Hiv Virus In Humans And Its Life Cycle Biology Essay

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Human immunodeficiency virus (HIV) is a lentivirus belonging to family Reteroviidae and was identified in early 1980s. Members of this family are responsible for causing various immunological and neurological diseases in humans and animals. Acquired immune deficiency syndrome (AIDS) is caused by HIV. AIDS is a condition in which the immune system of host begins to fail and ultimately leads to life threatening infections. HIV is an endemic infection that can be transferred by body fluids such as blood transfusion, semen, vaginal fluids, and breast milk and from an infected mother to child during birth.

Life cycle of HIV

HIV infection is caused by a number of controlled steps. Entry is one of the steps by which viral interaction with cellular membrane of host cell occurs. This interaction causes the deposition of HIV-1 genome in the target host cell. Membrane enclosed viruses can enter the host cells by two ways, pH-dependent endocytosis and direct interaction with the plasma membrane of the host cell. Entry of HIV is important to understand for the development of drugs in more advance way to treat the individuals infected with HIV-1.

Encapsidation of viral RNA genome, release of virus particles and their assembly is driven by Gag proteins. There are three pol encoded enzymes protease (PR), reverse transcriptase (RT) and integrase (IN). Gag Pol polyprotein precursors and Gag are cleaved by these enzymes at the time of absolution of virus particles. Hp68, a cellular protein reinforces the process of virus assembly. This cleavage causes the viral RNA genome to convert into double stranded DNA. Integration of viral DNA into the host cell chromosome is promoted by this process. These viral encoded proteins actively take the advantage from the host cell for viral dispersion. CD4 cells provide receptor for the binding of viral proteins. But solely CD4 cells are not responsible for HIV-1 infection. There are seven membrane connected G proteins having chemokine receptors promotes the binding of HIV-1 to CD4 receptor for facilitation of membrane fusion. Cholesterol rich lipid rafts of host cell facilitate the entry of virus for the replication cycle. Recruitment and concentrations of fusion reaction are associated with these lipid rafts by creating lipid microenvironment that shows compatibility with the fusion reaction. Another contribution of lipid rafts is to promote escape of infected cells. HIV-1 Gag protein interacts with lipid rafts to debilitate the production of HIV-1 particles.

Reverse transcriptase

Infectivity of cells is caused by Vif (viral infectivity factor). APOBEC3G (apolipoprotein

B mRNA-editing enzyme, catalytic polypeptidelike 3G) is identified recently, belonging to a family of enzymes called cytidine deaminases. This protein interacts with Vif. During reverse transcription cytosines are converted into uracils after the fusion of APOBEC3G in the target cell. There are two impacts of this process on virus, repair enzymes of the host cel uracil DNA degrades the newly synthesized viral DNA and secondly, hypermutation of DNA from G toA. Expression of APOBEC3G is low in the cells allowing Vif to bind.

Integration

Viral DNA, after finalization of reverse transcription, has more molecular mass containing cellular and viral proteins. Preintegration complex (PIC) is transported to nucleus. Along with the there are certain other proteins like matrix (MA), viral protein R (Vpr), the in enzyme (IN) that are used to make a DNA flap. Integration of viral DNA into host cell chromosome is catalysed by IN. intramolecular integration reactions are mediated by salt stripped PIC. Refined PIC contains many cellular protein i.e. barrier to auto-integration factor (BAF) which is 89 amino acids long. HMGa1 is high mobility group protein, INi-1 consisting of segments of SNFâ€"SWI (sucrose nonfermentingâ€"switch). LEDGF/p75 lens epithelium-derived growth factor is reported to have an interaction with IN and have participation in integration.

Envelop protein (env)

HIV-1 has enveloped protein which is responsible for regulation entry of virus into host cells. The Env gene encodes a protein gp160. After post translational changes, envelop is cleaved by protease enzyme to have gp120 and gp41. This process is elementary for the occurrence of viral infection. HIV cell surface receptors and coreceptors are bounded specifically by GP120, a surface subunit (SU) protein. There is a transmembrane protein (TM) GP41 that has two helical reigons HR1 and HR2 with a fusion peptide. Gp120 and gp41 are attached to each other through non covalent bonding on the viral membrane. Entry of viral core is initiated by first binding to the receptor, coreceptor and eventually membrane fusion. Conformational changes occur in gp120 after specific binding of gp120 to CD4 cell. This change helps in the exposure of coreceptor binding sites CCR5 and CXCR4. These coreceptors are recognized by V3 loop of gp120. At this certain point, formation of fusion pore begins. A six helical bundle structure is formed after the second conformational change that occurs by the interaction of HR1 and HR2 in gp41.

Transfer of viral core

After entry, viral core has to furnish its genetic material into the host cell nucleus. Research

showed that virus use microtubules fot furnishing its genetic material into the nucleus. Mostly atthis time, retroviruses become accessible for the host cell restriction enzymes to cause mutation in them such as APOBEC3G and Trim5.

There are three domains of uncleaved HIV-1, membrane targeting (M), interaction (I), late (L) domains. These three domains play a vital role in the assembly process. Generation of HIV-1 enclosed particles is propagated by two significant steps, assembly and budding. These noxious particles are comprised of three structural proteins nucleocapsid (NC), matrix (MA) and capsid (CA) along with the viral Env. Nucleocapsod is responsible for interaction with viral genomic RNA. The inner covering of the viral membrane is composed of matrix while conical capsid is composed of capsid. The viral RNA is confined within this capsid. Generation of the three proteins is processed by HIV-1p55 polyprotien which is accompanied by viral protease(PR). Besides these functions, MA, NC, CA and p55 possess a domain p6 which is known to be necessary for the process of viral budding.

Budding

TSG101 is a factor that is involved in the process of budding. This TSG101 interacts with PTAP motif. Mutations in the PTAP motif inhibit the process of budding by repressing TSG101 by siRNA. In HIV-1 budding, this association is vitally important. TSG101 is structurally similar protein to VPs23, a yeast protein involved in the vacuolar sorting system. it is a subunit of endosomal sorting complexes required for transport ESCRT-1 complex. Multivascular bodies (MVB) genesis machinery and plasma membrane are reformed by HIV-1 to promote the process of budding. In L domain, there is a region that also supports the process of budding. This region contain a protein AIP-1 which interacts with ESCRT-III complex. Different research groups have shown that interaction of AIP1 and TSG101 with ESCRT complexs at the budding sites allow ESCRT to carry on budding and fission process.

Glycosylation is one of the most important functions in the viral modification. It has to do a lot with the structure and function, the mechanism of which is still not fully understood. Scientists are still working at their best to discover better tools to understand the process of glycolysation and its importance in health and disease conditions. Glycolysation shows its importance in post translational changes in for protein functioning in the mammalian genome. Past research has helped us to understand that there are certain enzymes and functions involved in the biological processes such as, signal transduction, molecular trafficking, cell adhesion, receptor activation and endocytosis. N-linked glycolysation is one of the common protein modifications. A high mannose core is attached to the amide nitrogen aspargine Asn-X-Ser/Thr. This process, after attachment in the early protein synthesis, is followed by a complex process of trimming and remodeling of oligosaccharides during when they are being transited through endoplasmic reticulum and golgi apparatus. This process results in glycolysation and having different oligosaccharide structures. Viruses use this cell process in the modification of their surface proteins. This modification helps the viral glycoprtiens in stability, antigenicity and host cell invasion.

Recent studies have provided evidence of utilization of glycolysation pathways by the virus including the descriptions of attachment of N-linked oligosaccharides. This process causes two changes in the viral life cycle.

Surface proteins or N-linked glycolysation can utilize the host cell chaperons and folding factors in order to promote the proper folding and trafficking. Viruses that have been studided now show that they use calnexin and/or calreticulin for folding. Site of glycolysation is important as it can affect the proper folding, survival and transmissibility of the virus, which will influence the proteins of the whole molecule. Other changes in the glycolysation can make the virus to be more recognized by the host immune system, as these changes will be having an impact on the receptors.

HIV is one of the viruses that use glycolysation for the enhancement of their pathogenicity and immune evasion. HIV envelop protein (gp120) is composed of many mannose and glycosylated proteins. Carbohydrate on the surface of mature gp120 molecule plays a vital role in the interaction of CD4 and gp120. Earlier studies revealed that loss of glycan affects this interaction of virus with CD4 cells but this interaction is not suppressed. As a result of this decreased interaction with CD4 cell, infectivity and cytopathicity will also be decreased. According to a globally collected data for HIV gp120 sequences, showed that there are approximately 25 N-linked glycolysation sites. During the course of infection, V1-V2 envelop loop has sequences for the addition of glycosylation due to which alteration occurs in sensitivity and neutralizing antibody. N-linked glycans within these V1-V2 loop having fifteen variants is needed to promote viral infection and reduce its sensitivity to serum antibody. However, the question arises how the contribution of N-linked glycolysation provides protection as many glycans are preserved in gp120. We have an example of human monoclonal antibody 2G12 that acts on the epitope of gp120 having high mannose and/or hybrid glycans. The epitope was composed of mannose dependent carbohydrate and was found as a highly preserved reigon of gp120. After analyzing it was observed that D1 and D3 arms of Man9GlcNAc2 are very important, in the interaction with 2G12 neutralizing antibody. The epitope of gp120 plays a vital role in causing infection as it is thought to believe that mannaose dependent attachment of HIV with mannose receptor (MMR), promotes the entry into the host cells. Mutations and successional additions in the N-glycan sites provide a protective glycan shield which protects the virus against host neutralizing antibodies. By this it is being concluded that glycolysation is not solely, but partly responsible in producing the resistance against host neutralizing antibodies.

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