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Human T-cell lymphotropic virus type III shares sequence homology with a family of pathogenic lentiviruses
by MATTHEW A. GONDA, MICHAEL J. BRAUN, JANICE E. CLEMENTS, JOANNA M. PYPER, FLOSSIE WONG-STAAL, ROBERT C. GALLO, AND RAYMOND V. GILDEN
Proc. Natl. Acad. Sci. USA
Vol. 83, pp. 4007-4011, June 1986

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Human T-cell lymphotropic virus type III shares sequence homology with a family of pathogenic lentiviruses

(human and animal retroviruses/acquired immune deficiency syndrome/evolutionary relationships)

MATTHEW A. GONDA [ i], MICHAEL J. BRAUN [ i], JANICE E. CLEMENTS [ ii] , JOANNA M. PYPER [ ii], FLOSSIE WONG-STAAL [ oii], ROBERT C. GALLO [ iii], AND RAYMOND V. GILDEN [ iv]

ABSTRACT

The etiologic agent of the acquired immune deficiency syndrome, human T-cell lymphotropic virus type m (HTLV-III), has recently been shown to morphologically resemble and share sequence homology with visna virus, a pathogenic lentivirus. Molecular hybridization, heteroduplex mapping, and DNA sequence analyses were used to compare HTLV-III to other lentiviruses of domestic animals, including visna, caprine arthritis encephalitis, and equine infectious anemia viruses. Hybridization results showed that a substantial amount of sequence homology exists between each of these viruses and HTLV-III. In addition, a closer relationship was found between visna and caprine arthritis encephalitis viruses than for any of the other lentiviruses studied. These results, along with nucleotide and amino acid sequence comparisons, have been used in a comprehensive effort to derive a systematic relationship for lentiviruses and to provide further evidence for classifying HTLV-III with the Lentivirinae subfamily of retroviruses. This relationship predicts that similarities in biology and disease process can be expected between HTLV-III and other Lentivirioae members.

Gonda et al. (1) recently showed that human T-cell lymphotropic virus type III (HTLV-III) morphologically resembles and shares nucleotide sequence homology with visna virus, a pathogenic, neurotropic lentivirus of sheep. Visna virus also shares other biological similarities with HTLV-III. For example, HTLV-III exhibits a strong tropism for cells of the immune system, in particular, helper T-lymphocytes upon which it exerts its biologic effects. In culture, HTLV-III induces syncytia and is cytolytic (2). Moreover, HTLV-III-induced acquired immune deficiency syndrome (AIDS) is characterized by T-cell depletion, immunosuppression, and opportunistic infections, and the propensity for HTLV-III to infect brain cells suggests a possible neuropathic role for HTLV-III in AIDS-related encephalopathy and dementia (2, 3). Visna virus also infects cells of the immune system (monocytes) and is cytolytic in cell culture, and it produces a slowly progressive inflammatory condition of the central nervous system, often leading to total paralysis and death from inanition (4-7).

Lentiviruses (subfamily Lentivirinae in the family Retroviridae) are exogenous, nononcogenic retroviruses (8) that cause persistent but debilitating infections, replicate at a slow but progressive rate, and have been shown to have pathogenic potential in vitro. Lentiviruses have been isolated from a variety of domestic ungulates including ovine (4-7), caprine (9-12), equine (13), and bovine (14) species.

The morphologic, genetic, and biologic similarities with visna virus provide strong evidence for a close evolutionary relationship between HTLV-III and the Lentivirinae subfamily of retroviruses (1). Further analysis of the evolutionary and systematic relationship between HTL V-III and other lentiviruses has awaited the molecular cloning of representative species (15-18). As a sequel to the initial findings of Gonda et al. (1), we have used heteroduplex mapping, molecular hybridization, and DNA sequence analyses to further detail the genetic relationship of HTL V-III, visna virus, caprine arthritis encephalitis virus (CAEV), and equine infectious anemia virus (EIAV) and to provide a phylogeny for this evolutionarily diverse family.

MATERIALS AND METHODS

Heteroduplex Analysis. Heteroduplexes were prepared according to the method of Davis et at. (19) with modifications (1). The stringency of hybridization was calculated from the equations of McConaughy et al. (20) using the known G+C content (42%) of HTLV-III (21).

Southern Transfer Analysis. DNA fragments representing all or most of each lentiviral genome (see Fig. 2A) were electrophoresed, then transferred to nitrocellulose paper by the method of Southern (22). Nitrocellulose-bound DNAs were hybridized with the lentiviral probes (1 x 106 cpm/ml), which consisted of the virus genomes shown in Fig. 2A, radiolabeled with 32p to a specific activity of 1-3 x 108 cpm/ug by nick-translation (23). Hybridization was carried out in a buffer (24) containing 50% formamide and 1 M NaCI at 22°C [melting temperature (tm) - 40°C] for 72 hr. Filters were washed in 3x standard saline citrate (0.45 M NaCl/ 0.045 M sodium citrate, pH 7.0) at 37°C (tm - 55°C), and autoradiographed with Kodak XRP-5 x-ray film for 16 hr at -70°C with two Dupont Cronex Lightning Plus intensifying screens.

Nucleotide Sequencing. The visna virus sequence was determined from a previously described clone (16), by Maxam and Gilbert (25) chemical degradation from the BstEII site (see Fig. 3; nucleotides 71-77).

Phylogeny Reconstruction. Nucleotide sequences were aligned by the method of Dayhoff (26). The frequency of matching residues (M) was calculated from the optimal pairwise alignments, counting gaps as mismatches. By using -logM as a distance metric, a phylogenetic tree was con- structed by the method of Fitch and Margoliash (27) using the PHYLIP computer program package of J. Felsenstein (University of Washington, Seattle).

RESULTS AND DISCUSSION

We first constructed heteroduplexes between HTLV-III and CAEV, a neurotropic virus of goats (9-12). CAE V shares a considerable amount of sequence homology with visna virus over its entire genome, but this homology is greatest for the gag and pol genes and for a highly conserved region overlapping the carboxyl terminus of pol, analogous to the sor (short open reading frame) region in HTLV-III (18,21,28).

