Upstream AUG Codons in the Simian Immunodeficiency Virus SIVmac239 Genome Regulate Rev and Env Protein Translation

Velden, Gisela J. van der; Klaver, Bep; Das, Atze T.; Berkhout, Ben

doi:10.1128/jvi.01532-12

Cited by 9 publications

(8 citation statements)

References 60 publications

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“…All the reverse primers for spliced viral mRNA span at least one splice acceptor and one splice donor site ( Table 1 ). Thus, the vif PCR product crosses the SD1/SA1 splice junction ( 21 , 22 ), the tat PCR product spans the SD1/SA4^SD3/SA8 splice junctions ( 21 , 22 ), the rev PCR products span the SD1/SA6^SD3/SA7, SD1/SA6^SD3/SA8, SD1/SA5^SD3/SA7, and SD1/SA5^SD3/SA8 splice junctions ( 21 , 22 ), and the nef PCR products span the SD1/SA7 and SD1/SA8 splice junctions ( 21 , 22 ).…”

Section: Methodsmentioning

confidence: 99%

Lymphatic Dissemination of Simian Immunodeficiency Virus after Penile Inoculation

Dutra

Fritts

et al. 2016

J Virol

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The human immunodeficiency virus (HIV) is primarily transmitted by heterosexual contact, and approximately equal numbers of men and women worldwide are infected with the virus. Understanding the biology of HIV acquisition and dissemination in men exposed to the virus by insertive penile intercourse is likely to help with the rational design of vaccines that can limit or prevent HIV transmission. To characterize the target cells and dissemination pathways involved in establishing systemic simian immunodeficiency virus (SIV) infection, we necropsied male rhesus macaques at 1, 3, 7, and 14 days after penile SIV inoculation and quantified the levels of unspliced SIV RNA and spliced SIV RNA in tissue lysates and the number of SIV RNA-positive cells in tissue sections. We found that penile (glans, foreskin, coronal sulcus) T cells and, to a lesser extent, macrophages and dendritic cells are primary targets of infection and that SIV rapidly reaches the regional lymph nodes. At 7 days after inoculation, SIV had disseminated to the blood, systemic lymph nodes, and mucosal lymphoid tissues. Further, at 7 days postinoculation (p.i.), spliced SIV RNA levels were the highest in the genital lymph nodes, indicating that this is the site where the infection is initially amplified. By 14 days p.i., spliced SIV RNA levels were high in all tissues, but they were the highest in the gastrointestinal tract, indicating that the primary site of virus replication had shifted from the genital lymph nodes to the gut. The stepwise pattern of virus replication and dissemination described here suggests that vaccine-elicited immune responses in the genital lymph nodes could help prevent infection after penile SIV challenge. IMPORTANCE To be the most effective, vaccines should produce antiviral immune responses in the anatomic sites of virus replication. Thus, understanding the path taken by HIV from the mucosal surfaces, which are the site of virus exposure, to the deeper tissues where the virus replicates will provide insight into where AIDS vaccines should produce immunity to be the most effective. In this study, we determined that, by day 7 after penile inoculation, SIV has moved first to the inguinal lymph nodes and replicates to high levels. Although the virus is widely disseminated to other tissues by day 7, replication is largely limited to the inguinal lymph nodes. The step-by-step movement of SIV from penile mucosal surfaces to the draining lymph nodes may allow an HIV vaccine that produces immunity in these lymph nodes to block HIV from establishing an infection in an exposed person.

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Section: Methodsmentioning

confidence: 99%

Lymphatic Dissemination of Simian Immunodeficiency Virus after Penile Inoculation

Dutra

Fritts

et al. 2016

J Virol

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“…Mutations in this uORF drastically attenuate viral growth, indicating the importance of its regulatory function . More complex regulation mechanism was reported in the simian immunodeficiency virus (SIV), where translation from a number of different uORFs present in different splice variants of mRNAs encoding the rev and env genes regulate these genes to different extent …”

