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  • 1
    Online Resource
    Online Resource
    Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost
    American Society for Microbiology ; 2015
    In:  Journal of Virology Vol. 89, No. 12 ( 2015-06-15), p. 6462-6480
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 89, No. 12 ( 2015-06-15), p. 6462-6480
    Abstract: An effective human immunodeficiency virus type 1 (HIV-1) vaccine must induce protective antibody responses, as well as CD4 + and CD8 + T cell responses, that can be effective despite extraordinary diversity of HIV-1. The consensus and mosaic immunogens are complete but artificial proteins, computationally designed to elicit immune responses with improved cross-reactive breadth, to attempt to overcome the challenge of global HIV diversity. In this study, we have compared the immunogenicity of a transmitted-founder (T/F) B clade Env (B.1059), a global group M consensus Env (Con-S), and a global trivalent mosaic Env protein in rhesus macaques. These antigens were delivered using a DNA prime-recombinant NYVAC (rNYVAC) vector and Env protein boost vaccination strategy. While Con-S Env was a single sequence, mosaic immunogens were a set of three Envs optimized to include the most common forms of potential T cell epitopes. Both Con-S and mosaic sequences retained common amino acids encompassed by both antibody and T cell epitopes and were central to globally circulating strains. Mosaics and Con-S Envs expressed as full-length proteins bound well to a number of neutralizing antibodies with discontinuous epitopes. Also, both consensus and mosaic immunogens induced significantly higher gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses than B.1059 immunogen. Immunization with these proteins, particularly Con-S, also induced significantly higher neutralizing antibodies to viruses than B.1059 Env, primarily to tier 1 viruses. Both Con-S and mosaics stimulated more potent CD8-T cell responses against heterologous Envs than did B.1059. Both antibody and cellular data from this study strengthen the concept of using in silico -designed centralized immunogens for global HIV-1 vaccine development strategies. IMPORTANCE There is an increasing appreciation for the importance of vaccine-induced anti-Env antibody responses for preventing HIV-1 acquisition. This nonhuman primate study demonstrates that in silico -designed global HIV-1 immunogens, designed for a human clinical trial, are capable of eliciting not only T lymphocyte responses but also potent anti-Env antibody responses.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.00383-15
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
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  • 2
    Online Resource
    Online Resource
    Efficient expression of the human papillomavirus type 16 L1 protein in epithelial cells by using Rev and the Rev-responsive element of human immunodeficiency virus or the cis-acting transactivation element of simian retrovirus type 1
    American Society for Microbiology ; 1995
    In:  Journal of Virology Vol. 69, No. 9 ( 1995-09), p. 5607-5620
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 69, No. 9 ( 1995-09), p. 5607-5620
    Abstract: Production of the human papillomavirus (HPV) late gene products L1 and L2 is limited to terminally differentiated keratinocytes. Here, we demonstrate that mRNA encoding the HPV-16 L1 capsid protein contains cis-acting RNA elements that inhibit expression at the posttranscriptional level. While cytoplasmic L1 mRNA is detectable in transfected HeLa cells, L1 protein is not produced. We have identified at least one major inhibitory element that is located within the L1 open reading frame, whereas another negative element had been reported to lie in the 3'-untranslated region of L1. The presence of these elements may explain the lack of HPV late gene expression in undifferentiated epithelial cells. Efficient production of HPV-16 L1 could be achieved with posttranscriptional regulatory elements of human immunodeficiency virus type 1 or simian retrovirus type 1. L1 protein was expressed in the presence of human immunodeficiency virus type 1 Rev from hybrid mRNAs containing the RNA binding site for Rev (Rev-responsive element). In addition, we have achieved efficient expression of L1 from hybrid mRNAs containing a cis-acting transactivation element from simian retrovirus type 1. Our data show that HPV-16 L1 protein production is regulated posttranscriptionally. This regulated expression may allow virus production in terminally differentiated epithelial cells and is probably a conserved and important mechanism for HPV expression.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.69.9.5607-5620.1995
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 1995
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  • 3
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    Online Resource