Heteroduplexes between HTLV-III and CAE V spread at tm - 47°C revealed a substantial amount of homology (Fig. 1). Approximately 33% of the HTLV-III genome formed a duplex with CAEV. When the heteroduplexes were spread at tm - 39°C, 15% of the HTLV-III genome remained duplexed with CAE V , with the conserved sequences occurring largely in the gag/pol gene region (data not shown). This is in agreement with the extent and location of sequences conserved between HTLV-III and visna virus (1). As a negative control, we used a A clone ofHTLV-11I whose insert was in the reverse orientation of the clone used in Fig. 1A. No regions of hybridization were observed between CAEV and the reversed HTLV -III insert (data not shown), verifying that the conditions used for heteroduplex formation were not so mild as to allow nonspecific hybridization over short stretches of DNA. Furthermore, in previous heteroduplex studies between HTLV-III and HTLV-I or -II, conducted under similar low-stringency conditions, no hybridization was detected with HTLV-II and only a minimal amount was detected with HTL V-I (5-10% of that observed here between HTLV-III and CAEV) in the gag/pol region (1, 29).

Image
FIG. 1. Heteroduplexes were prepared with inserts in bacteriophage A. (A) Heteroduplex of HTLV-III and CAEV at tm - 47°C. (B) Interpretive drawing. The 5' and the 3' ends of the plus strand of the insert and the A arms are indicated. Regions of homology in A are represented by thick lines, and regions of nonhomology are represented by thin lines.

To confirm and extend the heteroduplex data, we attempted to detect genetic relatedness among lentiviruses by using cloned viral genomes of HTLV -III, CAEV, EIA V, and visna virus (15-18) (Fig. 2A) in Southern transfer molecular hybridization experiments. The HTLV-III probe showed homology with all the genomes tested (Fig. 2B). No nonspecific hybridization was detected with an equimolar amount of negative control DNA. In reciprocal hybridizations, EIA V and visna virus probes also detected HTLV-III and other lentiviruses (Fig. 2B). As the washing stringencies were increased (1m -34°C to -25°C), the heterologous hybridization intensities were reduced while the homologous reaction remained undiminished. Furthermore, when purified inserts were molecularly dissected with appropriate restriction enzymes, hybridization experiments showed that the greatest amount of homology between each of these viruses exists in the pol or the gag/pol region (data not shown) as has been shown for HTLV-III and visna virus (1).

To help quantify the relationship between HTLV-III, lentiviruses, and other retroviruses, we determined a ml\ior portion of the nucleotide sequence for a visna virus clone. A segment of this sequence from a region near the amino terminus of the visna virus pol gene is shown in Fig. 3. The nucleotide sequence homology between visna virus and HTL V-III is 66% over this entire region. Several segments of 25-40 nucleotides in this region have greater than 80% homology (visna nucleotides 1-39, 109-142, and 232-255), and several stretches have from 8 to 13 bases identical. Clearly, this degree of sequence conservation accounts for the specific hybridization seen under the relaxed conditions of the heteroduplex and Southern blot analyses (Figs. 1 and 2; refs. 1, 29) and contrasts strongly with the negative hybridization results between cloned visna virus and LA V reported by others (30, 31). An independently determined visna virus sequence from a different clone matches our sequence (Fig. 3) except for a single silent substitution at nucleotide 78 and shows a similar degree of conservation over the rest of the pol gene (28), thus further confirming our initial observations on the genetic relationship of visna virus and HTLV-III (1).

The predicted amino acid sequences for HTLV -III and the visna virus pol gene segments shown in Fig. 3 were aligned with the pol sequence of EIA V (17), CAEV (32), and several other representative retroviruses (Fig. 4A). It is obvious from inspection of this alignment that HTLV-III, visna virus, CAEV, and EIA V cluster together. Using the amount of amino acid homology computed for each pairwise comparison, we next derived a phylogenetic tree for these viral genes (Fig. 4B). In rooting this tree, Moloney murine leukemia virus (Mo-MuLV) was considered to be the outgroup taxon because it consistently had the lowest alignment score with each of the other viruses. This decision is supported by the fact that the reverse transcriptase of Mo-MuLV preferentially uses Mn2+ as cofactor, while the reverse transcriptases of all the other viruses prefer Mg2+, and by previous artalyses of the relationships of retroviral pol genes, which identified the mammalian type C pol genes as the most divergent (35).

The phylogenetic tree (Fig. 4B) clearly shows that HTL VIII clusters with the lentiviruses. Within this group, visna virus and CAEV are the most closely related with amino acid homology of 90%; HTL V -III is slightly closer to this pairthan is EIA V. The amino acid homology between HTL V -III, EIA V, and the CAEV /visna virus pair is approximately 60%. The next closest viruses are Rous sarcoma virus (RSV) and HTLV-I at about 40% amino acid homology. Finally, MoMuL V was the most divergent, with about 30% amino acid homology to the lentiviruses. While the tree topology derived from this region of the pol gene has HTL V-III more closely related to visna virus and CAEV than either is to EIAV, sequence comparisons from other segments of the genome suggest alternative tree topologies with HTLV-III or CAEV /visna virus diverging first (17). Therefore, aside from the close relationship of visna virus and CAEV, we consider the lentiviruses to be about equally related. Overall, the tree topology is in general agreement with other recent attempts at classification of retroviral pol genes (28, 32).

Image
FIG. 2. Detection of sequence homology between HTL V-III, CAEV, EIAV, and visna virus by molecular hybridization. (A) Restriction enzyme fragments used in the hybridization studies. The EIAV fragment contained about 1.4 kilobase pairs (kbp) of host flanking sequences at its left end. The relative genomic organization of each fragment is indicated by its alignment with the generalized lentivirus gene map shown at the bottom. The arrow over the env gene region indicates the 3' open reading frame (ORF) in HTLV-Ill. The genomic organization was determined from the nucleotide sequence for HTLV-III (21), EIAV (17), and visna virus (28) and by heteroduplex mapping for CAEV (18). H, HindIII; S, Sac I.

