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The Human Immunodeficiency Virus, belonging to the lentivirus family, is the result of infection by 1 of 2 retroviruses capable of using the enzyme reverse transcriptase to reverse the usual flow of genetic material, which can then be incorporated into the host's genome and inadvertently replicated. HIV impairs cell-mediated immunity primarily through the destruction or decreased population of CD4+ T-lymphocytes through 3 main mechanisms; First, direct degenerative effects on T-cells; second, increased rates of apoptosis in T-cells; and third, through the destruction of infected CD4+ T-cells by CD8 cytotoxic lymphocytes. The virus is characterised by long incubation periods and persistent opportunistic infections, eventually progressing into Acquired Immune Deficiency Syndrome (AIDS). (Willey. J et al, 2008)
The basic structure of HIV consists of a cylindrical inner core surrounded by a spherical outer envelope. The core of the virus contains nine HIV genes on two single positive RNA strands tightly bound to the enzymes, reverse transcriptase, integrase, ribonuclease, protease, and the nucleocapsid proteins, p7. The genomic RNA and proteins are enclosed within a conical capsid composed of 2000 copies of the gag-derived protein, p24. The gag gene (one of three principal HIV genes) encodes for core proteins, while the enzymes reverse transcriptase, protease and integrase are derived from Pol and surface glycoproteins (gp) from the env gene. The remainder of the genes - rev, ref, vif, vpu, vpr - function in controlling viral replication and enhancing the rate of infectivity.
The envelope, derived from the host cell, is composed of a lipid bilayer containing 72 external spikes (sugar chains attached to protein), formed by two major HIV glycoproteins essential for infectivity - gp120 and gp41. These glycoproteins are obtained from the precursor glycoprotein, gp160, once it has been cleaved by a HIV protease. The lipid bilayer is also studded with various host proteins, including Class 1 and 2 human lymphocyte antigen complexes vital for controlling the immune response and disease progression. The inner surface of the bilayer is surrounded by p17 proteins, which act in stabilizing the exterior and interior components of the virion.
Entry of the virus begins when HIV particles bind to the CD-SIGN glycoproteins expressed on the surface of dendritic cells present throughout the body's mucosal surfaces. Once attached the virus is migrated to CD4+ T-cells in lymphoid tissue, establishing the initimal HIV infection of a lymphocyte. Entry into the host cell begins with the high-affinity attachment of the gp120 glycoprotein to two CD4 glycoprotein plasma membrane receptors and a chemokine co-receptor (usually CCR5 or CXCR4 proteins) on the outside of the host CD4+ cell, helping facilitate the process of cell binding and entry. Other minor chemokine co-receptors - such as CCR1, CCR2, CCR3 and CCR4 - may also assist in the attachment of HIV to cells bearing CD4+ receptors.
The binding of viral glycoproteins and the host cell receptors then results in fusion of the two membranes, allowing the HIV nucleocapsid to be inserted into the CD4+ host cell. The lipid membrane of the virus then incorporates itself into the membrane, and the gp120 and gp41 glycoproteins spread over the surface of the infected host cell. The nucleocapsid, coating the viral core, then dissolves and the interaction of host cell enzymes with the viral core stimulates the release of its contents.
The contents of nucleocapsid include the reverse transcriptase enzyme, necessary to catalyse the reverse transcription of the viral RNA into single stranded complementary DNA sequences, whilst simultaneously degrading the RNA, due to its ribonuclease activity of reverse transcriptase. The virus then utilizes the host's cellular machinery to obtain viral proteins and additional copies of viral RNA for further infection. This process is unique to retroviruses and critical for the viral reproductive cycle, however, it is accompanied by a high mutation rate, as the viruses produced after each round of replication are not identical to the original infection virions. This allows for rapid evolution of HIV and contributes to its high level of drug resistance.
Once reverse transcribed, the newly formed viral transcript can be randomly integrated into the CD4+ host cell genome, forming a provirus. This step in viral reproduction is catalysed by the enzyme integrase within the cell nucleus, where it can remain in the latent stage of HIV infection for many years.
Upon proviral activation of infected cells, replication of the newly integrated DNA transcript occurs. This results in the translation of new viral mRNA strands containing the encoded genes necessary to initiate production of viral polypeptide sequences, such as capsid proteins and other essential enzymes. Once transcribed, viral assembly of newly replicated RNA and functional viral core complexes occurs at the plasma membrane of the host CD4+ cell.
Before budding can occur the gp160 must first be first cleaved into its two components, gp120 and gp41, by the protease enzyme at the Golgi apparatus where it is then transported to the plasma membrane. Gp41 attaches gp120 to the host cell membrane, as the core contents also begin to associate with the membrane. The nucleocapsid then buds off from the CD4+ cell, taking with it a portion of the cd4+ envelope studded with viral glycoproteins to form their own viral proteins.
Maturation, the final stage of the HIV viral lifecycle, can occur either during the formation of the bud or after the virus has left the host cell and is required in order for the virus to become infectious. This step involves the HIV protease enzyme within the new viral particle cleaving the gag (p55) and gag-pol (p160) precursors into individual functional proteins and enzymes. The remaining structural components of the virus then assemble, generating a mature and infectious HIV virion. The newly formed viral particles then enter the host's circulation and actively begin infecting other T-cells, initiating the viral life cycle once again.