    Long-Lasting Decrease in Viremia in Macaques Chronically Infected with Simian Immunodeficiency Virus SIVmac251 after Therapeutic DNA Immunization
    American Society for Microbiology ; 2007
    In:  Journal of Virology Vol. 81, No. 4 ( 2007-02-15), p. 1972-1979
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 81, No. 4 ( 2007-02-15), p. 1972-1979
    Abstract: Rhesus macaques chronically infected with highly pathogenic simian immunodeficiency virus (SIV) SIVmac251 were treated with antiretroviral drugs and vaccinated with combinations of DNA vectors expressing SIV antigens. Vaccination during therapy increased cellular immune responses. After the animals were released from therapy, the virus levels of 12 immunized animals were significantly lower ( P = 0.001) compared to those of 11 animals treated with only antiretroviral drugs. Vaccinated animals showed a persistent increase in immune responses, thus indicating both a virological and an immunological benefit following DNA therapeutic vaccination. Several animals show a long-lasting decrease in viremia, suggesting that therapeutic vaccination may provide an additional benefit to antiretroviral therapy.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01990-06
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2007
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  • 4
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    Online Resource
    Reduced viral load and lack of CD4 depletion in SCID-hu mice infected with Rev-independent clones of human immunodeficiency virus type 1
    American Society for Microbiology ; 1997
    In:  Journal of Virology Vol. 71, No. 12 ( 1997-12), p. 9817-9822
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 71, No. 12 ( 1997-12), p. 9817-9822
    Abstract: The posttranscriptional control element CTE of the simian type D retrovirus has been shown to support replication of Rev-Rev-responsive-element (RRE)-deficient molecular clones of human immunodeficiency virus type 1 (HIV-1). Upon infection of peripheral blood mononuclear cells in vitro, these CTE-containing Rev-independent viruses that are nef+ or nef-minus showed lower replicative capacity and infectivity than the wild-type HIV-1. We studied the effects of Rev-RRE replacement by the CTE on HIV-1 expression with SCID-hu mice. The nef+ and nef-minus Rev-independent viruses established infection with kinetics slower than that of the nef-minus NL4-3. Most importantly, no depletion of CD4-bearing thymocytes was observed after 6 weeks for mice infected with these Rev-independent viruses. This is in contrast to the infection with both wild-type and nef-minus viruses, which led to varying depletion of thymocytes. These data suggest an attenuated phenotype for growth and cytotoxicity of the Rev-independent HIV-1 clones in SCID-hu mice, independent of the presence of Nef. The mutant viruses, which have the essential Rev-RRE regulatory system eliminated, display a distinct phenotype not previously observed with HIV mutant viruses having deletions of accessory genes. Therefore, replacement of the Rev-RRE regulatory axis may generate viruses with altered biological properties in vivo.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.71.12.9817-9822.1997
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 1997
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  • 5
    Online Resource
    Online Resource
    Persistent Infection of Rhesus Macaques by the Rev-Independent Nef(−) Simian Immunodeficiency Virus SIVmac239: Replication Kinetics and Genomic Stability
    American Society for Microbiology ; 1999
    In:  Journal of Virology Vol. 73, No. 7 ( 1999-07), p. 6159-6165
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 73, No. 7 ( 1999-07), p. 6159-6165
    Abstract: We generated previously a Nef(−), replication-competent clone of SIVmac239 in which the Rev protein and the Rev-responsive element were replaced by the constitutive transport element (CTE) of simian retrovirus type 1 (A. S. von Gegerfelt and B. K. Felber, Virology 232:291–299, 1997). In the present report, we show that this virus was able to infect and replicate in rhesus macaques. The Rev-independent Nef(−) simian immunodeficiency virus induced a persistent humoral immune response in all monkeys, although viral loads were very low. Upon propagation in the monkeys, the genotype remained stable and the virus retained its in vitro growth characteristics. The infected monkeys showed normal hematological values and no signs of disease at more than 18 months post-virus exposure. Therefore, replacement of the essential Rev regulation by the CTE generated a virus variant that retained its replicative capacity both in vitro and in vivo, albeit at low levels.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.73.7.6159-6165.1999
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 1999
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  • 6
    Online Resource
    Online Resource
