Life Cycle
The very first thing that must occur in order for this life cycle to begin is that the virus must get past the body’s first line of defence and enter inside. This occurs through direct contact with infected bodily fluids such as blood or semen, as once it is in the body it begins to attack(3). The HIV virus targets any cell that has the CD4 protein which includes helper t-cells, some cytotoxic t-cells, monocytes and macrophages but the most important target cell is the T-Cell, 65% of which have the CD4 receptors(4).
Binding
After the virus enters the body and comes in contact with a host cell that has CD4 protein it will bind. This is where the gp120 comes into play, this glycoprotein binds with the CD4 like a lock and key(3). Alongside the primary CD4 receptor on T-cell’s there are also two chemokine receptors but only one or the other applies at once; CXCR5 or CXCR4(5). Once the gp120 is bound to the CD4 through intermolecular forces, a structural change occurs on the envelope exposing the chemokine binding domains on the gp120 and allowing for the chemokine receptor (CXCR4 or CXCR5) to bind creating a stronger bond allowing for next few steps to occur.(3)
Fusion
The conformational change also allows for the fusion portion of the gp41 to be exposed (fusion area is hydrophobic area that gets embedded in the cell membrane and fuses the lipid bilayer of the virus and host cell together)(3). This is what allows the RNA genome and various enzymes (reverse transcriptase, protease and integrase) to enter the host cell.
Reverse Transcription
This is the process of copying RNA into DNA so that it can integrated into the host cell’s DNA. This complex process begins with the binding of a tRNA primer to the binding site on the RNA, from here the reverse transcriptase (RT) copies the RNA into a single strand of complementary DNA(3). At this point only the long terminal repeat has been copied. RNase H comes in and destroys the RNA which was copied(3,5). This allows for the tRNA, RT and single stranded DNA to reattach to the other end of DNA where RT comes back in and copies the HIV RNA into DNA and RNase H comes back in and degrades the RNA except one small section called the polypurine tract(3). This is where the RT binds to create the second strand of DNA, once complete RNase H comes in and degrades all the remaining RNA including the polypurine tract. The two strands of DNA then join to form a helical shape, each DNA fragment has an LTR at each end (3) .
Integration
This is the process of the HIV DNA being integrated into the host DNA. Once inside the nucleus the enzyme integrase catalyzes the cleaving of the HIV DNA, the two strands are pried apart which leaves the DNA with “sticky ends” or the LTR(3). This enzyme also cuts the host DNA which also exposes these “sticky ends”, the sticky ends of the HIV DNA can then attach to the sticky ends of the host DNA and become integrated(3). At this point the viral genes have become a part of the host’s genome and the HIV can either stay latent or begin producing more HIV proteins via transcription. It may lay low and produce only small amounts of virus over a prolonged period of time in order to avoid being detected (virus production is suppressed via the regulatory genes)(3). It can stay in this dormant position from months to decades but when it does become activated, the real attack begins(4).
Replication/ Protein Synthesis
Now the host cell will not be able to tell the difference between its DNA and the HIV DNA, so unknowingly it will begin to produce HIV proteins. The HIV DNA in the host genome can be referred to as proviral DNA, RNA polymerase can then use this DNA to create mRNA and/or viral genome RNA in a process called RNA transcription. RNA transcription follows three basic steps; initiaton, elongation and termination. Transcription initiation begins when and enzyme called RNA polymerase binds to the promoter region of the gene being copied, which in this case would be viral genes. Once the RNA poymerase binds to this region it begins the elongation process in which it begins synthesizing mRNA in a 5' to 3' direction (5' to 3' is regards to the orientation of the hydroxyl and phosphates on the DNA strands)(9). Once the ends of the target gene is reached RNA polymerase recognizes a termination sequence resulting in the mRNA disassociating. In eukaryotes there is one further step where the mRNA recieves a Poly A- Tail and a 5' guanine cap. The poly A tail plays a role in protecting the mRNA from being digested by nucleases when leaving the nucleus and the 5' cap helps with translation(9).The mRNA can now be translated to form viral enzymes and structural proteins through the process of translation. Translation requires the use of the tRNA molecule and the ribosomal units. First the mRNA transcript enters the cytoplasm and the 5' cap attracts the large ribosomal unit which prompts the binding of the small ribosomal unit(9). The fully formed ribosomal unit moves along the mRNA in a 5' to 3' direction until a start codon is reached and the synthesis of the polypeptide chain begins. Once the polypeptide chain is complete it will disassociate from the tRNA and the ribsomal units(9). Some of these proteins are created via the cleavage of long poly-protein chains through protease.
Assembly/Budding
After the replication of all the important components of this virus, the gp41 and gp120 proteins are embedded into the host cell membrane (lipid bilayer) and the structural proteins ( p17 and p24) surround the genome and enzymes(made by the host cell), the new virus (made up of proviral RNA and HIV enzymes) is released through budding and takes a piece of the membrane of the cell along with it. Sometimes if a large amount of virus buds off it may lyse the cell(5).