Structural Biochemistry/Carbohydrates/Virus/Mechanism behind HIV Infection

History
When Human Immunodeficiency Virus (HIV) first began showing up in 1981 in the United States, medical professionals originally determined it to be a rare form of cancer that infected homosexual men, known as Kaposi Sarcoma. Emergency rooms in New York suddenly had a strange influx of seemingly healthy young males coming in with flu-like symptoms and Pneumocystis Jiroveci Pneumonia (PCP), a fungal pneumonia that only affected individuals with HIV. (Normally, this fungal infection affects everyone, but since people without HIV have normal, healthy immune systems, they can prevent the infection from spreading. However, individuals with compromised immune systems, like those with HIV, cannot dispose of the fungus properly and therefore get sick.) Within the first year of the outbreak, out of the 1600 cases that were present in New York, almost 50% of the individuals died from it. This lead to a state of panic and medical experts hurried to find a cure. The Center for Disease Control was able to link the disease to affecting something in a person's blood.

The virus was finally discovered in 1984 at the Institut Pasteur in France, but in 1985, a U.S scientist finally determined the cause of the Acquired Immunodeficiency Syndrome (AIDS), a term pioneered by the CDC, was caused by the HIV virus. However, a cure couldn't be made quickly enough, so by 1987, six years after the first public case, there were over 71,000 confirmed cases of AIDS, of which there were more than a 50% casualty rate. Nowadays, as science and medicine have progressed, multiple drug regiments have been created to combat the progress of the virus, giving affected individuals a healthier lives and longer lifespans.

+== Structure == HIV structure consists of the outer coat, known as the viral envelope, that is made up of two layers of lipids derived from an infected individual. On the virus membrane there are two different proteins embedded within it. A protein called gp120 is a glycoprotein that allows the virus to attach itself to the white blood cells within the human body. In addition, a protein called gp41 is another glycoprotein that allows the virus to pass through a cell. These proteins are the main focus to anti-retroviral medications because they are crucial in the infection of a host cell.

Within the viral envelope contains all of the genetic information that is needed to infect a host cell. A viral core consisting of 2000 proteins protects the viral DNA along with all of the enzymes necessary for infection, including integrase and reverse transcriptase. In addition, the virus contains three structural genes that allow it to make more virus particles as well having six regulatory genes to control the virus's ability of infecting a cell; these genes include tat, rev, nef, vif, vpr, and vpu.

How HIV Infects a Cell
One of the unique properties of HIV is that it is a retrovirus; it carries its genetic material as RNA and creates viral DNA with the help of an enzyme called reverse transcriptase. It targets the T-cells in the human body because it contains genetics information in the form of DNA, which is crucial to HIV infection. However other cells, like macrophages, B-cells, and monocytes can be infected as well. Through many years of research, the method by which HIV infects a cell has been revealed. The virus begins its infection by first binding itself to the receptor proteins on a human cell, which enables the membranes to fuse and allows the virus to enter the cell. Once inside the cell, HIV has an enzyme known as reverse transcriptase that makes viral DNA from the RNA already present in the HIV core. Next, the DNA gets integrated into the human DNA via the enzyme integrase that was also present in the viral core. At this stage, the host cell becomes the site of replication for the virus and it creates viral RNA and long virus protein strands. The proteins and viral RNA are assembled into immature cells and eventually pinch off and leave the mature cell. HIV protease, another key enzyme in HIV reproduction, cleaves the immature strands out and splices together the mature proteins (similar to the function of spliceosome making mature proteins from introns and exons) to create mature virus particles, which are then free to infect other cells. This cycles just propagates and amplifies as the virus infects more and more cells.

How is HIV Spread
HIV thrives inside semen, vaginal fluid, blood, and other bodily fluids. It is spread via unprotected sex, sharing needles, and breast-feeding. HIV cannot be contracted through saliva, kissing, or other means of physical contact.

APOBEC3G: a Double Agent in Defense Against HIV
APOBEC3G (A3G) is an enzyme of the cytidine deaminases family. It is a host defense factor against the proliferation of HIV viruses under experimental conditions. HIV viral cells can only bind to host cells without the display of A3G on the surface. Some HIV viral cells contain Vif, Viral infectivity factor that degrades A3G before invading the. HIV viruses without Vif will less likely be penetrating a host cell displaying A3G enzymes on its membrane. However, it is also observed that A3G has the ability to aid in the mutation and proliferation of HIV viral DNA inside host cells. By mutating the sequencial HIV viral DNA, the new viral DNA can transcribe and mature without being noticed. A3G undergo two different mechanisms that lead to opposite effects. The deaminase-dependent mechanism leads to the proliferation of mutated HIV viral DNA, and the deaminase-independent mechanism, which prevent HIV viral DNA from translating and maturing.

A3G Deaminase-independent mechanism
A3G contains a C-terminus and an N-terminus. Attached to the C terminus is a zinc-dependent deaminase (ZDD fold). This ZDD fold is responsible for all the deaminase activity that A3G undergoes. A3G was found to have an innate ability to bind nonspecific RNA and single strand DNAs. This property is essential to the deaminase-independent antiviral mechanism that A3G has to potentially stop HIV viral proliferation. When both A3G and HIV viral DNA are introduced inside a host cell. First, A3G binds to the nucleic acids within a host cell to block the tRNA strands that deliver the matching amino acids that the HIV viral DNA requires to elongate. Without the amino acids, the HIV viral DNA cannot transcribe and translate into mature viral DNA, thus, the antiviral activity of A3G.

A3G deaminase-dependent mechanism
The A3G deaminase-dependent mechanism binds to HIV viral single stranded DNA and catalyzes dC to dU in the primary strand. This point mutation can cause the translation of a mutated HIV viral DNA. After translation, the second strand would contain dA instead of dG. Some mutated viral DNA can integrate into the host cell chromosomes, leading to the expression of viral protein with missense or nonsense substitutions. Viral replication would continue to produce both HIV DNAs leading to viral proliferation. These mechanistic pathways are actually observed in HIV infected patients, where numerous dG to dA mutations were identified in their cellular sequences.