Image
(B) Southern transfers of the lentiviral genomic fragments shown in A hybridized with 32P-labeled HTLV-III, visna, and EIA V probes under relaxed conditions (tm - 40°C). The amount of DNA loaded into each lane was 100 pg for lanes homologous to the probe and 100 ng for heterologous lanes, except for the hybridization of CAEV with the visna probe, for which 1 ng of CAEV DNA was used because of the extensive homology between CAEV and visna. Each gel also contained 500 ng of HindIII-digested DNA fragments as molecular weight markers and negative hybridization controls. Lanes: C, CAEV; V, visna; E, EIAV; III, HTLV-III; A.

Because the amino acid sequences provided a data set of discrete characters including a well-defined outgroup (MoMuLV), we used cladistic analysis (36) to confirm the kinship of HTLV-III and lentiviruses. This analysis revealed that there are at least 10 positions where visna virus, CAEV, HTLV -III, and EIAV share a potentially derived character state (shared amino acids that are not shared with the other viruses). Of these, residues 11, 28, 43, 46, and 59 (Fig. 4A) are especially good candidates, because HTLV-I, RSV, or both share the putative ancestral character state with Mo-MuL V while visna virus, CAEV, HTLV-III, and EIAV share a potentially derived character state. Thus, beyond their overall similarity, HTL V-III is united with the lentivirus group by a number of probable shared derived characters.

Our efforts to detect and compare conserved nucleotide and amino acid sequences in the pol gene of lentiviruses have enabled us to derive the first comprehensive systematic relationship for this group. Biologically significant similarities extend to the genomic organization of these viruses. For example, the topographies of the HTLV -III and visna virus genomes, like those of other retroviruses, contain gag, pol, and env structural genes located 5' to 3', respectively. In addition, there are two extra ORFs in HTLV-III that are unique among retroviruses (21, 30, 34, 37-39). The first ORF, sor, is located immediately 3' to the pol gene and partially overlaps its carboxyl terminus. The second (3' ORF) overlaps the carboxyl terminus of the env gene and extends into the 3' long terminal repeat (LTR) (21,30,39). Visna virus (28) and CAEV, based on the extensive sequence homology of CAE V with visna virus in this region (18), contain a sor. A 3' ORF has not been identified in the one visna virus clone sequenced to date (28).

A novel feature of HTL V -III and visna virus is a gene called tat, for trans-activating transcriptional regulation, that encodes a factor that is believed to modulate viral expression in infected cells (40, 41). HTLV-I and -II and bovine leukemia virus also contain a tat gene, which has been localized to a region between the env gene and the 3' LTR (42-44), called pX (33). However, in contrast to these viruses, the tat gene for HTLV-III is not contained in the analogous 3' post-en v region (3' ORF) but is in the middle of the genome in a region between the sor and the env genes (41). Such a region also exists for visna virus (28) and is strongly conserved both structurally and functionally between visna virus and CAEV (18, 40), which, by extrapolation, suggests that the tat gene for both of these viruses will also be localized to this area.

Image
FIG. 3. Nucleotide sequence comparison between homologous regions of the pol genes of visna virus and HTLV-III. The HTLV-III sequence is from the BH10 clone (21); published sequences of lymphadenopathy virus (LAV) and HTLV-III are identical in this region (30).

Image
FIG. 4. (A) Alignment of lentivirus pol genes with those of other retroviruses. The visna virus amino acid sequence predicted by the segment of nucleotide sequence shown in Fig. 3 was aligned with those of six other retrovirus pol genes including HTLV-III (21), EIAV (17), CAEV (32), HTLV-I (33), RSV (34), and Mo-MuLV (30). The alignment shown for each virus is generally that optimal with visna virus; slight improvements in the other pairwise alignment scores can be made by minor shifts in the placement of gaps. Boxes are drawn around identical residues when at least two lentiviruses (visna virus, CAEV, HTLV-III, or EIAV) share that residue.

Image
(B) Fitch-Margoliash phylogenetic tree of retroviral relationships based on the pol gene region shown in A. Branch lengths are in units of -logM, where M is the frequency of matching residues. The tree was rooted with Mo-MuL V as the outgroup. The average percent standard deviation of the tree was 3.3.

HTLV-III shares other structural and biologic features in common with lentiviruses. On the basis of their morphologic fine structure, the viruses now classified as Lentivirinae are indistinguishable from HTLV-III (45-47). They all contain, in their outer membrane, a very large (90-135 kDa) glycosylated envelope protein and a transmembrane protein of 40 kDa (48-52); the large size of the envelope protein is unique to this subfamily of retroviruses. The major core protein (P24) of LAV and HTLV-III can be immunoprecipitated by antibodies to EIAV (53), predicting that nucleotide sequence homology would be found in the gag gene as recently demonstrated (17).

HTLV-III is a lentivirus as supported by the criteria outlined above. However, there are indications that there may be other family members more closely related to HTLV-III than those we have analyzed. A new viral isolate, simian T-lymphotropic virus type III (STLV-III), possesses ultrastructural morphology and other biologic properties similar to those of lentiviruses and viral proteins that are immunologically crossreactive with those of HTLV-III (54, 55). These data imply a genetic relationship for HTLV-III and STLV-III. If such is the case, it will be important to isolate molecular clones to establish the relationship between STL V-III and the lentiviruses used in this study.

Many factors in lentivirus-host interactions may have relevance to HTLV -III-induced disease. CAEV (56), EIAV (57), and bovine visna-like virus (BVV) (14), like HTLV-III and visna virus, also infect the cells of the immune system and, although the clinical sequelae vary for each virus, parallels with AIDS are apparent. Visna infection is associated with chronic pneumonitis, encephalitis, and wasting (6, 7); CAEV with crippling arthritis and encephalitis (9-12); EIAV with intermittent anemia, bouts of fever, and immune-complex glomerulonephritis (13); and BYV with lymphadenopathy and persistent lymphocytosis (14).