    Rev-Independent Simian Immunodeficiency Virus Strains Are Nonpathogenic in Neonatal Macaques
    American Society for Microbiology ; 2002
    In:  Journal of Virology Vol. 76, No. 1 ( 2002-01), p. 96-104
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 76, No. 1 ( 2002-01), p. 96-104
    Abstract: The viral protein Rev is essential for the export of the subset of unspliced and partially spliced lentiviral mRNAs and the production of structural proteins. Rev and its RNA binding site RRE can be replaced in both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) by the constitutive RNA transport element CTE of the simian type D retroviruses. We used neonatal macaques as a sensitive animal model to evaluate the pathogenicity of a pair of SIV mutant strains generated from Rev-independent molecular clones of SIVmac239 which differ only in the presence of the nef open reading frame. After high primary viremia, all animals remained persistently infected at levels below the threshold of detection. All macaques infected as neonates developed normally, and none showed any signs of immune dysfunction or disease during follow-up ranging from 2.3 to 4 years. Therefore, the Rev-RRE regulatory mechanism plays a key role in the maintenance of high levels of virus propagation, which is independent of the presence of nef . These data demonstrate that Rev regulation plays an important role in the pathogenicity of SIV. Replacement of Rev-RRE by the CTE provides a novel approach to dramatically lower the virulence of a pathogenic lentivirus. These data further suggest that antiretroviral strategies leading to even a partial block of Rev function may modulate disease progression in HIV-infected individuals.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.76.1.96-104.2002
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2002
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  • 7
    Online Resource
    Online Resource
    Mutational inactivation of an inhibitory sequence in human immunodeficiency virus type 1 results in Rev-independent gag expression
    American Society for Microbiology ; 1992
    In:  Journal of Virology Vol. 66, No. 12 ( 1992-12), p. 7176-7182
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 66, No. 12 ( 1992-12), p. 7176-7182
    Abstract: We have characterized an inhibitory RNA element in the human immunodeficiency virus type 1 (HIV-1) gag coding sequence that prevents gag expression. The inhibition exerted by this element could be overcome by the presence of the Rev-responsive element in cis and of Rev protein in trans. To understand the mechanism of function, we inactivated the inhibitory element by mutagenesis while maintaining an intact gag coding region. A constitutive high level of Rev-independent gag expression was achieved only after the introduction of 28 point mutations over a large region of 270 nucleotides within the gag coding region. To our knowledge, this is the first demonstration of inactivation of a negative RNA element within a coding region without alteration of the expressed protein. Elimination of the inhibitory element in the p17gag region, named INS-1, offered the opportunity to detect a second inhibitory element in the gag-pol region. The presence of either INS element is sufficient to inhibit gag expression, demonstrating that multiple INS elements acting independently can inhibit HIV RNA expression. Expression of gag from Rous sarcoma virus, a retrovirus that does not require Rev-like regulatory proteins, revealed that the Rous sarcoma virus p19gag region does not contain inhibitory elements. These results demonstrate the presence of a strong inhibitory element acting at the level of mRNA and provide a general method for the removal of such elements from mRNA coding regions. The inhibitory element functions in the absence of any HIV-1 proteins, suggesting that cellular factors are responsible for this inhibition.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.66.12.7176-7182.1992
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 1992
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  • 8
    Online Resource
    Online Resource
    Elements distinct from human immunodeficiency virus type 1 splice sites are responsible for the Rev dependence of env mRNA
    American Society for Microbiology ; 1994
    In:  Journal of Virology Vol. 68, No. 5 ( 1994-05), p. 2986-2993
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 68, No. 5 ( 1994-05), p. 2986-2993
