Replication Of Hiv1 Proteins In Genomes Biology Essay


The replication of HIV-1 is dependent upon some special proteins encoded in its genome. The protein involves Gag proteins that carry assembly and causes the release of viral particle. The Gag proteins are also involved in viral RNA genome encapsidation. The enzymes encoded by pol gene involve protease (PR), integrase (IN) and transcriptase (RT). At the release time of virus, protease enzyme cleaves the precursor of GagPol and Gag polyprotein. When the viral RNA genome enters the host cell, its single strand of RNA is converted into double stranded DNA by the action of reverse transcriptase enzyme. After the formation of double stranded DNA it is integrated into the host genome by the action of integrase enzyme. Envelope (Env) glycoprotein helps in the interaction between viral and host cellular membranes and thus helps in virus binding. HIV-1 also encodes some other proteins that helps the viral propagation in the host cell.

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The work done on HIV-1 concludes that the number of CD4+ (subset of T helper cells) decrease dramatically in HIV infection. This concludes that CD4+ cells contain receptor for HIV-1 virus. It has also been observed that Env-mediated membrane fusion of HIV-1 is facilitated by CD4 with the involvement of other factors. These factors involve seven membrane-spanning-G-protein-coupled which belongs to chemokines receptor family. Two co-receptors CCR5 and CXCR4 plays important role in membrane fusion. Another factor i.e. Cholesterol rich lipid rafts are involved in the viral entry into the host cell. These rafts make a useful lipid micro environment in the fusion of virus with the host and this cholesterol helps in lateral movement of receptors at the time of viral interaction.

There are two basic method used by membrane enclosed viruses for entering into the host cells. These methods are pH dependent endocytosis and the other method is direct fusion with plasma membrane. HIV-1 virus undergoes receptor mediated fusion for the choice of entering method. Env gene encodes for a polyprotein gp 160 that mediate the entering of virus in the host cell. Protease enzyme cleaves this gp160 into gp120 and gp41. This gp120 which is a surface subunit (SV) is responsible for cell surface receptor and co-receptor binding of HIV-1. GP41 is a transmembrane protein (TM) and it contains two helical regions which are HR1 and HR2. Gp120 and gp41 undergoes non-covalent joining in the viral membrane making a trimeric structure. The Gag gene encodes for marix antigen p17MA for the formation of 7nm shell under the viral envelope. The Gag gene also encodes for capsid anigen p24CA that surrounds the two copies of viral RNA genome.

The CD4 molecule is comprised of four extracellular domains D1, D2, D3 and D4 which are immunoglobulin related domains. It also contains a single transmembrane domain and short cytoplasmic tail. The co-receptors comprises N terminal extracellular domain, cytoplasmic tail, three intracellular loops (ICL1, ICL2 and ICL3) and three extracellular loops (ECL1, ECL2 and ECL3). There are five variable regions (V1-V5) in gp120.

The HIV-1 infection develops with the entry of virus in the host cell. This step involves the binding of receptors and then co-receptors, forming a membrane fusion which allows the entry of viral core in the host cell. The binding of HIV-1 gp120 and CD4 is very strong and this binding is considered as a critical step in initial phases of HIV life cycle. This binding leads to conformational changes exposing the binding sites of co-receptor CCR5 and CXCR4. Afterwards, pore formation occurs and another conformational change takes place forming six helix bundle structure with the interaction between HR1 and HR2. This leads to the fusion between viral and host membrane leading to the entry of viral core in the host cell. The host cell contain a counter mechanism against certain retroviruses and they release an restriction enzyme APOBEC3G (apolipo-protein B mRNA editing enzyme, catalytic polypeptide like 3G) cytidine deaminase Trim5α which counteracts with retroviruses. To avoid this mechanism HIV-1 produces a special protein i.e. Vif (viral infectivity factor) that interacts with APOBEC3G and helps to harbor its genome from its action. After entering in the host cell, the single strande RNA genome of virus in converted into double stranded DNA by the action of RT enzyme. The one drawback of RT enzyme is that it lacks proofreading mechanism and thus creates mutations. These mutations infact helps the virus to dodge different antiviral immune responses. The pre-integration complex (PIC) is formed of DNA under the action of RT enzyme that contains both viral and cellular proteins. Afterwards, various factors take part in actively transporting PIC in the nucleus. These factors include matrix protein (MA), IN enzyme, viral protein R (VPR) and DNA flap (triple stranded DNA fragment). IN enzyme is also responsible for the integration of PIC in the host cell chromosome. Another associated factor lens epithelium-derived growth factor (LEDGF/p75) is also responsible for PIC integration in accordance with IN enzyme. PIC also contain many proteins which are barrier to auto- integration factor (BAF), HMGa1 (high mobility group protein) and IN- interactor1 (Ini-1) protein.

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Now the PIC is a part of host chromosome and it use the host cell machinery for its transcription into RNA molecules. Some transcribed into new viral particle RNA and some are transcribed as mRNA for the translation into various viral proteins called viral Rev Protein. The production of viral genome RNA and new viral proteins results in the assembly of viral particle. These viral particles leave the host cell by the process of budding and form a viral envelope by taking some of the membrane of host cell. The host contains a restriction factor Ref1, the action of which is inhibited by the interaction between CyPA (gag interacting protein) and CA domain of Gag which is a proline rich loop.

The HIV contains three structural proteins i.e. nucleocapsid (NC), capsid (CA) and matrix (MA). Matrix forms the inner shell and viral genome is enclosed in conical capsid. NC carries out the interaction of viral genome. These structural proteins are formed by p55 polypeptide precursor present in HIV-1 and this precursor is processed by PR. The viral budding is controlled by the p6 domain which is also present on p55 precursor. The PTAP motif working is also dependent upon its interaction with ubiquitin-protein ligase hPOSH domain and TSG101 domain. This PTAP motif is present on p6 domain and has a role in budding.

The transport of molecules between plasma membrane and lysosomes is carried out by membrane bound compartments called Endosomes. Lately these endosomes were named as multi-vascular body (MVB). Endosomal sorting complex required for transport (ESCRT-1) complex is actively involved in the formation of MVB. TSG101 is a subunit of ESCRT that helps in viral budding by guiding the complex to the site of budding. The phenomena of the budding process of HIV-1 is called Trojan exosome hypothesis.

The mammalian cell undergoes the post translational modifications of the proteins that helps in protein stability and diversify its function. One of the major post translational modifications is glycosylation. The N-linked glycosylation involves the attachment of high mannose core to the amide nitrogen of asparagine. The trimming and remodeling of oligosaccharides takes place that results in various oligosaccharide structures in glycoprotein. This post translational modification by the host cell is used by the viruses to update their surface protein that leads to increase their antigenicity, stability and invasion. The protein folding mechanism and cytoplasmic trafficking by the virus is enhanced to use host cell chaperons and folding factors by the N-glycosylation of its envelope. The second major change from the glycosylation in viral life cycle is the affect on receptors and its affinity to immune cells innate factors is increased and disguise from antibodies recognition.

The N-glycosylation helps the HIV-1 virus in increasing its virulence and immune interactions. The HIV-1 envelope gp120 is the heavily glycosylated protein in nature with high mannose composition. The oligosaccharides present on gp120 helps in interaction between gp120 and CD4 cells. The N-glycosylation occurs on gp120 at 18 and 33 sites. If somehow the N-glycosylation of HIV-1 is disrupted it will lead to decrease infectivity and cytopathicity. V1-V2 loop of gp120 get glycosylated that alters its sensitivity to antibodies. The attachment of gp120 is mannose dependent to mannose receptor (MMR), DC-SIGN or lectins that facilitates the entry of virus in the host. The glycosylation mediated shield formation on the envelope of the virus also helps in deceiving antibodies. The other major factor for antibodies resistance is the highly mutagenic behavior of HIV-1, thus glycosylation is not the only process involves in antibody resistance. Certain molecules in the host are responsible for sensing and recognizing the pathogens. These molecules are calcium dependent lectin group including MMR, SP-A, SP-B, MBL and DC-SIGN. Instead of sensing and recognizing, the HIV-1 with the help of N-glycosylation use these molecules for binding and entry in the host.