Action d'oligonucleotides modifies sur la transcription inverse ou sur la traduction. Etude de leur effet sur la proliferation de retrovirus murins

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Antigenic Subclasses of Polytropic Murine Leukemia Virus (MLV) Isolates Reflect Three Distinct Groups of Endogenous Polytropic MLV-Related Sequences in NFS/N Mice

Polytropic murine leukemia viruses (MLVs) are generated by recombination of ecotropic MLVs with members of a family of endogenous proviruses in mice. Previous studies have indicated that polytropic MLV isolates comprise two mutually exclusive antigenic subclasses, each of which is reactive with one of two monoclonal antibodies termed MAb 516 and Hy 7. A major determinant of the epitopes distinguishing the subclasses mapped to a single amino acid difference in the SU protein. Furthermore, distinctly different populations of the polytropic MLV subclasses are generated upon inoculation of different ecotropic MLVs. Here we have characterized the majority of endogenous polytropic MLV-related proviruses of NFS/N mice. Most of the proviruses contain intact sequences encoding the receptor-binding region of the SU protein and could be distinguished by sequence heterogeneity within that region. We found that the endogenous proviruses comprise two major groups that encode the major determinant for Hy 7 or MAb 516 reactivity. The Hy 7-reactive proviruses correspond to previously identified polytropic proviruses, while the 516-reactive proviruses comprise the modified polytropic proviruses as well as a third group of polytropic MLV-related proviruses that exhibit distinct structural features. Phylogenetic analyses indicate that the latter proviruses reflect features of phylogenetic intermediates linking xenotropic MLVs to the polytropic and modified polytropic proviruses. These studies elucidate the relationships of the antigenic subclasses of polytropic MLVs to their endogenous counterparts, identify a new group of endogenous proviruses, and identify distinguishing characteristics of the proviruses that should facilitate a more precise description of their expression in mice and their participation in recombination to generate recombinant viruses

Precise Identification of Endogenous Proviruses of NFS/N Mice Participating in Recombination with Moloney Ecotropic Murine Leukemia Virus (MuLV) To Generate Polytropic MuLVs

Polytropic murine leukemia viruses (MuLVs) are generated by recombination of ecotropic MuLVs with env genes of a family of endogenous proviruses in mice, resulting in viruses with an expanded host range and greater virulence. Inbred mouse strains contain numerous endogenous proviruses that are potential donors of the env gene sequences of polytropic MuLVs; however, the precise identification of those proviruses that participate in recombination has been elusive. Three different structural groups of proviruses in NFS/N mice have been described and different ecotropic MuLVs preferentially recombine with different groups of proviruses. In contrast to other ecotropic MuLVs such as Friend MuLV or Akv that recombine predominantly with a single group of proviruses, Moloney MuLV (M-MuLV) recombines with at least two distinct groups. In this study, we determined that only three endogenous proviruses, two of one group and one of another group, are major participants in recombination with M-MuLV. Furthermore, the distinction between the polytropic MuLVs generated by M-MuLV and other ecotropic MuLVs is the result of recombination with a single endogenous provirus. This provirus exhibits a frameshift mutation in the 3′ region of the surface glycoprotein-encoding sequences that is excluded in recombinants with M-MuLV. The sites of recombination between the env genes of M-MuLV and endogenous proviruses were confined to a short region exhibiting maximum homology between the ecotropic and polytropic env sequences and maximum stability of predicted RNA secondary structure. These observations suggest a possible mechanism for the specificity of recombination observed for different ecotropic MuLVs

In Vivo Interactions of Ecotropic and Polytropic Murine Leukemia Viruses in Mixed Retrovirus Infections

