* # Nilay Kurtuluş - 1605A033

# **Human Immunodeficiency Viruses (HIV)**

# General Informations About HIV Virion
* HIV is a member of the *genus Lentivures*, part of *Retroviridae family*.
* HIV is an enveloped retrovirus of ∼120nm in diameter with a 9.7 kb +ssRNA genome.
* There are two types of HIV, HIV-1 and HIV-2.
* HIV virion has cone shamped capsid and complex constraction.
* Because there are two complete copies of the +ssRNA genome, HIV is considered diploid, only one of the two copies is used for reverse transcription
***Figure 1 : HIV Virion***
* As seen in Figure 1, HIV contain several types of proteins that are necessary for infection (RT, IN, PR, NC, CA, MA, SU, TM).
* Genome contains 3 structural genes ( gag, pol, env) and 6 regulatory genes(Tat, Rev, Nef, Vif, Vpr, and Vpu).
* HIV cause acquired Immunedeficiency syndrome (AIDS).
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# Acquired Immunedeficiency syndrome (AIDS)
The clinical course of HIV infection is divided into three stages: acute (or primary) infection, asymptomatic infection, and **AIDS.**
* Characterized by slow viral replication and gradual decline of CD4 T cells in blood.


HIV/AIDS is transmitted primarily in three ways
* Through sexual contact that exposes a mucosal epithelium
* Transmitted from mother to child, which can occur transplacentally.
* By injectable-drug use, improperly sterilized needles and equipment, or through accidental exposure to infectious materials
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# The Genomic Structure of HIV
HIV mRNAs are extensively spliced. The mRNAs for the Gag and Gag-Pol precursors are unspliced, but mRNAs for vif, vpr, vpu, and env are singly spliced, while mRNAs for tat, rev, and nef are multiply spliced.

***Figure 2: Genome Organization of HIV***
Source:[MolecularVirology of Human Pathogenic Viruses-Academic Press(2017)]

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*Functions of HIV proteins are given in table below.*

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# The Life Cycle of HIV
**HIV Attachment, Penetration, and Reverse Transcription**
HIV gp120 binds to CD4(main receptor), that leads conformational change in the gp120 molecule and reveals the binding site for the co-receptor CCR5 or CXCR4, that reveals the gp41 fusion peptide and creates pore in membrane, allows the nucleocapsid releasing inside the cell.
***Figure 3: HIV attachment and fusion***
Upon entry into the target cell, the viral RNA genome is reverse transcribed into double-stranded DNA (cDNA) by a virally encoded enzyme, reverse transcriptase, that is transported along with the viral genome in the virus particle.

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* ##### *Once integrated, the virus may become latent, allowing the virus and its host cell to avoid detection by the immune system, for an indeterminate amount of time*
* ##### *In contrast the retrovirus, the HIV capsid has the ability to enter the nucleus via a nuclear pore in nondividing cells (ie, resting cells or cells in G0 phase).* this became a critical point in using the lentivirus vector for gene delivery, because the majority of human cells are non-dividing cells.
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**Integration and Replication**

* The preintegration complex assists the cDNA in entering the nucleus. Integrase joins the proviral DNA into the host’s chromosomal DNA.
* Transcription of viral genes by cellular RNA polymerase II generates viral mRNA. vif, vpr, vpu, env, tat, rev, and nef mRNAs are spliced before exiting the nucleus. Rev assists in the export of gag and gag-pol mRNAs. Viral mRNAs are translated into viral proteins.


***Figure 4: HIV‑1 replication cycle***
Source : The structural biology of HIV-1: mechanistic and therapeutic insights

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**Assembly**
New HIV proteins and RNA move to the surface of the cell and assemble into the immature(noninfective) HIV.

**Budding, Release and Maturation**
The immature HIV push itself out of the host cell, release protease enzyme, protease breaks long proteins chains in immature virus, creating the mature (infective) virus.

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## Summary of the splicing pathways in HIV

In the literature, there are anti-HIV therapeutic strategies which target the inhibition of the splicing mechanisms of the HIV.

* HIV-1 is able to express multiple protein types and isoforms from a single 9 kb mRNA transcript.This is achieved through the control of alternative splicing and the export of these transcripts from the nucleus.
* The specificity and regulation of splicing in HIV-1 is controlled by the use of specific splice sites as well as exonic splicing enhancer and exonic splicing silencer sequences.

In Fıgure 5, splicing mechanism of HIV and alternative drug mechanism is shown. For more information, you can visit the source of the figure.

***Figure 5 : A summary of the splicing pathways in HIV***
Source : Can the HIV-1 splicing machinery be targeted for drug discovery? (Review Article-2017)

During the early phase, unspliced RNA is exported through association with Rev, where it associates with the ribosome and is translated into Gagpol and Gag proteins. Partially spliced mRNAs are also exported and translated into proteins Env, Vpr, Vif, and Tat. During the late phase of viral infection, multiple spliced mRNAs are exported to the cytoplasm where they are translated into Tat, Vpu, Nef, and Rev