Despite differences in the outcome with infection by lentiviruses, one point remains in common; infected individuals remain infected for life. The exact mechanism of persistence by HTLV-III is not known. Lentiviruses, like other retroviruses, can integrate into the host cell DNA and produce latent infections. Once expressed, lentiviruses have developed different strategies to evade elimination by the immune response of the host. For example, visna virus and EIA V induce binding antibodies to all of their respective polypeptides and titratable neutralizing antibodies; however, "antigenic drift" in their env genes yields variants that escape immune surveillance mechanisms and induce a new cycle of disease (58, 59). CAEV also induces binding antibodies but, in contrast, titratable neutralizing antibodies are rare, and they are effective against only a narrow range of CAEV strains (60).

Genomic diversity for HTLV-III, particularly in the env region, is well documented (21,39,61,62) and is suggestive of antigenic variation. Neutralizing antibodies of low titer have also been detected in patients with AIDS and AIDS-related complex (63, 64). However, in one of these studies (64), neither early nor late serum relative to HTLV-III isolation from a single individual was strongly neutralizing, and different viral isolates from geographically separated areas did not vary significantly in sensitivity to neutralization by selected sera. Thus, the mechanism of persistence for HTLV-III may be more reminiscent of CAEV in that neutralizing antibodies are rarely achieved. The phylogenetic relationship of HTLV-III and lentiviruses imply that a better understanding of mechanisms of lentivirus persistence and the parameters of neutralization by antibodies could contribute t9 the effective control of HTLV-III-induced disease.

We thank N. Rice for allowing use of her EIAV nucleotide sequence data; K. Nagashima, J. Shumaker, and J. E. Elser for technical contributions; D. Lomb for assistance with computer analysis; J. Felsenstein for advice on the use of PHYLIP; and J. Hopkins for assistance in preparing the manuscript. M.A.G., M.J .B., and R.V.G. were supported by Public Health Service Contract NOl-CO-23910 ·with Program Resources, Inc., from the National Cancer Institute.

_______________

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56. Narayan, 0., Kennedy-Stoskopf, S., Sheffer, D., Griffin, D. E. & Clements, J. E. (1983) Infect. Immun. 41, 67-73.

57. Kobayashi, K. & Kono, Y. (1967) Nat. Inst. Anim. Health Q. 7, 8-20.

58. Narayan, 0., Griffin, D. E. & Chase, J. (1977) Science 197, 376-378.

59. Payne, S., Parekh, B., Montelaro, R. C. & Issei, C. J. (1984)J. Gen. Virol. 65, 1395-1399.

60. Narayan, O., Sheffer, D., Griffin, D. E., Clements, J. & Hess, J. (1984) J. Virol. 49, 349-355.

61. Hahn, B. H., Gonda, M. A., Shaw, G. M., Popovic, M., Hoxie, J. A., Gallo, R. C. & Wong-Staal, F. (1985) Proc. Natl. Acad. Sci. USA 82, 4813-4817.

62. Wong-Staal, F., Shaw, G. M., Hahn, B. H., Salahuddin, S. Z., Popovic, M., Markham, P., Redfield, R. & Gallo, R. C. (1985) Science 229, 759-762.

63. Robert-Guroff, M., Brown, M. & Gallo, R. C. (1985) Nature (London) 316, 72-74.

64. Weiss, R. A., Clapham, P. R., Cheingsong-Popov, R., Dalgleish, A. G., Came, C. A., Weller, I. V. D. & Tedder, R. S. (1985) Nature (London) 316, 69-72.

________________

[i] Laboratory of Cell and Molecular Structure. Program Resources, Inc., National Cancer Institute-Frederick Cancer Research Facility, Frederick, MD 21701

[ii] Departments of Neurology and Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205

[iii] Laboratory of Tumor Cell Biology, National Cancer Institute, Bethesda, MD 20892

[iv] Program Resources. Inc., National Cancer Institute-Frederick Cancer Research Facility, Frederick, MD 21701

Communicated by Paul C. Zamecnik, January 2, 1986

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked" advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Abbreviations: AIDS, acquired immune deficiency syndrome; HTLV-I, -II, and -III, human T-cell lymphotropic virus type I, II, and III; CAEV, caprine arthritis encephalitis virus; EIAV, equine infectious anemic virus; tm, melting temperature; LA V, lymphadenopathy virus; Mo-MuLV, Moloney murine leukemia virus; RSV, Rous sarcoma virus; ORF, open reading frame; LTR, long terminal repeat.

Re: GAO-02-809R Origin of the AIDS Virus

PostPosted: Mon Jan 04, 2016 3:56 am
by admin
Maedi-visna virus and its relationship to human immunodeficiency virus
by Thormar H.
University of Iceland, Institute of Biology, Sturlugata 7, 101 Reykjavik, Iceland. halldort@hi.is
AIDS Rev. 2005 Oct-Dec;7(4):233-45.

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Abstract

Maedi-visna is a slow virus infection of sheep leading to a progressing lymphoproliferative disease which is invariably fatal. It affects multiple organs, but primarily the lungs where it causes interstitial pneumonia (maedi). Infection of the central nervous system was commonly observed in Icelandic sheep (visna), infection of mammary glands (hard udder) in sheep in Europe and the USA, and infection of the joints in sheep in the USA. The name ovine progressive pneumonia (OPP) is commonly used in the USA and ovine lentivirus (OvLV) infection is also a name used for maedi-visna. A related infection of goats, caprine arthritis-encephalitis (CAE), is common in Europe and the USA. The natural transmission of maedi-visna is mostly by the respiratory route, but also to newborn lambs by colostrum and milk. Intrauterine transmission seems to be rare and venereal transmission is not well documented. Macrophages are the major target cells of maedi-visna virus (MVV), but viral replication is greatly restricted in the animal host, apparently due to a posttranscriptional block. The low-grade viral production in infected tissues can explain the slow course of the disease in sheep. The lesions in maedi-visna consist of infiltrates of lymphocytes, plasma cells, and macrophages, and are detectable shortly after experimental transmission. Several studies indicate that the lesions are immune mediated and that cytotoxic T-lymphocytes may be important effector cells. The persistence of the MVV infection is explained by a reservoir of latently infected blood and bone marrow monocytes, which migrate into the target organs and mature into macrophages with proviral DNA transcription, but limited replication of virus. The MVV particles are morphologically similar to those of other retroviruses and the mode of replication follows the same general pattern. The genome organization and gene regulation resembles that of other lentiviruses. In addition to gag, pol and env, MVV has three auxiliary genes (tat, rev and vif), which seem to have similar functions as in other lentiviruses, with a possible exception of the tat gene. A determination of the 9200 nucleotide sequence of the MVV genome shows a close relationship to CAE virus, but limited sequence homology with other lentiviruses, and only in certain conserved domains of the reverse transcriptase and possibly in the surface protein. MVV infection in sheep and HIV-1 infection in humans have a number of features in common such as a long preclinical period following transmission, and a slow development of multiorgan disease with fatal outcome. A brief early acute phase, which is terminated by the immune response, is also an interesting common feature. Like HIV-1, MVV is macrophage tropic and the early stages of the HIV-1 infection which affect the central nervous system and the lungs are in many ways comparable to maedi-visna. In contrast to HIV-1, MVV does not infect T-lymphocytes and does not cause T-cell depletion and immunodeficiency. This is responsible for the difference in the late stages of the HIV-1 and MVV infections and the final clinical outcome. Despite limited sequence homology, certain proteins of MVV and HIV-1 show structural and functional similarities. Studies of MVV may therefore help in the search for new drugs against lentiviruses, including HIV-1.