Mixed retrovirus infections are the rule rather than the exception in mice and other species, including humans. Interactions of retroviruses in mixed infections and their effects on disease induction are poorly understood. Upon infection of mice, ecotropic retroviruses recombine with endogenous proviruses to generate polytropic viruses that utilize different cellular receptors. Interactions among the retroviruses of this mixed infection facilitate disease induction. Using mice infected with defined mixtures of the ecotropic Friend murine leukemia virus (F-MuLV) and different polytropic viruses, we demonstrate several dramatic effects of mixed infections. Remarkably, inoculation of F-MuLV with polytropic MuLVs completely suppressed the generation of new recombinant viruses and dramatically altered disease induction. Coinoculation of F-MuLV with one polytropic virus significantly lengthened survival times, while inoculation with another polytropic MuLV induced a rapid and severe neurological disease. In both instances, the level of the polytropic MuLV was increased 100- to 1,000-fold, whereas the ecotropic MuLV level remained unchanged. Surprisingly, nearly all of the polytropic MuLV genomes were packaged within F-MuLV virions (pseudotyped) very soon after infection. At this time, only a fractional percentage of cells in the mouse were infected by either virus, indicating that the coinoculated viruses had infected the same small subpopulation of susceptible cells. The profound amplification of polytropic MuLVs in coinfected mice may be facilitated by pseudotyping or, alternatively, by transactivation of the polytropic virus in the coinfected cells. This study illustrates the complexity of the interactions between components of mixed retrovirus infections and the dramatic effects of these interactions on disease processes

Higher efficacy of nevirapine than efavirenz to achieve HIV-1 plasma viral load below 1 copy/ml

a Objectives: To compare the level of HIV-1 residual viremia, defined by a viral load below 50 copies/ml in patients receiving a tenofovir/emtricitabine and nevirapine (NVP) or efavirenz (EFV)-containing regimen. Design: One hundred and sixty-five HIV-1-infected patients were retrospectively included since they achieved virological suppression (viral load <50 copies/ml) for at least 6 months with a tenofovir/emtricitabine and non-nucleoside reverse transcriptase inhibitor-containing regimen (NVP, n ¼ 75 and EFV, n ¼ 90). Methods: Residual plasma viremia was measured using an ultrasensitive assay with a limit of quantification of 1 copy/ml. A Fisher's exact test was used to compare the percentage of patients with HIV-1 RNA below 1 copy/ml between the two treatment groups. Logistic regression was used to search for factors associated with a viral load below 1 copy/ml among the different patient characteristics. Results: Patients in the NVP group had more frequently a viral load below 1 copy/ml than patients in the EFV group (81.3 vs. 55.6%, P < 0.001). In multivariate analysis, only NVP vs EFV (P ¼ 0.005) and duration of viral suppression under antiretroviral treatment (P ¼ 0.005) were independently associated with viral load below 1 copy/ml. Conclusions: It is well known that NVP has a good penetration in anatomic compartments that could explain a deep control of virus replication in some compartments and consequently decrease the residual level of viral load. The clinical relevance of having a viral load below 1 copy/ml has now to be studied for example on systemic inflammatory or immune activation markers

Tipranavir-Ritonavir Genotypic Resistance Score in Protease Inhibitor-Experienced Patients▿

To identify mutations associated with the virological response (VR) to a tipranavir-ritonavir (TPV/r)-based regimen, 143 patients previously treated with protease inhibitor (PI) were studied. VR was defined by a decrease of at least 1 log10 in, or undetectable, human immunodeficiency virus (HIV) RNA at month 3. The effect of each mutation in the protease, considering all variants at a residue as a single variable, on the VR to TPV/r was investigated. Mutations at six residues were associated with a lower VR (E35D/G/K/N, M36I/L/V, Q58E, Q61D/E/G/H/N/R, H69I/K/N/Q/R/Y, and L89I/M/R/T/V), and one mutation was associated with a higher VR (F53L/W/Y). The genotypic score M36I/L/V − F53L/W/Y + Q58E + H69I/K/N/Q/R/Y + L89I/M/R/T/V was selected as providing a strong association with VR. For the seven patients with a genotypic score of −1 (viruses with only mutation at codon 53), the percentage of responders was 100% and the percentages were 79%, 56%, 33%, 21%, and 0% for those with scores of 0, 1, 2, 3, and 4, respectively. The percentage of patients showing a response to TPV/r was lower for patients infected with non-clade B viruses (n = 16, all non-B subtypes considered together) than for those infected with clade B viruses (n = 127) (25% and 59%, respectively; P = 0.015). Most mutations associated with VR to TPV/r had not previously been associated with PI resistance. This is consistent with phenotypic analysis showing that TPV has a unique resistance profile. Mutations at five positions (35, 36, 61, 69, and 89) were observed significantly more frequently in patients infected with a non-B subtype than in those infected with the B subtype, probably explaining the lower VR observed in these patients