated lymphocytes. Lymphocytes were obtained from an HIV-1-infected patient, isolated, and stimulated for 2 days with phytohemagglutinin and IL-2. Subsequently, hydroxyurea and ddl were added at the concentrations illustrated, and replication was analyzed as follows: every 3 to 4 days, supernatants were harvested for p24 analysis, and fresh supernatant and drugs were added. Partial inhibition was obtained when the drugs were used separately, and complete block of HIV-1 replication was achieved when hydroxyurea and ddl were used in combination. Hydroxyurea concentrations necessary to block HIV-1 (in combination with ddl) were not toxic and corresponded to the lower concentrations measured in the sera of cancer patients treated with hydroxyurea ( 4 ). (Reprinted with permission from Lori et al., Science 266:801-805, 1994.)
HIV-1 inhibitory genes. Indicated above are some of the HIV-1 inhibitory genes currently being developed by us for possible clinical use. Poly(TAR) is an oligomer containing 30 to 50 repeats of the Tat activation response (TAR) region ( 33 ). trans-dominant Gag is a mutant with a short deletion encompassing a Gag precursor cleavage site ( 56 , 58 ). trans-dominant rev is a mutant of rev which interferes with the activity of the wild-type gene product ( 45 ). Antisense oligonucleotides are antisense to the indicated genes and have phosphorothioate or phosphodiester backbones.
HIV-1 inhibitory genes. Indicated above are some of the HIV-1 inhibitory genes currently being developed by us for possible clinical use. Poly(TAR) is an oligomer containing 30 to 50 repeats of the Tat activation response (TAR) region ( 33 ). trans-dominant Gag is a mutant with a short deletion encompassing a Gag precursor cleavage site ( 56 , 58 ). trans-dominant rev is a mutant of rev which interferes with the activity of the wild-type gene product ( 45 ). Antisense oligonucleotides are antisense to the indicated genes and have phosphorothioate or phosphodiester backbones.
Inhibition of HIV-lmB replication in MOLT-3 cells by intracellular anti-RT antibody fragments. HIV-1 replication over 30 days in MOLT-3 cell cultures was derived after, minimally, 2 weeks of selection. Values are means of triplicate experiments (standard deviation, ≥15%); multiplicity of infection was 2.0.
Inhibition of HIV-lmB replication in MOLT-3 cells by intracellular anti-RT antibody fragments. HIV-1 replication over 30 days in MOLT-3 cell cultures was derived after, minimally, 2 weeks of selection. Values are means of triplicate experiments (standard deviation, ≥15%); multiplicity of infection was 2.0.
(A) Schematic of Tat-Tat activation response (TAR) region interaction leading to transcriptional activation. Tat binds to the bulge of the stem-loop structure of the TAR element and also interacts with a cellular factor(s) (CF) which binds to the loop of the stem-loop. The diagram on the left assumes that Tat has an activation domain that interacts with the promoter element to activate transcription. The diagram on the right on the other band assumes that Tat does not have an activation domain and that its role is to recruit a cellular factor(s) which activates transcription. The lower diagram depicts a combination of the two possibilities. (B) Tat-mediated transcriptional activation. Tat is depicted to promote both transcriptional initiation and elongation. Its major effect may be to enhance the processivity of transcription.
(A) Schematic of Tat-Tat activation response (TAR) region interaction leading to transcriptional activation. Tat binds to the bulge of the stem-loop structure of the TAR element and also interacts with a cellular factor(s) (CF) which binds to the loop of the stem-loop. The diagram on the left assumes that Tat has an activation domain that interacts with the promoter element to activate transcription. The diagram on the right on the other band assumes that Tat does not have an activation domain and that its role is to recruit a cellular factor(s) which activates transcription. The lower diagram depicts a combination of the two possibilities. (B) Tat-mediated transcriptional activation. Tat is depicted to promote both transcriptional initiation and elongation. Its major effect may be to enhance the processivity of transcription.
Electron micrograph illustrating the ultrastructures of mature HHV-6 and HHV-7 virions.
Electron micrograph illustrating the ultrastructures of mature HHV-6 and HHV-7 virions.