    Abstract: In the absence of the viral regulatory protein Rev, the human immunodeficiency virus type 1 gag/pol and env mRNAs are inefficiently expressed, since nucleocytoplasmic transport, stability, and polysomal loading are impaired. It has been suggested that splicing is necessary for Rev function and that the low expression of the unspliced and intermediate spliced mRNAs in the absence of Rev is associated with specific splice sites. Previous studies identified distinct RNA elements within the gag/pol region responsible for low expression that are not associated with splice sites. Here we study the determinants for Rev dependence of the authentic env mRNA. We demonstrate that upon removal of all the utilized splice sites, the env mRNA is still Rev dependent and Rev responsive for expression in human cells. We have identified several regions within the env mRNA that inhibit expression of a gag-env hybrid mRNA. Elimination of one of these elements, located within the Rev-responsive element, did not result in virus expression, supporting our model that several independently acting elements are responsible for the downregulatory effect. By analogy to the RNA elements within the gag/pol region, we propose that elements unrelated to utilized splice sites are responsible for the posttranscriptional regulation of env mRNA.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.68.5.2986-2993.1994
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 1994
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  • 9
    Online Resource
    Online Resource
    Identification of an RNA sequence within an intracisternal-A particle element able to replace Rev-mediated posttranscriptional regulation of human immunodeficiency virus type 1
    American Society for Microbiology ; 1997
    In:  Journal of Virology Vol. 71, No. 1 ( 1997-01), p. 95-101
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 71, No. 1 ( 1997-01), p. 95-101
    Abstract: Human immunodeficiency virus type 1 (HIV-1) replication depends on the posttranscriptional regulation by the viral Rev protein and can be replaced with the posttranscriptional RNA control element (CTE) of the type D simian retroviruses. We have identified a sequence which shares only nucleotide sequences of the internal loops and secondary structure with the CTE and which is part of a novel murine intracisternal-A particle (IAP) retroelement, inserted within the transcribed mouse osteocalcin-related gene. This sequence, named CTE(IAP), can replace the Rev-mediated regulation of HIV-1, hence it is a posttranscriptional regulatory element. Related elements have been identified in other IAPs. These results suggest that insertional mutagenesis can affect gene expression by providing a functional posttranscriptional control element. The CTE(IAP) and CTEs of the type D simian retroviruses represent a novel class of RNA elements characterized by unique sequences within the internal loops which are predicted to represent the interaction site with cellular factor(s). These findings suggest that such elements may be involved in posttranscriptional regulation of cellular mRNAs.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.71.1.95-101.1997
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 1997
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  • 10
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    Online Resource
    The posttranscriptional control element of the simian retrovirus type 1 forms an extensive RNA secondary structure necessary for its function
    American Society for Microbiology ; 1996
    In:  Journal of Virology Vol. 70, No. 9 ( 1996-09), p. 5998-6011
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 70, No. 9 ( 1996-09), p. 5998-6011
    Abstract: It was previously shown that a 240-nucleotide (nt) RNA element (cis-acting transactivation element [CTE]) located between the env gene and the 3' long terminal repeat of simian retrovirus type 1 (SRV-1) can functionally replace posttranscriptional activation directed by Rev and the Rev-responsive element (RRE) when inserted into a Rev- and RRE-deficient molecular clone of human immunodeficiency virus type 1, resulting in efficient virus replication. Here, we analyze the molecular and structural requirements for function of this RNA element. Deletion mutagenesis demonstrated that the core element spans 173 nt. SRV-2 and Mason-Pfizer monkey virus have highly homologous elemen ts, which function similarly when inserted into the Rev/RRE-deficient human immunodeficiency virus type 1. Computer prediction indicated that the core CTEs of all three viruses have similar extensive secondary structures. Mutagenesis of the SRV-1 CTE revealed that both sequence and secondary structure are essential for function. Nuclease probing of the SRV-1 CTE further supported the genetic analysis and confirmed the predicted structural features of the RNA element. Sequence analysis of the 240-nt SRV-1 CTE, after continuous long-term propagation of the Rev-independent viruses, revealed that the genetically defined core element remained unchanged, while regions outside the core CTE underwent deletions or duplications. These data further support our in vitro mutagenesis data and demonstrate the importance of the sequence and structure of the SRV-1 CTE for appropriate function.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.70.9.5998-6011.1996
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 1996
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