In order to understand the molecular processes by which HIV infiltrates a human cell and replicates, consider the following:

Franz Schroeder is an out-of-work conductor living in Vienna. He’s just finished his latest masterpiece, but all the orchestras in Vienna are booked for the current season. However, looking in the newspaper one day he sees a notice: “Royal Symphony Orchestra of Copenhagen seeks orchestra master. Auditions ongoing.” Overjoyed, Franz immediately boards a plane to Denmark, carrying the newspaper clipping with him to identify the Royal Symphony Orchestra Hall. After hours of searching the streets of Copenhagen, he finds an imposing building at the corner of the marketplace. He checks the name on the billboard outside against his clipping: they are the same.

However he finds that the building is locked. Inquiring with the doorman, Franz learns that he needs to get a key from the bank across the street, which is helping to organize the search for an orchestra master for the Royal Symphony. Obtaining the key from the bank, Franz finally enters the symphony hall and, when greeted by the musicians, realizes he has a large problem: they speak Danish, and he only knows German! The sheet music itself may be universal, but Franz’s liner notes are in his native script.

Returning to the bank across the street, the frustrated conductor manages to get the address of a translator, who returns with him to the symphony hall. After a few hours of work, she is able to transcribe his liner notes into Danish, and musicians begin playing Franz’s latest work. They are impressed, and decide to hire him, inserting his piece into their current repertoire. However, the old walls of the Royal Symphony Hall are fragile, having been disturbed by an earthquake a few years back. While this hasn’t been problem so far, Franz’s symphony happens to contain the exact vibrational frequencies that will cause the building to collapse, which it does after the first few performances of the season.

So how does the story of this disastrous performance relate to viral replication? Let’s start with the conductor.

The Conductor: HIV

millimeter across, the HIV virion appears as a spherical plasma membrane, or viral envelope, encasing an inner core of viral proteins and RNA⁴³. Like most biological membranes, the viral envelope of HIV consists of a lipid bilayer punctuated by spines of glycoproteins or protein molecules that combine carbohydrates in their structures⁴³. Underneath this bristling exterior is a layer called the matrix, a type of “inner envelope” composed of only proteins⁴³. If the envelope is the “skin” of the virion, then this inner layer of protein forms a “skeleton.” Finally, encircled by the matrix is the capsid, a projectile-shaped mass of protein⁴³. The contents of this protein bullet are the HIV’s RNA genome and the three enzymes it needs to replicate it: protease, integrase, and reverse transcriptase⁴³. While the protease clips viral proteins into their final, functional form, and integrase allows the viral genome to be integrated into its host’s genome, reverse transcriptase is perhaps the most important of the three: by translating RNA instructions into DNA language, it allows HIV to replicate using it host’s machinery⁴³. This is how the HIV “conductor” translates its “sheet music.”

The Sheet Music: the HIV genome

If the immense human genome is a symphony, then HIV has only a few lines of music by comparison. However, even these nine RNA genes are sufficient for the virus’ deadly activity⁴⁵. These nine genes, when produced by the cell’s protein-making machinery, are divided into three functional classes:*

Structural Proteins: These are the proteins found in viral envelope⁴⁶

Regulatory Proteins: These proteins ensure that the viral RNA is copied correctly, during infection⁴⁶

Accessory Proteins: These four proteins determine the effectiveness with which HIV colonizes a cell⁴⁶

How the Conductor Moves: HIV Transmission

Clearly, unlike our conductor, the virus can’t move between bodies by boarding a plane. So how does HIV actually move between human bodies and into the blood stream where it causes so much damage? The most common means of transmission is unprotected sex of any sort – vaginal, oral, or anal. The virus enters the body through the mucosal lining of any of these organs⁴⁷.

In addition, there are also a number of non-sexual means of transmission to keep in mind as well⁴⁷. Since the virus is present in the serum of infected individuals, exchanging needles (a common practice among intravenous drug users) can serve as a means of infection⁴⁷. Similarly, there have been documented cases in which AIDS was contracted through a blood transfusion though transmission through this particular route is almost non-existent with the development of routine HIV testing⁴⁷. Blood or breast milk can also facilitate transmission of the virus between mother and child, a phenomenon responsible for a proportion of HIV proliferation in sub-Saharan Africa^47,48.

The Symphony Hall: Human Immune Cells

Once inside the human body – whether it is carried in by blood or other bodily fluids – the HIV conductor looks for the right home, using its glycoprotein spines to prod adjacent cell surfaces. What it is looking for is the protein CD4, a protein found jutting from the membranes of two kinds of white blood cells: “helper” T cells and macrophages⁴³. Helper T Cells excrete chemicals that help fight off invading pathogens; macrophages directly engulf these intruders⁴³. Thus, like our conductor, the virus locates the right place to play its RNA notes.

However, even having located the CD4 “sign”, the virus still needs a key to enter. This key is the co-receptor, a second molecule that completes the link between the virion and the cell. This link allows HIV to be absorbed in an envelope of plasma membrane⁴³. The specific co-receptor molecule employed by the virion varies based on how far HIV infection has progressed⁴³. For example, during the early stages of infection the co-receptor CCR5 is the virion’s exclusive target⁴³. However, over time a wide array of molecules can be utilized as secondary attachment points by HIV⁴³.

Translating the Sheet Music: Reverse Transcriptase

Having entered a white blood cell in a pocket of plasma membrane, HIV uses reverse transcriptase to copy its RNA genome into DNA⁴³. The integrase enzyme then cuts and pastes the DNA into the host genome⁴³. At this point, the virus has two options: it can either hide from the immune system in its untranslated form, or forge ahead with the creation of new copies of itself.

This first possibility accounts for the frequent gap between HIV infection and the appearance of AIDS symptoms. While on a microscopic scale HIV’s replication is dramatic, it is only slowly recognizable in the human scale. In fact, it rightfully earns its title as a lentivirus, a class of viruses sharing an extended period from the point of infection to the first clinical signs of disease⁴³. For HIV, this “incubation period” can last 10 or more years, a pause explained on a cellular level by the initially aggressive response to infection by the body’s immune system⁴³. However, the high number of cells where the virus is replicating coupled with rapid mutations that hides it from the body’s homing systems, ensures that not every virus is destroyed⁴³. Also, the viral genome sequence can remain invisible to the immune system by remaining latent (though integrated) in the host genome⁴³. Even the trace amounts of virus remaining are responsible for the devastating clinical symptoms that ultimately result⁴³.

Alternatively, the virus borrows its host’s enzymes, and it’s a simple matter of the cell carrying out its normal transcription and translation processes on this foreign DNA sequence, producing the proteins and RNA strands necessary to build a new virus. Both these components, once they are relocated from the nucleus to the cytoplasm, are bundled into a pocket of plasma membrane⁴³. However, the new virus must use the enzyme protease to finish assembly, since the proteins that compose its inner core have to be cut to a specific size before the component can be turned into a fully operational virus⁴³. Like the orchestra hall weakened by the music performed within, the cell begins to crumble after repeated viral replications, unleashing new virions into the body.

Precisely how the HIV destroys its host cell, though, has not yet been entirely resolved⁴³. One theory is that the high volume of viral replication within the host simply overwhelms it, preventing its internal machinery from functioning⁴³. The virus may also signal the cell to kill itself, or other blood cells to engulf the host^43,47.

Comprehension Questions:
1. What are the components of the HIV virion?
2. What are the stages of its replication?
3. What enzyme does the virus use to replicate its RNA genome?
4. What molecule allows the HIV virion to stick to its target cell?