Antisense phosphorothioate oligodeoxynucleotides directed against bFGF (AS bFGF) but not sense oligomers (S bFGF) block the growth of AIDS-KS cells derived from different patients (AIDS-KS3, -KS4, and -KS6) (A) but not the proliferation of normal endothelial cells (human umbilical-vein-derived endothelial cells [H-UVE]) grown under standard conditions (aFGF and heparin) (B). □, medium; ▪, AS bFGF; □-S bFGF. Reproduced from the Journal of Clinical Investigation, 1994, 94:1736-1746, by permission of The Society for Clinical Investigation.
Antisense phosphorothioate oligodeoxynucleotides directed against bFGF (AS bFGF) but not sense oligomers (S bFGF) block the growth of AIDS-KS cells derived from different patients (AIDS-KS3, -KS4, and -KS6) (A) but not the proliferation of normal endothelial cells (human umbilical-vein-derived endothelial cells [H-UVE]) grown under standard conditions (aFGF and heparin) (B). □, medium; ▪, AS bFGF; □-S bFGF. Reproduced from the Journal of Clinical Investigation, 1994, 94:1736-1746, by permission of The Society for Clinical Investigation.
Inhibitory properties of antitat gene a
a PBMC, peripheral blood mononuclear cells; SIV, simian immunodeficiency virus.
Inhibitory properties of antitat gene a
a PBMC, peripheral blood mononuclear cells; SIV, simian immunodeficiency virus.
Cultured AIDS-KS spindle cells express endothelium-specific markers and activation molecules which are also present in KS spindle cells in vivo a
a Cultured AIDS-KS spindle cells and frozen sections of AIDS-KS lesions were stained by immunohistochemistry for markers expressed by the activated endothelial cells which are listed here. +, Positive expression.
b Positive after culture in the absence of HTLV-II CM.
Cultured AIDS-KS spindle cells express endothelium-specific markers and activation molecules which are also present in KS spindle cells in vivo a
a Cultured AIDS-KS spindle cells and frozen sections of AIDS-KS lesions were stained by immunohistochemistry for markers expressed by the activated endothelial cells which are listed here. +, Positive expression.
b Positive after culture in the absence of HTLV-II CM.
Activated T cells release inflammatory cytokines which induce endothelial cells in vitro and in vivo to acquire the phenotypic and functional features of KS spindle cells a
a See text for explanations. Table is modified from a table in reference 12 .
b -, Negative or activity absent; +, positive or activity present.
c Adhesion molecules mediating contact with inflammatory cells (ICAM, VCAM, ELAM).
Activated T cells release inflammatory cytokines which induce endothelial cells in vitro and in vivo to acquire the phenotypic and functional features of KS spindle cells a
a See text for explanations. Table is modified from a table in reference 12 .
b -, Negative or activity absent; +, positive or activity present.
c Adhesion molecules mediating contact with inflammatory cells (ICAM, VCAM, ELAM).
Cytokine expression and production by AIDS-KS cells a
a mRNAs from AIDS-KS cells were analyzed for expression of a variety of cytokines. The content of each cytokine was analyzed by radioimmunoprecipitation and/or enzyme-linked immunoassay and is the sum of the intra- and extracellular proteins produced by AIDS-KS cells. Table is modified from a table in reference 12. ND, not done; -, negative; +, detectable levels. + +, + + +, and + + + +, are twofold, threefold, and fourfold the level of +, respectively.
b aFGF, acidic FGF; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor beta.
Cytokine expression and production by AIDS-KS cells a
a mRNAs from AIDS-KS cells were analyzed for expression of a variety of cytokines. The content of each cytokine was analyzed by radioimmunoprecipitation and/or enzyme-linked immunoassay and is the sum of the intra- and extracellular proteins produced by AIDS-KS cells. Table is modified from a table in reference 12. ND, not done; -, negative; +, detectable levels. + +, + + +, and + + + +, are twofold, threefold, and fourfold the level of +, respectively.
b aFGF, acidic FGF; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor beta.
Evidence for role of bFGF in KS lesion formation
a Increased by inflammatory cytokines.
Evidence for role of bFGF in KS lesion formation
a Increased by inflammatory cytokines.
Effects of HIV-1 Tat protein on KS and endothelial-cell properties
Effects of HIV-1 Tat protein on KS and endothelial-cell properties