Journal article
An in Vivo Replication-important Function in the Second Coding Exon of Tat Is Constrained against Mutation despite Cytotoxic T Lymphocyte Selection
The Journal of biological chemistry, v 278(45), pp 44816-44825
07 Nov 2003
PMID: 12947089
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Human and simian immunodeficiency virus (HIV/SIV) Tat proteins are specified by two coding exons. Tat functions in the transcription of primate lentiviruses. A plethora of in vitro data currently suggests that the second coding exon of Tat is largely devoid of function. However, whether the second exon of Tat contributes functionally to viral pathogenesis in vivo remains unknown. To address this question directly, we compared infection of rhesus macaques with an SIV, engineered to express only the first coding exon of Tat (SIVtat1ex), to counterpart infection with wild-type SIVmac239 virus, which expresses the full 2-exon Tat. This comparison showed that the second coding exon of Tat contributes to chronic SIV replication in vivo. Interestingly, in macaques, we observed a cytotoxic T lymphocytes (CTL) response to the second coding exon of Tat, which appears to durably control SIV replication. When SIV mutated in an attempt to escape this second Tat-exon-CTL, the resulting virus was less replicatively fit and failed to populate the host in vivo. Our study provides the first evidence that the second coding exon in Tat embodies an important function for in vivo replication. We suggest the second coding exon of Tat as an example of a functionally constrained “epitope” whose elicited CTL response cannot be escaped by virus mutation without producing a virus that replicates poorly in vivo.
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Details
- Title
- An in Vivo Replication-important Function in the Second Coding Exon of Tat Is Constrained against Mutation despite Cytotoxic T Lymphocyte Selection
- Creators
- Stephen M. Smith - Rutgers, The State University of New JerseySara Pentlicky - Saint Michael's Medical CenterZachary Klase - Saint Michael's Medical CenterMahender Singh - Saint Michael's Medical CenterChristine Neuveut - Institut PasteurChun-yi Lu - Molecular Virology Section, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892Marvin S. Reitz - University of Maryland, BaltimoreRobert Yarchoan - National Institutes of HealthPreston A. Marx - Tulane UniversityKuan-Teh Jeang - Molecular Virology Section, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
- Publication Details
- The Journal of biological chemistry, v 278(45), pp 44816-44825
- Publisher
- Elsevier
- Number of pages
- 10
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000186306700116
- Scopus ID
- 2-s2.0-0242342409
- Other Identifier
- 991021902506804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology