Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Robert J. Natuk is active.

Publication


Featured researches published by Robert J. Natuk.


Journal of Virology | 2008

Attenuation of Recombinant Vesicular Stomatitis Virus-Human Immunodeficiency Virus Type 1 Vaccine Vectors by Gene Translocations and G Gene Truncation Reduces Neurovirulence and Enhances Immunogenicity in Mice

David A. Cooper; Kevin J. Wright; Priscilla Calderon; Min Guo; Farooq Nasar; J. Erik Johnson; John W. Coleman; Margaret Lee; Cheryl S. Kotash; Irene Yurgelonis; Robert J. Natuk; R. Michael Hendry; Stephen A. Udem; David K. Clarke

ABSTRACT Recombinant vesicular stomatitis virus (rVSV) has shown great potential as a new viral vector for vaccination. However, the prototypic rVSV vector described previously was found to be insufficiently attenuated for clinical evaluation when assessed for neurovirulence in nonhuman primates. Here, we describe the attenuation, neurovirulence, and immunogenicity of rVSV vectors expressing human immunodeficiency virus type 1 Gag. These rVSV vectors were attenuated by combinations of the following manipulations: N gene translocations (N4), G gene truncations (CT1 or CT9), noncytopathic M gene mutations (Mncp), and positioning of the gag gene into the first position of the viral genome (gag1). The resulting N4CT1-gag1, N4CT9-gag1, and MncpCT1-gag1 vectors demonstrated dramatically reduced neurovirulence in mice following direct intracranial inoculation. Surprisingly, in spite of a very high level of attenuation, the N4CT1-gag1 and N4CT9-gag1 vectors generated robust Gag-specific immune responses following intramuscular immunization that were equivalent to or greater than immune responses generated by the more virulent prototypic vectors. MncpCT1-gag1 also induced Gag-specific immune responses following intramuscular immunization that were equivalent to immune responses generated by the prototypic rVSV vector. Placement of the gag gene in the first position of the VSV genome was associated with increased in vitro expression of Gag protein, in vivo expression of Gag mRNA, and enhanced immunogenicity of the vector. These findings demonstrate that through directed manipulation of the rVSV genome, vectors that have reduced neurovirulence and enhanced immunogenicity can be made.


Journal of Virology | 2007

Synergistic Attenuation of Vesicular Stomatitis Virus by Combination of Specific G Gene Truncations and N Gene Translocations

David K. Clarke; Farooq Nasar; Margaret Lee; J. Erik Johnson; Kevin J. Wright; Priscilla Calderon; Min Guo; Robert J. Natuk; David A. Cooper; R. Michael Hendry; Stephen A. Udem

ABSTRACT A variety of rational approaches to attenuate growth and virulence of vesicular stomatitis virus (VSV) have been described previously. These include gene shuffling, truncation of the cytoplasmic tail of the G protein, and generation of noncytopathic M gene mutants. When separately introduced into recombinant VSV (rVSV), these mutations gave rise to viruses distinguished from their “wild-type” progenitor by diminished reproductive capacity in cell culture and/or reduced cytopathology and decreased pathogenicity in vivo. However, histopathology data from an exploratory nonhuman primate neurovirulence study indicated that some of these attenuated viruses could still cause significant levels of neurological injury. In this study, additional attenuated rVSV variants were generated by combination of the above-named three distinct classes of mutation. The resulting combination mutants were characterized by plaque size and growth kinetics in cell culture, and virulence was assessed by determination of the intracranial (IC) 50% lethal dose (LD50) in mice. Compared to virus having only one type of attenuating mutation, all of the mutation combinations examined gave rise to virus with smaller plaque phenotypes, delayed growth kinetics, and 10- to 500-fold-lower peak titers in cell culture. A similar pattern of attenuation was also observed following IC inoculation of mice, where differences in LD50 of many orders of magnitude between viruses containing one and two types of attenuating mutation were sometimes seen. The results show synergistic rather than cumulative increases in attenuation and demonstrate a new approach to the attenuation of VSV and possibly other viruses.


Journal of Virology | 2006

Recombinant Vesicular Stomatitis Virus Vectors Expressing Herpes Simplex Virus Type 2 gD Elicit Robust CD4+ Th1 Immune Responses and Are Protective in Mouse and Guinea Pig Models of Vaginal Challenge

Robert J. Natuk; David A. Cooper; Min Guo; Priscilla Calderon; Kevin J. Wright; Farooq Nasar; Susan E. Witko; Diane Pawlyk; Margaret Lee; Joanne DeStefano; Donna Tummolo; Aaron S. Abramovitz; Seema Gangolli; David K. Clarke; R. Michael Hendry; John H. Eldridge; Stephen A. Udem; Jacek Kowalski