Section: Virally Encoded Short Proteinsmentioning

confidence: 98%

Viral Short ORFs and Their Possible Functions

2018

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Definition of functional genomic elements is one of the greater challenges of the genomic era. Traditionally, putative short open reading frames (sORFs) coding for less than 100 amino acids were disregarded due to computational and experimental limitations; however, it has become clear over the past several years that translation of sORFs is pervasive and serves diverse functions. The development of ribosome profiling, allowing identification of translated sequences genome wide, revealed wide spread, previously unidentified translation events. New computational methodologies as well as improved mass spectrometry approaches also contributed to the task of annotating translated sORFs in different organisms. Viruses are of special interest due to the selective pressure on their genome size, their rapid and confining evolution, and the potential contribution of novel peptides to the host immune response. Indeed, many functional viral sORFs were characterized to date, and ribosome profiling analyses suggest that this may be the tip of the iceberg. Our computational analyses of sORFs identified by ribosome profiling in DNA viruses demonstrate that they may be enriched in specific features implying that at least some of them are functional. Combination of systematic genome editing strategies with synthetic tagging will take us into the next step-elucidation of the biological relevance and function of this intriguing class of molecules.

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“…In simian immunodeficiency retrovirus (SIV), an uORF also regulates sorting of ribosomes between two long ORFs ( van der Velden et al, 2012 , 2013 ). SIV genomic RNA undergoes several splicing events producing monocistronic mRNAs for translation of each viral protein, except for the env protein, which is translated from a dicistronic mRNA containing the env ORF downstream of a rev ORF.…”

Section: The Regulatory Role Of Short Uorfs In 5′-leader Regions Of Ementioning

confidence: 99%

“…Thus, the uORF4 is an important element of the leader that maintains balanced production of rev and env proteins ( van der Velden et al, 2013 ). By analogy with SIV, uORF-mediated ribosomal sorting was proposed to operate in the human retrovirus HIV-1 for translation of vpu and env proteins from a dicistronic mRNA ( van der Velden et al, 2012 ).…”

Section: The Regulatory Role Of Short Uorfs In 5′-leader Regions Of Ementioning

confidence: 99%

Ribosome Shunting, Polycistronic Translation, and Evasion of Antiviral Defenses in Plant Pararetroviruses and Beyond

Pooggin

Ryabova

2018

Front. Microbiol.

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Viruses have compact genomes and usually translate more than one protein from polycistronic RNAs using leaky scanning, frameshifting, stop codon suppression or reinitiation mechanisms. Viral (pre-)genomic RNAs often contain long 5′-leader sequences with short upstream open reading frames (uORFs) and secondary structure elements, which control both translation initiation and replication. In plants, viral RNA and DNA are targeted by RNA interference (RNAi) generating small RNAs that silence viral gene expression, while viral proteins are recognized by innate immunity and autophagy that restrict viral infection. In this review we focus on plant pararetroviruses of the family Caulimoviridae and describe the mechanisms of uORF- and secondary structure-driven ribosome shunting, leaky scanning and reinitiation after translation of short and long uORFs. We discuss conservation of these mechanisms in different genera of Caulimoviridae, including host genome-integrated endogenous viral elements, as well as in other viral families, and highlight a multipurpose use of the highly-structured leader sequence of plant pararetroviruses in regulation of translation, splicing, packaging, and reverse transcription of pregenomic RNA (pgRNA), and in evasion of RNAi. Furthermore, we illustrate how targeting of several host factors by a pararetroviral effector protein can lead to transactivation of viral polycistronic translation and concomitant suppression of antiviral defenses. Thus, activation of the plant protein kinase target of rapamycin (TOR) by the Cauliflower mosaic virus transactivator/viroplasmin (TAV) promotes reinitiation of translation after long ORFs on viral pgRNA and blocks antiviral autophagy and innate immunity responses, while interaction of TAV with the plant RNAi machinery interferes with antiviral silencing.

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Upstream AUG Codons in the Simian Immunodeficiency Virus SIVmac239 Genome Regulate Rev and Env Protein Translation

Cited by 9 publications

References 60 publications

Lymphatic Dissemination of Simian Immunodeficiency Virus after Penile Inoculation

Lymphatic Dissemination of Simian Immunodeficiency Virus after Penile Inoculation

Viral Short ORFs and Their Possible Functions

Ribosome Shunting, Polycistronic Translation, and Evasion of Antiviral Defenses in Plant Pararetroviruses and Beyond

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