Re: GAO-02-809R Origin of the AIDS Virus

PostPosted: Mon Jan 04, 2016 3:59 am
by admin
The origin of lentivirus research: Maedi-visna virus
by Thormar H.
University of Iceland, Reykjavik, Iceland. halldort@hi.is
Curr HIV Res. 2013 Jan;11(1):2-9.

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Abstract

Maedi and visna are contagious sheep diseases which were introduced into Iceland in 1933 by imported sheep of Karakul breed. Maedi, a slowly progressing pneumonia, and the central nervous system disease visna were shown to be transmissible in sheep and most likely caused by a virus. In 1957, visna virus was isolated in tissue culture from sheep brain and maedi virus was isolated the following year from sheep lungs. Both viruses showed similar cytopathic effect in tissue culture. Electron microscope studies of ultrathin sections from visna virus infected cells demonstrated spherical particles, 70-100 nm in diameter, which were formed by budding from the cell membrane. Later studies showed identical particles in maedi virus infected cultures. These, and several other comparative studies, strongly indicated that maedi and visna were caused by strains of the same virus, later named maedi-visna virus (MVV). Comparative studies in tissue culture suggested that MVV was related to RNA tumor viruses of animals, the oncornaviruses. This was later supported by the finding that MVV is an RNA virus. A few months after reverse transcriptase was demonstrated in oncornaviruses, the enzyme was also found in MVV virions. Thus, MVV was classified as a retrovirus together with the oncornaviruses. However, MVV is not oncogenic in vivo or in vitro and was in 1975 placed in a subgroup of retroviruses named lentiviruses, which cause cytopathic effect in vitro and slowly progressing inflammatory disease in animals, but are nononcogenic. In the early 1980s, the causative agent of AIDS was found to be a non-oncogenic retrovirus and was classified as a lentivirus. Thus, HIV became the first human lentivirus.

Re: GAO-02-809R Origin of the AIDS Virus

PostPosted: Mon Jan 04, 2016 4:01 am
by admin
Virucidal effect of lipids on visna virus, a lentivirus related to HIV
by Hilmarsson H, Larusson LV, Thormar H.
Institute of Biology, University of Iceland, Reykjavik, Iceland. hilmarh@hi.is
Arch Virol. 2006 Jun;151(6):1217-24. Epub 2006 Jan 3.

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Abstract

Natural lipids and fatty alcohols show virucidal activities against enveloped viruses. A virucidal profile of these compounds against visna virus (VV), a lentivirus related to HIV, or against other viruses of the genus Lentivirus has not been established before and could help elucidate how lipids inactivate enveloped viruses and assist in the development of virucidal drugs. The activity profile for VV may not exactly reflect the profile for HIV or for the lentivirus subgroup in general, but the results for VV are in agreement with earlier studies, which have shown that lipids become generally more virucidal at low pH.

Re: GAO-02-809R Origin of the AIDS Virus

PostPosted: Mon Jan 04, 2016 4:04 am
by admin
Visna virus encodes a post-transcriptional regulator of viral structural gene expression
by Tiley LS1, Brown PH, Le SY, Maizel JV, Clements JE, Cullen BR.
Proc Natl Acad Sci U S A. 1990 Oct;87(19):7497-501.
Erratum in
Proc Natl Acad Sci U S A 1990 Dec;87(23):9508.

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Abstract

Visna virus is an ungulate lentivirus that is distantly related to the primate lentiviruses, including human immunodeficiency virus type 1 (HIV-1). Replication of HIV-1 and of other complex primate retroviruses, including human T-cell leukemia virus type I (HTLV-I), requires the expression in trans of a virally encoded post-transcriptional activator of viral structural gene expression termed Rev (HIV-1) or Rex (HTLV-I). We demonstrate that the previously defined L open reading frame of visna virus encodes a protein, here termed Rev-V, that is required for the cytoplasmic expression of the incompletely spliced RNA that encodes the viral envelope protein. Transactivation by Rev-V was shown to require a cis-acting target sequence that coincides with a predicted RNA secondary structure located within the visna virus env gene. However, Rev-V was unable to function by using the structurally similar RNA target sequences previously defined for Rev or Rex and, therefore, displays a distinct sequence specificity. Remarkably, substitution of this visna virus target sequence in place of the HIV-1 Rev response element permitted the Rev-V protein to efficiently rescue the expression of HIV-1 structural proteins, including Gag, from a Rev- proviral clone. These results suggest that the post-transcriptional regulation of viral structural gene expression may be a characteristic feature of complex retroviruses.

Re: GAO-02-809R Origin of the AIDS Virus

PostPosted: Mon Jan 04, 2016 4:05 am
by admin
The origin of HIV-1, the AIDS virus
by Siefkes D.
Med Hypotheses
1993 Oct;41(4):289-99.