ABSTRACT Recombinant vesicular stomatitis virus (rVSV) vectors offer an attractive approach for the induction of robust cellular and humoral immune responses directed against human pathogen target antigens. We evaluated rVSV vectors expressing full-length glycoprotein D (gD) from herpes simplex virus type 2 (HSV-2) in mice and guinea pigs for immunogenicity and protective efficacy against genital challenge with wild-type HSV-2. Robust Th1-polarized anti-gD immune responses were demonstrated in the murine model as measured by induction of gD-specific cytotoxic T lymphocytes and increased gamma interferon expression. The isotype makeup of the serum anti-gD immunoglobulin G (IgG) response was consistent with the presence of a Th1-CD4+ anti-gD response, characterized by a high IgG2a/IgG1 IgG subclass ratio. Functional anti-HSV-2 neutralizing serum antibody responses were readily demonstrated in both guinea pigs and mice that had been immunized with rVSV-gD vaccines. Furthermore, guinea pigs and mice were prophylactically protected from genital challenge with high doses of wild-type HSV-2. In addition, guinea pigs were highly protected against the establishment of latent infection as evidenced by low or absent HSV-2 genome copies in dorsal root ganglia after virus challenge. In summary, rVSV-gD vectors were successfully used to elicit potent anti-gD Th1-like cellular and humoral immune responses that were protective against HSV-2 disease in guinea pigs and mice.


The Journal of Infectious Diseases | 2015

Immunogenicity and Safety of 13-Valent Pneumococcal Conjugate Vaccine in HIV-Infected Adults Previously Vaccinated With Pneumococcal Polysaccharide Vaccine

Marshall J. Glesby; Wendy Watson; Cynthia Brinson; Richard N. Greenberg; Jacob Lalezari; Daniel J. Skiest; Vani Sundaraiyer; Robert J. Natuk; Alejandra Gurtman; Daniel A. Scott; Emilio A. Emini; William C. Gruber; Beate Schmoele-Thoma

BACKGROUND Persons with human immunodeficiency virus (HIV) infection are at increased risk of pneumococcal disease. We evaluated the safety and immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13) in this population. METHODS HIV-infected persons ≥ 18 years of age who were previously vaccinated with ≥ 1 dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and had CD4 cell counts ≥ 200 cells/mm(3) and HIV viral loads <50 000 copies/mL were enrolled in this 3-dose PCV13 open-label study. RESULTS A total of 329 subjects received ≥ 1 dose, and 279 received 3 doses administered at 6-month intervals. Increases in anticapsular polysaccharide immunoglobulin G concentrations and opsonophagocytic antibody titers were demonstrated 1 month after each of the 3 doses of PCV13. Antibody levels were generally similar after each dose. The responses were similar whether subjects had previously received 1 or ≥ 2 doses of PPSV23. Pain at the injection-site was the most common local reaction. Severe injection site or systemic events were uncommon. CONCLUSIONS Vaccination with PCV13 induces anticapsular immunoglobulin G and opsonophagocytic antibody responses in HIV-infected adults with prior PPSV23 vaccination and CD4 cell counts ≥ 200 cells/mm(3). The observations support the use of PCV13 in this population. CLINICAL TRIALS REGISTRATION NCT00963235.


Journal of Virology | 2005

Herpes Simplex Virus Type 2 UL24 Gene Is a Virulence Determinant in Murine and Guinea Pig Disease Models

Susan Blakeney; Jacek Kowalski; Donna Tummolo; Joanne DeStefano; David A. Cooper; Min Guo; Seema Gangolli; Deborah Long; Timothy J. Zamb; Robert J. Natuk; Robert J. Visalli

ABSTRACT A herpes simplex virus type 2 (HSV-2) UL24 β-glucuronidase (UL24-βgluc) insertion mutant was derived from HSV-2 strain 186 via standard marker transfer techniques. Cell monolayers infected with UL24-βgluc yielded cytopathic effect with syncytium formation. UL24-βgluc replicated to wild-type viral titers in three different cell lines. UL24-βgluc was not virulent after intravaginal inoculation of BALB/c mice in that all inoculated animals survived doses up to 400 times the 50% lethal dose (LD50) of the parental virus. Furthermore, few UL24-βgluc-inoculated mice developed any vaginal lesions. Intravaginal inoculation of guinea pigs with UL24-βgluc at a dose equivalent to the LD50 of parental virus (≈5 × 103 PFU) was not lethal (10/10 animals survived). Although genital lesions developed in some UL24-βgluc-inoculated guinea pigs, both the overall number of lesions and the severity of disease were far less than that observed for animals infected with parental strain 186.


Vaccine | 2009

In vivo biodistribution of a highly attenuated recombinant vesicular stomatitis virus expressing HIV-1 Gag following intramuscular, intranasal, or intravenous inoculation

J. Erilc Johnson; John W. Coleman; Priscilla Calderon; Kevin J. Wright; Jennifer Obregon; Eleanor Ogin-Wilson; Robert J. Natuk; David K. Clarke; Stephen A. Udem; David A. Cooper; R. Michael Hendry

