The Replication Cycle Of Viruses Biology Essay

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Cell tropism is defined as the ability of viral strain to infect the particular type of cells. The HIV has the ability to infect CD4 T cell, macrophage and dendritic cells. (1) The viral envelope protein, gp120, needs to bind both cell receptor CD4 and co receptor for its entry. The co receptor has a important role in viral tropism. There are two major types of cell tropism. (2)

M tropic: The ability of viral strain to infect macrophage is termed as M tropic. These viruses utilize the CD4 receptor and CCR5 co receptor on the surface of macrophage for its entry. These viruses do not produced syncytium in host cell. So it is also called non syncytium induced virus. Some T cells have CCR5 co receptor on their surface. (2).

T tropic: The ability of viral strain to infect T cell line is termed as T tropic. These viruses utilize the CD4 receptor and CXCR4 co receptor on the surface of T cell for its entry. These viruses induced to produce syncytium during later stages of infection. So it is also called syncytium induced virus. (2)

The V3 loop of envelope protein, gp120, is responsible for viral determination of cell tropism. (2).

Viral Replication:

The following steps are involved in HIV virus replication.(2)

Attachment:

The viral attachment occurs through the binding of viral envelope protein, gp120, to CD4 receptor and co receptor CXCR4 or CCR5 of host cell. After binding of gp120 to CD4, it induced to produce conformational changes in gp120 glycoprotein. It allows exposing the V3 loop of gp120 which has the ability to bind co receptor with high affinity. Then it further induced to produce conformational changes and allowed to expose gp41 glycoprotein. The exposed gp41 becomes active.(2)

Entry:

The active gp41 inserts into plasma membrane of target cell which leads to fusion of target cell plasma membrane and viral envelope directly. So the viral core particle is released into cytoplasm of host cell. (2)

Uncoating:

Once the core particle enters in to cytoplasm, it undergoes uncoating to release the nucleoprotein complex.(2)

Reverse transcription of viral RNA:

During this process the viral RNA genome is converted into double stranded DNA by virally encoded reverse transcriptase enzyme in cytoplasm.(2)

The both ends of viral genome are flanked by direct repeat R region. The unique region called U5 is also present near R region of 5' end of genome. The unique region called U3 is also present before the R region of 3' end of genome. The viral genome has primer binding site (PBS) which is located near the U5 region. The PBS site is complementary to 3' end of tRNA. The poly purine tract (PPT) region is present near the U3. The genome of virus looks like the following order.(3)

5'-R-U5-PBS-Leader-gag-pol-env-PPT-U3-R-3'(3)

The tRNAlys3 binds to PBS site and acts as primer.(2). After 3' end of tRNA binds to PBS site of viral genome, the reverse transcriptase (RT) elongates the primer towards U5 and R region of 5' end of viral genome. Then RT stops elongation when it reaches the end. Now part of 5' end of viral genome is hybridized with newly synthesized DNA. Now it looks like the following way.(3)

5'-R-U5-PBS-Leader-gag-pol-env-PPT-U3-R-3' RNA

3'-R'-U5'-tRNA-5' DNA (3)

Then the viral RNA strand in the region of RNA/DNA duplex is degraded by RNase H activity of RT. Now the newly synthesized DNA which is attached to tRNA is free and it is called minus strand strong stop DNA. This minus strand strong DNA is moved and binds to R region of 3' end of viral genome. Now it looks like the following way.(3)

5'-PBS-Leader-gag-pol-env-PPT-U3-R-3' RNA

3'-R'-U5'-tRNA-5' DNA (3)

Then the DNA is elongated at the 3' end by using RNA genome of virus as template.(3)

5'-PBS-Leader- gag- pol- env- PPT- U3- R-3' RNA

3'-PBS'-Leader'-gag'-pol'-env'-PPT'-U3'-R'-U5'-tRNA-5' DNA (3)

The RNA strand in RNA/DNA hybrid is digested by RNase H activity of RT except PPT region of RNA. Now it is looks like by the following way.(3)

5'- PPT-3' RNA

3'-PBS'-Leader'-gag'-pol'-env'-PPT'-U3'-R'-U5'-tRNA-5' DNA (3)

