Viruses

27_AdvanceTopics

Virus Exploration

https://media.hhmi.org/biointeractive/click/virus-explorer/

Viruses Reveal the Secrets of Biology

Virus induced cancers and proto-oncogenes

Rous Sarcoma Virus Genome

Peyton Rous was interested in the transplantability of tumors. In 1910, a rock hen was brought to the Rockefeller Institute with a large tumor. Rous found that a filtrate from the tumor, devoid of cells, had the capacity to induce tumor formation in other chickens in 1911.Ā  This led to the idea of an infectious agent that could cause cancers. He would receive the Nobel Prize for this in 1966 due to the subsequent ability of infecting isolate avian cells in culture by Temin and Rubin in 1958.Ā  Howard Temin and David Baltimore would later independently discover and characterize an RNA-dependent DNA polymerase we know as Reverse Transcriptase from the Rous Sarcoma Virus that was pivotal for the life cycle of this tumor inducing virus. This resulted in a shared Nobel Prize in 1975.

Src tree and alignment
The Nobel Prize was awarded to Michael Bishop and Harold Varmus for illustrating the cellular origin of retroviral oncogenes. This work was initially published in 1976 and demonstrated that v-src in particular, was nearly identical to avian c-src. The main difference in the highly conserved protein was the absence of the C-terminal autoinhibitory Tyrosine residue that resulted in constant activity of the enzyme.

src activation
Credit: David S. Goodsell and the RCSB PDB (CC-BY 4.0)

Read more about src
An interview with Harold Varmus from the Journal of Clinical Investigations.

Viral classification

Baltimore virus classification
The Baltimore classification system is based on their type of genome and replication. Credit:Thomas Splettstoesser (CC-BY-SA)

 

Viral life cycle

Teven Bacteriophage

11 Hegasy Phage T4 Wiki E CCBYSA
Genomes of Teven bacteriophages are ~169kb of DNA and code for 300 proteins.

Influenza A

Influenza A is an orthomyxovirus that contains a segmented genome of 8 negative strand RNA molecules encoding at least 10 proteins. Segmentation of the genome increases the the diversity of the virus in rare cases of double infection where each RNA segment acts almost like a chromosome that is packaged in the appropriate complement of segments per functional virion. This shuffling of segments can result in antigenic shift, the shuffling of surface antigens on the surface of the virus particle. The surface antigens are encoded by the hemagglutinin (H)Ā  and neuraminidase (N) genes. Hence, the strain of flu viruses are often referred to by the types of these antigens, such as H1N1. This shuffling can also result in hybrid viruses that express the enzymology that has been optimized to specific hosts.
AntigenicShift HiRes vectorIn addition to the surface antigens, local isolates of influenza are named by their strain type, geographical location, lineage number and year of isolate. Hence, the reconstructed virus from the 1918 pandemic was isolated from a body in permafrost in Brevig Mission, Alaska and is called A/Brevig Mission/1/1918 (H1N1). Learn more about this deadly virus here.

ReverseGeneticsFlu
Reverse genetics to create a vaccine strain.
    • Reconstruction of influenza viruses uses cloned segments of the RNA into plasmids. Vaccine strains against specific surface antigens uses the specific H/N combination with the remaining 6 segments that are transfected into susceptible host strain cells where the viruses will multiply and package into infectious particles.

Measles and other Paramyxoviruses

Phylogenetic tree based on the N protein sequences of selected paramyxoviruses.
A phylogenetic tree of the Family Paramyxoviridae which includes Measles (MeV) and Mumps (MuV) .

    • Paramyxovirus genomes are negative strand RNA molecules. The L protein corresponds to the viral polymerase which acts as an RNA-dependent RNA polymerase and replicase. The 5′ leader of this RNA serves as the promoter to continue creating sense strand RNAs for translation.

Flaviviruses

Flaviviruses like Dengue, Zika and West Nile Virus contain positive single-stranded RNA genomes that code for three structural proteins (capsid protein C, membrane protein M, envelope protein E) and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5).

Wikipedia project 1
Dengue and Zika are in the family Flaviviridae. These viruses have ~9-12kb (+) single stranded RNA genomes that encode a single polyprotein that weaves through the membrane.

SAG Dengue-Virus 160413 01

Aedes aegypti during blood meal
Aedes aegypti is the primary vector for Dengue and Zika.
Pipiens feeding
Culex pipiens transmit West Nile virus


http://pdb101.rcsb.org/motm/103

http://pdb101.rcsb.org/motm/197

Coronavirus

SARS-CoV MERS-CoV genome organization and S-protein domains

CoronavirusesĀ  are (+) ss-RNA viruses with genomes ranging from 26.4 to 31.7 kb. two thirds of this genome is occupied by two reading frames called ORF1a and ORF1b. These large open reading frames are translated into large polyproteins that are later cleaved into smaller non-structural proteins. More information onĀ  coronavirus proteases involved in these processing steps can beĀ  visualized at PDB MOTM.

HIV

HIV-genome
Fifteen viral proteins are produced from 9 genes. The genes gag, pol and emv encode polyproteins that are cleaved by viral protease .
HI-virion-structure en
Structure of the HIV virus
HIV-replication-cycle-en
HIV replication cycle
HIV Membrane fusion panel
gp120 of HIV gains entry to cells through the association with the CD4 surface protein and the CCR5 (chemokine receptor 5)
 

Zidovudine
Azidothymidine is a Thymidine analog that interferes with the reverse transcriptase.
Tenofovir disoproxil structure
Tenofovir
Lamivudine structure
Lamivudine
Emtricitabine skeletal
Emtricitabine

Ebola

Ebola Genome
Ebola virus is a (-) single stranded RNA virus with 7 ORFs of the Family Filoviridae.

http://pdb101.rcsb.org/motm/178

Virus Ecology and Evolution