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Abstract

This article proposes a series of experiments to determine if cows and sheep could be used as animal models for HIV-1, the AIDS virus. To justify this effort, a substantial case is presented that HIV-1 is a natural recombinant of Bovine Leukemia Virus (BLV) and Visna Virus. This natural recombinant may have been inadvertently transferred to humans through the Intensified Smallpox Eradication Program conducted in sub-Saharan Africa in the late 1960s and most of the 1970s.

Re: GAO-02-809R Origin of the AIDS Virus

PostPosted: Mon Jan 04, 2016 4:13 am
by admin
Visna virus
by Wikipedia
1/3/2016

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Visna virus
Virus classification
Group: Group VI (ssRNA-RT)
Order: Unassigned
Family: Retroviridae
Subfamily: Orthoretrovirinae
Genus: Lentivirus
Species: Visna virus
Synonyms: Maedi virus


Visna virus (also known as visna-maedi virus, maedi-visna virus and ovine lentivirus[1]) from the genus lentivirinae and subfamily Orthoretrovirinae, is a "prototype"[2] retrovirus[3] that causes encephalitis and chronic pneumonitis in sheep.[4] It is known as visna when found in the brain, and maedi when infecting the lungs. Lifelong, persistent infections in sheep occur in the lungs, lymph nodes, spleen, joints, central nervous system, and mammary glands;[2][5] The condition is sometimes known as "ovine progressive pneumonia" (OPP), particularly in the United States,[1] or "Montana sheep disease".[6] White blood cells of the monocyte/macrophage lineage are the main target of visna virus.[7]

Viral infection

First described in 1954 by Bjorn Sigurdsson in Iceland,[6] Maedi-visna virus was the first lentivirus to be isolated and characterized, accomplished in 1957 by Sigurdsson.[6][7][8] "Maedi" (Icelandic for dyspnoea) and "visna" (Icelandic for "wasting"[9] or "shrinking" of the spinal cord) refer to endemic sheep herd conditions that were only found to be related after Sigurdsson's work.[6]

Visna infection may progress to total paralysis leading to death via inanition; however, if given assistance in eating and drinking, infected animals may survive for long periods of time, sometimes greater than ten years.[9] Viral replication is almost exclusively associated with macrophages in infected tissues; however, replication is restricted in these cells—that is, the majority of cells containing viral RNA do not produce infectious virus.[5]

The disease was introduced to Iceland following an import of Karakul sheep from Germany in 1933.[6] The susceptibility to maedi-visna infection varies across sheep breeds, with coarse-wool breeds apparently more susceptible than fine-wool sheep.[6] Attempts at vaccination against maedi-visna virus have failed to induce immunity, occasionally causing increased viremia and more severe disease. [7] Eradication programs have been established in countries worldwide.[6]

Associated Diseases and Symptoms

Visna – Maedi is a chronic viral disease prevalent in adult sheep. The disease is rarely found in certain species of goat. Maedi Visna virus is also referred to as ovine progressive pneumonia. (OPP ) This disease corresponds to two clinical entities caused by the same Maedi is a form that results in a chronic progressive pneumonia. Visna refers to the neurological form of the disease and predominantly causes meningoencephalitis in adult sheep. This disease has inflicted many economic losses worldwide due to the long incubation period and the high mortality rate of sheep and goats. MV virus can infect sheep of any age but clinical symptoms rarely occur in sheep less than two years old. The onset of the diseases is gradual resulting in relentless loss of weight in addition to breathing problems. Cough, abortion, rapid breathing, depression, chronic mastitis and arthritis are also additional symptoms observed. These symptoms appear mostly in animals over the age of three and therefore might spread to other flocks before clinical diagnosis can be achieved. Animals showing the above symptoms might die within six months of infection. This causal lentivirus can be found in monocytes, lymphocytes and macrophages of infected sheep in the presence of humoral and cell mediated immune response and can also be detected by conducting several serological tests.[10] Transmission of the disease occurs most commonly via the oral route caused by ingestion of colostrum or milk that contains the virus or inhalation of infected aerosol droplets. Due to variation of the strains of MVV, some of the association clinical symptoms may be more pre-dominant in a flock relative to others along with differences in genetic susceptibility patterns.[11]

Viral Replication

Entry


Visna Maedi virus (VMV) belongs to the small ruminant lentivirus group (SRLV). In general, SRLVs enter the cell through the interaction of their glycosylated envelope protein with a cellular receptor on the cell's plasma membrane facilitating fusion of the viral and cellular membrane.[12] However, the specific cellular receptor that VMV binds is not entirely certain. A few studies have proposed MHC class II, CD4 and CXCR4 proteins as possible receptors however, none of these proteins have been established as the main receptor.[13][14] Another study suggests that C-type lectins part of the mannose receptor (MR) family play a role as an alternative SRLV receptor.[15] The mannose receptor is a 180-kDa transmembrane protein with eight tandem C-type lectin carbohydrate recognition domains (CRD) of which CRD4 and CRD5 are essential in recognizing mannose, fucose and N-acetyl glucosamine residues. Studies suggest that VMV gains entrance to the cell via mannosylated residues on its envelope proteins.[15] MR is involved in recognizing the surface of pathogens and is involved in phago- and endocytosis and mediating antigen processing and presentation in a variety of cells including monocyte/macrophages and endothelial cells.[16][17]

Replication

Visna Maedi virus is a retrovirus meaning its genome consists of a (+)RNA that undergoes reverse transcription and then is integrated into the host's genome after infection. This integration is what leads to VMV's lifelong persistent infection.[7] VMV has a long incubation period. During the initial outbreak among sheep in Iceland, there was no sign of clinical disease until six years after the importation of the Karakul sheep, which brought the virus from Germany to Iceland.[18] Susceptibility to infection also increases with a higher level. VMV infects cells of the monocyte lineage, but only replicates at high levels when the monocytes are more mature/differentiated.[19] of maturity/differentiation of the monocytes. Infected differentiated monocytes, also known as macrophages, will continuously present VMV antigens inducing T-lymphocytes to produce cytokines that in turn induce the differentiation of monocytes.[7]

Viral Transmission

Horizontal Transmission


Horizontal transmission plays an important role among livestock due to their often close quarters, especially during winter stabling. Free virus or virus infected cells are generally transferred in through inhalation of respiratory secretions. Additionally, fecal-oral transmission often occurs through contamination of drinking water.[20] Sexual transmission has also been shown to be possible [21] No link has yet been made between transmission and other excretory products such as saliva and urine.