Now PPT region from virus RNA is served as primer for positive strand of DNA synthesis by using negative DNA strand as template. The primer (PPT) is elongated towards U3', R', U5' and until PBS complementary region of tRNA by RT. The RT does not copy the whole tRNA because of modified nucleotides of tRNA. (3)

5'- PPT- U3- R- U5- part of tRNA (PBS)-3' +ve strand DNA

3'-PBS'-Leader'-gag'-pol'-env'-PPT'-U3'-R'-U5'-tRNA-5' -ve strand DNA(3)

Then the PPT region from positive strand and the tRNA from negative strand are removed by RNase H activity of RT. Now the partially synthesized positive strand is transferred from 5' end to 3' end of negative strand and binds to PBS region of negative strand.(3)

5'- U3- R- U5- PBS-3' +ve strand DNA

3'-PBS'-L'-gag'-pol'-env'-PPT'-U3'-R'-U5'-5' -ve strand DNA (3)

Then both strands are elongated at 3' end to produce full length linear double stranded DNA which contains LTR (long terminal repeat) sequence (U3-R-U5) at both ends. (3)

5'- U3- R- U5- PBS- L- gag- pol- env- PPT- U3- R- U5-3' +ve strand DNA

3'-U3'-R'-U5'-PBS'-L'-gag'-pol'-env'-PPT'-U3'-R'-U5'-5' -ve strand DNA (3)

Integration:

After formation of double stranded DNA, the pre initiation complex (PIC) is formed in cytoplasm. The PIC contains double stranded DNA, RT, integrase (IN) enzyme, matrix protein (MA), nucleo capsid protein (NC), and Vpr protein. Then the PIC is translocated from cytoplasm to nucleus by the aid of MA and Vpr proteins. These proteins allow translocation of PIC via nuclear pore by nuclear localization sequence. After entry in to nucleus the viral DNA genome is integrated into host genome randomly by virally encoded integrase enzyme.(2)

If viral DNA is integrated into host genome, it is called provirus. The provirus is stable and able to transmit to its daughter cells. (3)

Viral gene expression:

Early gene expression: After the formation of pro virus, the integrated form of viral DNA is transcribed by using host RNA polymerase II. The cellular RNA polymerase II recognize promoter region which is present in LTR region of viral DNA to produce primary transcripts. Some cellular transcription factors like NF-kB,Sp1, and Ap-1 are also involved in transcription. Then the primary transcripts can undergo multiple splicing by host spliceosome. These multiple spliced mRNA encodes single protein. These multiple spliced mRNA is translocated from nucleus to cytoplasm where translation takes place. In this stage the early proteins like Tat, Rev and Nef are accumulated. The accumulation of early proteins can able to switch from early phase to late phase of gene expression. (2)

Late gene expression: During this stage the late proteins like Gag, Env, Vif, and Vpu proteins are produced. The full length of genomic RNA is also produced. The late gene expression is dependent on rev protein. The early protein, Tat, increases the transcription by stabilizing the RNA polymerase II and produced longer mRNA. The Rev protein is interact with this longer mRNA and allowed to transport unspliced or partially spliced mRNA from nucleus to cytoplasm. In cytoplasm the partially spliced mRNA are translated by using cellular translation machinery. The unspliced mRNA is served as RNA genome of virus particle during encapsidation. (2)

The large precursor proteins are produced from gag gene. Sometimes gag and pol together produced large precursor proteins. The precursor env protein, gp160, is processed in endoplasmic reticulum and transferred to golgi complex where glycosylation occur. This precursor gp160 is cleaved into gp120 and gp41 by cellular protease to produce mature proteins. Then the mature gp41 is inserted into plasma membrane and mature gp120 is attached to gp41 in plasma membrane. (1)

Assembly:

The assembly of virus particle occurs at budding site of host cell plasma membrane where the env proteins are inserted. The precursor gag proteins are assembled near the budding site of plasma membrane to produce capsid. Then two copies of RNA genome associated with tRNAlys3 and other proteins are packaged in to capsid. (2)

Budding:

Finally the assembled virus particle is released by budding through plasma membrane and simultaneously acquire envelope from host cell plasma membrane.(2)

Maturation:

Because the newly released virus particle has precursor proteins in their capsid, it is not matured particle. This unmatured particle does not have infectious ability. During maturation the cleavage of gag and gag-pol proteins takes place by virally encoded protease. (2)

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