Abstract Recombinant vesicular stomatitis viruses (rVSVs) are being developed as potential HIV-1 vaccine candidates. To characterize the in vivo replication and dissemination of rVSV vectors in mice, high doses of a highly attenuated vector expressing HIV-1 Gag, rVSVIN-N4CT9-Gag1, and a prototypic reference virus, rVSVIN-HIVGag5, were delivered intramuscularly (IM), intranasally (IN), or intravenously (IV). We used quantitative, real-time RT-PCR (Q-PCR) and standard plaque assays to measure the temporal dissemination of these viruses to various tissues. Following IM inoculation, both viruses were detected primarily at the injection site as well as in draining lymph nodes; neither virus induced significant weight loss, pathologic signs, or evidence of neuroinvasion. In contrast, following IN inoculation, the prototypic virus was detected in all tissues tested and caused significant weight loss leading to death. IN administration of rVSVIN-N4CT9-Gag1 resulted in detection in numerous tissues (brain, lung, nasal turbinates, and lymph nodes) albeit in significantly reduced levels, which caused little or no weight loss nor any mortality. Following IV inoculation, both prototypic and attenuated viruses were detected by Q-PCR in all tissues tested. In contrast to the prototype, rVSVIN-N4CT9-Gag1 viral loads were significantly lower in all organs tested, and no infectious virus was detected in the brain following IV inoculation, despite the presence of viral RNA. These studies demonstrated significant differences in the biodistribution patterns of and the associated pathogenicity engendered by the prototypic and attenuated vectors in a highly susceptible host.


Vaccine | 2014

Vaccination with a HSV-2 UL24 mutant induces a protective immune response in murine and guinea pig vaginal infection models.

Robert J. Visalli; Robert J. Natuk; Jacek Kowalski; Min Guo; Susan Blakeney; Seema Gangolli; David A. Cooper

The rational design and development of genetically attenuated HSV-2 mutant viruses represent an attractive approach for developing both prophylactic and therapeutic vaccines for genital herpes. Previously, HSV-2 UL24 was shown to be a virulence determinant in both murine and guinea pig vaginal infection models. An UL24-βgluc insertion mutant produced syncytial plaques and replicated to nearly wild type levels in tissue culture, but induced little or no pathological effects in recipient mice or guinea pigs following vaginal infection. Here we report that immunization of mice or guinea pigs with high or low doses of UL24-βgluc elicited a highly protective immune response. UL24-βgluc immunization via the vaginal or intramuscular routes was demonstrated to protect mice from a lethal vaginal challenge with wild type HSV-2. Moreover, antigen re-stimulated splenic lymphocytes harvested from immunized mice exhibited both HSV-2 specific CTL activity and IFN-γ expression. Humoral anti-HSV-2 responses in serum were Th1-polarized (IgG2a>IgG1) and contained high-titer anti-HSV-2 neutralizing activity. Guinea pigs vaccinated subcutaneously with UL24-βgluc or the more virulent parental strain (186) were challenged with a heterologous HSV-2 strain (MS). Acute disease scores were nearly indistinguishable in guinea pigs immunized with either virus. Recurrent disease scores were reduced in UL24-βgluc immunized animals but not to the same extent as those immunized with strain 186. In addition, challenge virus was not detected in 75% of guinea pigs subcutaneously immunized with UL24-βgluc. In conclusion, disruption of the UL24 gene is a prime target for the development of a genetically attenuated live HSV-2 vaccine.


Nature Medicine | 1997

Long-term protection of chimpanzees against high-dose HIV-1 challenge induced by immunization

Michael D. Lubeck; Robert J. Natuk; Maria Myagkikh; Kristine Aldrich; Faruk Sinangil; Shabnam Alipanah; Shri C.S. Murthy; Pranab K. Chanda; Stephen M. Nigida; Phillip D. Markham; Susan Zolla-Pazner; Kathy Steimer; Mark R. Wade; Marvin S. Reitz; Larry O. Arthur; Satoshi Mizutani; Alan R. Davis; Paul P. Hung; Robert C. Gallo; Jorg W. Eichberg; Marjorie Robert-Guroff


Journal of Virology | 1998

Induction of Neutralizing Antibodies to T-Cell Line-Adapted and Primary Human Immunodeficiency Virus Type 1 Isolates with a Prime-Boost Vaccine Regimen in Chimpanzees

Susan Zolla-Pazner; Michael D. Lubeck; Serena Xu; Sherri Burda; Robert J. Natuk; Faruk Sinangil; Kathelyn S. Steimer; Robert C. Gallo; Jorg W. Eichberg; Thomas J. Matthews; Marjorie Robert-Guroff


Archive | 1994

Recombinant Adenovirus Vaccines

Alan R. Davis; Paul P. Hung; Michael D. Lubeck; Robert J. Natuk; Pranab K. Chanda; Shridhara Murthy; Shawguang Lin Lee

Collaboration


Dive into the Robert J. Natuk's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Farooq Nasar

United States Army Medical Research Institute of Infectious Diseases

View shared research outputs
Top Co-Authors

Avatar

Pranab K. Chanda

Baylor College of Medicine

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Kevin J. Wright

International AIDS Vaccine Initiative

View shared research outputs
Top Co-Authors

Avatar

Michael D. Lubeck

Icahn School of Medicine at Mount Sinai

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Stephen A. Udem

Albert Einstein College of Medicine

View shared research outputs
Top Co-Authors

Avatar

John H. Eldridge

University of Alabama at Birmingham

View shared research outputs
Researchain Logo
Decentralizing Knowledge