Fidelity of reverse transcriptase of the simian immunodeficiency virus from African green monkey

Manns, Andreas; König, Herbert; Baier, Michael; Kurth, Reinhard; Grosse, Frank

doi:10.1093/nar/19.3.533

Cited by 20 publications

(7 citation statements)

References 39 publications

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“…Higher rates of nucleotide misincorporation by HIV RT may occur compared with rates found for murine or avian type C RT (3,36). Similar high rates of misincorporation have been documented in in vitro assays for other lentiviral RTs, such as SIV (35) and EIAV (4,6) RTs.…”

supporting

confidence: 54%

Localized sequence heterogeneity in the long terminal repeats of in vivo isolates of equine infectious anemia virus

Maury

Perryman

Oaks

et al. 1997

J Virol

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The role of in vivo long terminal repeat (LTR) sequence variation of the lentivirus equine infectious anemia virus (EIAV) has not been explored. In this study, we investigated the heterogeneity found in the LTR sequences from seven EIAV-seropositive horses: three horses with clinical disease and four horses without any detectable signs of disease. LTR sequences were targeted in this study because the LTR U3 enhancer region of tissue culture-derived isolates has been identified as one of the few hypervariable regions of the EIAV genome. Furthermore, LTR variation may regulate EIAV expression in vivo. Both intra-and interanimal sequence variations were investigated. The intra-animal variation was low in seropositive, healthy horses (on average 0.44%). Intra-animal variation was consistently higher in clinically ill horses (0.99%), suggesting that greater numbers of quasispecies of EIAV are present when active virus replication is ongoing. Interanimal comparisons of consensus sequences generated from each horse demonstrated that the enhancer region is a hotspot of sequence variation in vivo. Thirty-seven of the 83 nucleotides that compose the U3 enhancer region were variable between the different in vivo-derived LTRs. The remainder of the LTR that was analyzed was more conserved, 8 of 195 nucleotide positions being variable. Results of electrophoretic mobility shift assays demonstrated that some nucleotide substitutions that occurred in the enhancer region eliminated or altered transcription factor binding motifs that are known to be important for EIAV LTR expression. These data suggested that the selective pressures exerted on the EIAV LTR enhancer sequences are different from those exerted on the remainder of the LTR. Our findings are consistent with the possibility that enhancer sequence hypervariability can alter expression of the virus in tissue macrophages and therefore contribute to clinical disease in infected horses.

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supporting

confidence: 54%

Localized sequence heterogeneity in the long terminal repeats of in vivo isolates of equine infectious anemia virus

Maury

Perryman

Oaks

et al. 1997

J Virol

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“…The variability of the primate lentiviruses is due to the relative inaccuracy of the viral enzyme reverse transcriptase that has no proofreading capability. However, the fact that the SIVagm RT is intrinsically as error prone as that of HIV-1 was readily demonstrable in vitro (30). Furthermore, by inoculating animals with a molecular clone of SIVagm, it was possible to precisely measure the rate of mutation in vivo (31,32).…”

Section: Lack Of Inherent Pathogenicitymentioning

confidence: 99%

The role of the immune response during SIVagm infection of the african green monkey natural host

Norley

Kurth²

2004

Front Biosci

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The African green monkey (AGM) is one of many African species endemically infected with simian immunodeficiency virus (SIV). Like the other natural hosts, AGMs do not succumb to AIDS and understanding the basis for this resistance to disease progression would be of enormous theoretical and practical importance. Early efforts by our group that concentrated on identifying immune mechanisms presumed to keep the virus under control failed to find any obvious candidates. The presumption of virus control was invalidated by the finding that SIVagm replicates in AGMs with the same vigor as HIV-1 does in humans. Focus therefore shifted to identifying possible immunopathologic features present in disease susceptible hosts but absent in the AGM natural host. The apparent immunologic tolerance of AGMs to the SIVagm core protein led to the development of a hypothesis implicating anti-Gag antibodies in the formation of immune complexes, virus trapping in the lymph nodes and immune dysfunction. The idea proved difficult to test in vivo and present work focuses on the possibility that Gag tolerance at the T-cell level plays an important role in preventing the catastrophic demise of the immune system characteristic of immunodeficiency virus infection of the heterologous primate host.

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“…Indeed, recent kinetic analyses suggest that efficient extension from 3'-terminal mispairs is a major factor in the production of mutations by the enzyme [11]. Unexpectedly, the RT of simian immunodeficiency virus (S1V), an HIV-related retrovirus, with high genetic diversity [12], was reported recently to be 2-to 20-fold more accurate than HIV-1 RT [13].…”

Section: Introductionmentioning

confidence: 99%

Fidelity of the reverse transcriptase of human immunodeficiency virus type 2

Bakhanashvili

Hizi

1992

FEBS Letters

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The relatively low fidelity of human immunodeficiency virus type 1 reverse transcriptase (HIV‐1 RT) was implicated as a major factor that contributes to the genetic variability of the virus. Extension of mismatched 3′ termini of the primer DNA was shown to be a major determinant of the infidelity of HIV‐1 RT. Human immunodeficiency virus type 2 (HIV‐2) also shows extensive genetic variations. Therefore, we have analyzed the fidelity of the DNA‐dependent DNA polymerase activity of HIV‐2 RT and compared it with those of RTs of HIV‐1 and murine leukemia virus (MLV). Like other retroviral RTs, the HIV‐2 RT was shown to lack a 3′→5′ exonuclease activity. The ability of HIV‐2 RT to extend preformed 3′‐terminal A:A, A:C and A:G mispairs was examined by quantitating the amount and length of extended primers. The results demonstrate a relatively efficient mispair extension by HIV‐2 RT with a specificity of A:C⪢A:A>A:G. The mispair extension appears to be affected mainly by the increase of apparent K m values rather than by the change in V max values. The relative extension frequencies from all mispairs with HIV‐1 and HIV‐2 RTs was 6‐ to 9‐fold greater than that of MLV RT, suggesting that the HIV enzymes are substantially more error‐prone than MLV RT.

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Fidelity of reverse transcriptase of the simian immunodeficiency virus from African green monkey

Cited by 20 publications

References 39 publications

Localized sequence heterogeneity in the long terminal repeats of in vivo isolates of equine infectious anemia virus

Localized sequence heterogeneity in the long terminal repeats of in vivo isolates of equine infectious anemia virus

The role of the immune response during SIVagm infection of the african green monkey natural host

Fidelity of the reverse transcriptase of human immunodeficiency virus type 2

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