World AIDS Day: Understanding HIV
December 1 marked World AIDS Day, an international day dedicated to raising awareness of the AIDS pandemic caused by the spread of human immunodeficiency virus (HIV) infection. According to UNAIDS, 37.9 million people globally were living with HIV at the end of 2018. Although the development of life-saving antiretroviral therapies has changed the disease from the death sentence it once was to a chronic disease, about one-third of those infected—24.5 million—do not have access to these drugs. And for those that do have access, the treatments come with major side effects, including fatigue, nausea, muscle pain, and even kidney or liver damage.
These statistics illustrate the need to improve access to treatments as well as to develop effective vaccines and, ultimately, a cure for the disease. This week, we cover the basics of the HIV lifecycle, describing how it infects cells and makes people sick. Next week, we’ll cover how drug discovery researchers have used their understanding of the viral lifecycle to develop treatments that are currently on the market, and take a peek at new developments in the drug discovery pipeline.
HIV causes acquired immunodeficiency syndrome (AIDS) because it infects and disables helper T-cells, a critical type of white blood cell. This incredibly destructive power is carried out by just a handful of proteins and a lipid envelope encapsulating the RNA-based genetic material.
On the virus’ surface are the proteins glycoprotein 120 (GP120) and glycoprotein 41(GP41). A glycoprotein is simply a protein with carbohydrates attached to it. This type of protein is often found on the surface of viruses as well as human cells. They play a role in cell-cell interactions. The HIV glycoproteins enable the virus to attach to and fuse with target T-cells in order to initiate the infectious cycle. Other key viral proteins include capsid proteins, which protect the viral RNA, and matrix proteins, which are thought to play a role in viral assembly.
HIV is a retrovirus, meaning its genome is single-stranded RNA (ssRNA). For retroviruses to multiply, they need to convert their ssRNA genome into double-stranded DNA (dsDNA). This is accomplished by an enzyme contained within the virus capsid called reverse transcriptase (RT). Once ssDNA has been formed from RNA, cellular DNA polymerase enzymes convert it to double-stranded DNA (dsDNA).
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The Viral Lifecycle
Scientists have learned how HIV enters the cell, replicates and releases new viral particles. Let’s take a look at the steps:
- Receptor binding: Viruses can only replicate inside cells and so must gain entry to host cells. GP120 binds to the receptor proteins CD4 and CCR5 on the surface of helper T-cells. Receptor binding selectivity accounts for the limited host range of most viruses.
- Host cell entry (Fusion): After receptor binding, the virus’ membrane fuses with the host cell membrane, allowing the capsid to enter the cell.
- Release of viral RNA and reverse transcription: The capsid shell is broken down by the cell and the viral RNA serves a template for the viral RT to make DNA.
- Integration of viral genome into host cell genome: The viral dsDNA is then integrated into the host cell DNA.
- Production of new viral proteins: The integrated DNA produces viral RNA and viral proteins using the host cell’s machinery. This is why viral infection is sometimes referred to as “hijacking” a cell.
- Viral assembly: New virus particles assemble with the viral RNA and viral components created. Before leaving the cell, the viral proteins that belong on the viral envelope are added at the plasma membrane and the newly-formed virus leaves the cell to infect other host cells.
The HIV genome is known to mutate frequently. This is why successful antiviral regimens involve a cocktail of different drugs, and why drug developers must continuously discover new drugs—as the virus mutates, resistance to different drugs emerges. The source of that high mutation rate? The viral RT enzyme is “sloppy” meaning it makes lots of mistakes when copying the viral genome.
By deciphering key steps in viral infection and replication, researchers have been able to come up with drugs to stop the virus. Join us next week to find out how these drugs work, as well as an update on what’s in the pipeline.