Vertical Transmission

In endemically infected flocks of livestock, free virus and virus infected cells are passed through from mothers to lambs via colostrumand milk.[22] This is one of the key features in affected populations, as it contributes greatly to the virus becoming endemic in the flock.[23] Lambs are extremely vulnerable to infection due to the permeability of the guts of newborns [24]

Virion Structure

Visna virus particles are spheres approximately 100 nm in diameter. Virions consist of an icosahedral capsid surrounded by an envelope derived from the host plasma membrane.[25] Inside the capsid are the nucleoprotein-genome complex and the reverse transcriptase and integrase enzymes. A crystal structure of the virion has not been obtained and the triangulation number of the icosahedron is unknown.

Tropism

The term viral tropism refers to the cell types a virus infects. Visna virus is generally known to target cells of the immune system, mainly monocytes and their mature form, macrophages. Studies suggest that the amount of viral replication appears to have a direct correlation with the maturity of the infected cells, with relatively little virus replication in monocytes when compared to more mature macrophages [26]

Infection can also occur in mammary epithelial and endothelial cells, implying mammary glands as a main viral reservoir, showing the importance that vertical transmission plays in the spread of the virus [27]

Genome Structure

Visna virus has a positive-strand RNA genome approximately 9.2 kilobases in length. As a retrovirus in the genus lentivirinae, the genome is reverse transcribed into proviral DNA. The visna virus genome resembles that of other lentiviruses, in terms of the gene functions that are present. Visna virus is closely related to the caprine arthritis encephalitis virus but has limited nucleotide sequence similarity with other lentiviruses.[1]

The visna viral genome encodes three structural genes characteristic of retroviruses, gag (group specific antigen), pol (polymerase), and env (envelope protein).[25] The genome also encodes two regulatory proteins, tat (trans-activator of transcription) and rev(regulator of virion protein expression). A rev response element (RRE) exists inside the env gene. An auxiliary gene, vif (viral infectivity factor), is also encoded. However, the number and role of auxiliary genes varies by strain of visna virus. The genome sequence is flanked by 5’ and 3’ long terminal repeats (LTRs).

The viral LTRs are essential for viral transcription.[28] The LTRs include a TATA box at the -20 position and a recognition site for the AP-4 transcription factor at the -60 position.[29] There are several AP-1 transcription factor binding sites in the viral LTRs. The closest AP-1 binding site is bound by the Jun and Fos proteins to activate transcription.[30] A duplicated motif in the visna virus LTR is associated with cell tropism and neurovirulence.[31]

The gag gene encodes three final glycoprotein products: the capsid, the nucleocapsid, and the matrix protein which links the capsidand the envelope.

The env gene is translated into a single precursor polyprotein that is cleaved by a host protease into two proteins, the surface glycoprotein and the transmembrane glycoprotein. The transmembrane glycoprotein is anchored inside the envelope lipid bilayer while the surface glycoprotein is non-covalently linked to the transmembrane glycoprotein.[25]

The pol gene encodes five enzymatic functions: a reverse transcriptase, RNase H, dUTPase, integrase, and protease.[25] The reverse transcriptase is an RNA-dependent DNA polymerase that exists as a heterodimer protein with RNase H activity. The dUTPase enzyme is not present in all lentiviruses. The role of the dUTPase in the visna virus life cycle is unclear. dUTPase-deficient visna virus knockout strains show no decrease in pathogenicity in vivo.[32] The integrase enzyme exists inside the viral capsid, facilitating integration into the host chromosome after entry and virion uncoating. The protease cleaves the gag and pol polyprotein precursor.

The viral tat gene encodes a 94-amino acid protein. Tat is the most enigmatic of the proteins of the visna virus. Most studies have indicated that Tat is a transcription factor necessary for viral transcription from the LTRs. Tat contains both a suppressor domain and a powerful acidic activator domain on the N-terminus.[33] It has been suggested that Tat interacts with the cellular AP-1 transcription factors Fos and Jun to bind to the TATA-binding protein and activate transcription.[30] However, other studies have suggested that the visna virus "Tat" protein is not a trans-activator for transcription but instead exhibits a function involved in cell cycle arrest, making it more closely related to the HIV-1 Vpr protein than Tat.[34]

The viral rev gene encodes a post-transcriptional regulatory protein.[35] Rev is required for expression of unspliced or partially spliced mRNA coding for the viral envelope protein, including gag and env in a similar manner as the HIV Rev protein.[36] Rev binds as a multimer to the Rev Response Element (RRE) which has a stem-loop secondary structure.

The function of the auxiliary gene vif is not fully known. The vif gene product, a 29 kDa protein, induces a weak immune response in animals.[37] Deletion experiments have demonstrated that the vif gene is essential for infectivity.[38]

Model system for HIV infection

Though it does not produce severe immunodeficiency, visna shares many characteristics with human immunodeficiency virus, including the establishment of persistent infection with chronic active lymphoproliferation;[2] however, visna virus does not infect T-lymphocytes.[7]The relationship of visna and HIV as lentiviruses was first published in 1985 by visna researcher Janice E. Clements and colleagues in the HIV field.[39] It has been postulated that the effects of maedi-visna infection in sheep are the "equivalent" of central nervous system disease and wasting syndrome found in human AIDS patients.[1][40] Despite limited sequence homology with HIV,[1] the genomic organization of visna is very similar, allowing visna infection to be used as an in vivo[41] and in vitro model system for HIV infection.[42][43][44]

Research using visna was important in the identification and characterization of HIV. Nucleotide sequence analysis demonstrated that the AIDS virus was a retrovirus related to visna and provided early clues as to the mechanism of HIV infection.[9]

The Cow Theory

ROBERT: Yeah. It is interesting. And so we tracked NBC, I think it's [NBC-] XIII . . . back to Louisiana State Agriculture Farm (LSAF) cow BFC-44. And what happens was you see, they were looking a lot at HLTV-I, which is like bovine leukemia virus (BLV), [5] and this cow at the LSAF got they thought a BLV infection. She got huge lymph nodes in the neck just like HLTVV-I/BLV in cattle. And then she apparently conquered it because the lymph nodes went down; she got better after a mononucleosis-like disease, and she made lots and lots and lots of antibodies against this virus.

Then about five or six years later, she started losing weight rapidly, developed diarrhea, and died with pneumonia. And they autopsied her and of course she had no immune system left.

And as far as we can tell, that was the original bovine visna virus isolate.

LEN: What year was that?

ROBERT: 1969. And that virus was capable of wiping out T-cells selectively, it produced syncytium [a mass of cell fluids containing many cell nuclei formed by the joining of originally separate cells as a result of infection or disease] [6] in tissue culture, and it does everything that AIDS does.

LEN: Now, who was studying that?

ROBERT: That was isolated from the LSAF outside of New Orleans.

LEN: So Gallo wasn't the only one studying that virus?

ROBERT: No, everybody was. These [cultures] were [widely distributed]. If you go back and look at the veterinary literature, they were looking at all the BLV, bovine leukemia virus lines, bovine syncytium viruses, and bovine visna viruses. And all these things were being studied. . . .

Well, at this point, they were still essentially noninvasive because they were restricted to animals. But, then what happened was in the late '60s and early '70s they started growing these in human tissue.

Early Researchers

LEN: Now when you say 'they,' can you be more specific in terms of the labs that you're familiar with that were doing this work?

ROBERT: Yeah, well virtually every lab in the world that was doing sophisticated lymphocyte studies. But particularly Gallo and company at the NIH, ahh . . . ahh . . . actually there were only a few guys you know - Gallo, Montagnier, a couple of guys that are dead, Baltimore, [7] Teman, [8] and a few others and a few veterinarians. . . .

Dmochowski was interesting because he was the first one to show that you could basically adapt retroviruses to different mammalian species by growing them in the tissue cultures that you wanted them to go to. Now he's down in Texas. [9]

Miller, in 1969, took bovine leukemia virus and injected it into chimpanzees, and the chimpanzees formed antibodies against the virus. [10] So they concluded that these chimpanzees were immune. And so that was the decision for telling everybody that bovine viruses in human beings posed no threat; which is relatively true, there is a species barrier.

Since the 1950s and even the 1940s Bumy, [11] Bobrow, [12] and all these guys from Europe said these [bovine] viruses posed a threat to humans, so they began a whole program of mass extermination of cattle in Europe that carried BLV and other viruses. [13]

In this country, half of our herds are infected with BLV, BFC, or BVV, and the only thing that has prevented, in my opinion, everyone from dying of T-cell leukemia is the fact that pasteurization of the milk kills viruses.

Now if you look at the distribution of T-cell leukemia across the upper United States, from like Minnesota to Wisconsin, there's a huge incidence of T-cell leukemia in dairy farmers.

And if you actually look at some of the studies done in France, they found that guys working in meat-packing plants had a greater incidence of T-cell leukemia too. [13]

So there's all this evidence that T-cell leukemia is related to BLV, which it certainly is, [and] for sure, if you culture the virus in human tissue and adapt it, what you get [is an HTLV-I-like virus that thrives in humans]. . . .

If you look at BVV, bovine visna virus, [13] . . . it's very closely related [to HIV], but it's still not there; it's not the same as AIDS because what you have is bovine visna virus - a virus growing in cattle - and that's not adapted to humans yet. To adapt it to humans, you've got to grow it in human tissue, as they were doing in those early '70s. And what they discovered was that it was a selective T-cell destroyer [just as the AIDS virus is].

-- Emerging Viruses: AIDS & Ebola: Nature, Accident or Intentional?, by Leonard G. Horowitz, DMD, MA, MPH


Control programs

Many countries have some sort of national programme to prevent and control a situation where the virus spreads. These programs include:

•Frequent serological testing- Aids in a fast diagnosis.
•Removal of seropositive animals from breeding program
•Separation of animal born to seropositive dam (milk re-placer).
•Quarantine of animal before introduction into heard.
•Disinfection (sensitive).

References

1. Thormar H (2005). "Maedi-visna virus and its relationship to human immunodeficiency virus". AIDS Rev 7 (4): 233–45. PMID 16425963.
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Re: GAO-02-809R Origin of the AIDS Virus

PostPosted: Mon Jan 04, 2016 6:34 am
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Transduction of endogenous envelope genes by feline leukaemia virus in vitro
by JULIE OVERBAUGH, NORBERT RIEDEL, EDWARD A. HOOVER & JAMES I. MULLINS
Nature 332, 731 - 734 (21 April 1988); doi:10.1038/332731a0

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Transduction of endogenous envelope genes by feline leukaemia virus in vitro

JULIE OVERBAUGH, NORBERT RIEDEL*, EDWARD A. HOOVER† & JAMES I. MULLINS‡

* Department of Cancer Biology, Harvard School of Public Health, 665 Huntington Ave., Boston, Massachusetts 02115, USA

† Department of Pathology, Colorado State University, Fort Collins, Colorado 80523, USA

* Present address: Boston University School of Medicine, 80 East Concord Street, Boston, Massachusetts 02118, USA.

‡ To whom correspondence should be addressed.

Feline leukaemia viruses (FeLV) are exogenous retroviruses that can be detected in most cats with leukaemia, aplastic anaemia, myeloproliferative diseases and fatal immunosuppression1,2. FeLV isolates have been divided into three subgroups, based on the viral envelope-determined properties of interference and host range in vitro 3,4. FeLV-A is present in all natural isolates4,5 and is generally minimally pathogenic6,7. FeLV-B is found with FeLV-A in isolates from ~40% of natural infections and in a higher percentage of cats with lymphoma5. Following the fundamental observations of genetic reassortment of avian retroviruses with endogenous viral genes8 and the origination of lymphomagenic viruses during the ontogeny of AKR mice9, we show here that transfection of feline cells with FeLV-A DNA results in its recombination with endogenous FeLV-related sequences to produce viruses with the structural and host range properties of FeLV-B. Thus in vitro propagation of a retro virus may result in the generation of variants with very different properties.

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