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Virology - HIV

Introduction to HIV

The human immunodeficiency virus (HIV) is a deadly retrovirus that leaves the body vulnerable to opportunistic infections. It does this by infecting cells of the immune system and destroying them. This unique niche means that it is extremely difficult for the immune system to detect the virus and destroy it. Infection with HIV can lead to a condition called acquired immune deficiency syndrome (AIDS), but not all patients develop this condition.  

HIV was first discovered in 1983 and since then, there have been over 60 million people infected and 30 million deaths. The magnitude of this problem has led to the allocation of huge amounts of money and time to the study of HIV and the development of treatments and a vaccine. 

HIV is transmitted in a number of ways, but the most common is sexual contact with an infected person, which accounts for 80% of HIV infections in the world. It is prevalent in areas where contraception use is limited and sanitation is poor. The worst affected areas include sub-Saharan Africa and Southeast Asia, where an estimated 26.5 million people are infected. 

 

Definitions:

Retrovirus A virus with an RNA genome that is able to convert it into DNA and insert it into the DNA of its host cell.  

 Opportunistic infection An infection by a microorganism that does not usually cause disease in humans.

Niche A place where an organism lives. In the case of HIV, this refers to the cell type that it infects, reproduces and replicates inside of.

Budding The release of new viral particles from a host cell, during which the virus acquires its viral envelope.

Glycoprotein A protein that is linked to a carbohydrate. They are found on the surface of human cells.

Dormant An organism that is alive, but not actively growing and dividing.

T lymphocytes A group of white blood cells that are able to detect and remove foreign particles, known as antigens, from the body.

Transcription The process of converting DNA into RNA. The reverse of this is converting RNA into DNA, as in reverse transcription.

Virion An infectious particle that transports the viral genome to a host cell.

Selective toxicity A drug that is toxic to pathogens, without damage to humans.

 

Evolution of HIV

There are two subtypes of HIV: HIV-1 and HIV-2. Both viruses evolved independently from similar viruses in chimpanzees and sooty mangabeys respectively, known as simian immunodeficiency viruses (SIVs). Evidence has shown that SIVs crossed over to humans in south-east Cameroon in Africa, and mutated to become better adapted to infecting humans. The crossover most likely occurred from interaction with contaminated blood and tissue of infected primates. Hunting and the eating of meat from primates is extremely common in Africa, and so this is most plausible explanation for the crossover. 

 

 

Structure of the virus

HIV is a tiny machine. It is not capable of producing its own energy or replicating its own genome. It is a parasite - it uses the cellular machinery of its host, such as ribosomes, to reproduce. The genome itself is very primitive; it contains just nine protein-coding genes, compared to 20,000-25,000 in humans! These genes encode for all the essential structures of the virus, but do not code for the machinery to produce them. Because of this, HIV cannot replicate outside of human cells.

Figure 1: A scanning electron micrograph of HIV virions (green) budding from a cultured immune cell

Structure Of HIV

Structure Of The HIV Virus

The virus consists of a protein case, called a capsid, inside a viral envelope. The capsid contains two copies of its single-stranded RNA genome, and a few structural proteins. The viral envelope is a lipid bilayer, which is derived from the host cell during budding. The envelope is divided into subunits, and each subunit consists of many copies of two different glycoproteins: gp120 and gp41. The viral envelope is highly variable and confers a unique combination of antigenic diversity. 

 

Infection with HIV

Healthy people that become infected with HIV usually experience flu-like symptoms that can last up to six weeks. The most common symptoms are fever, sore throat and body rash, although some patients can feel drowsy and have joint and muscle pain.  After these initial symptoms, the virus can become dormant for many years: this is known as an asymptomatic HIV infection.

During infection, HIV attaches to receptors using gp120 on the surface of immune cells, most commonly T lymphocytes. This induces membrane fusion, where the virus is engulfed by the target cell and the contents of the viral envelope are released into the cytoplasm of the host cell. Once inside the cell, HIV converts its RNA genome into DNA, a process known as reverse transcription. This process requires the enzyme reverse transcriptase and the resulting DNA is known as a provirus. The provirus is integrated into the genome of the host cell using an integrase enzyme. Every time the DNA inside the host cell is replicated, the provirus is replicated too.

When the host cell is activated, the provirus DNA is used to make a polyprotein, which is a continuous protein made up of all of the HIV proteins. The polyprotein is later broken up into individual functional proteins using a viral protease enzyme. The proteins are used to make a new capsid and assembly takes place close to the plasma membrane. When the new virus is assembled, it fuses with the membrane and is released. Once outside the host cell, HIV alters some of its proteins so that it becomes a mature virion: it can now go on to infect more cells.

Accuracy of reverse transcriptase

The reverse transcriptase enzyme is very error-prone and doesn’t copy the HIV genome perfectly every time it is converted to DNA. Because of this, mutations are introduced, producing a lot of genetic diversity between viruses. The mutations can be advantageous or damaging; advantageous mutations contribute to avoiding host defences while damaging mutations may mean the virus cannot infect more cells. The gp120 protein is one of the most highly variable components of HIV. Since this is a surface protein, the variability contributes to evasion of the host immune response. Mutations can also lead to drug resistance, which is why HIV drugs are administered in combination with other drugs (see treatment of HIV). 

 

 

Treatment of HIV

Currently, there is no cure for HIV. Since the virus evolves approximately a million times faster than humans, developing treatments has been a huge challenge. Because HIV uses the host cell machinery, any treatment must exhibit selective toxicity. There are over 20 antiretroviral drugs available against HIV in the UK. Antiretroviral drugs do not cure an HIV infection; instead, they suppress the virus to very low levels. These drugs have increased the life span of HIV sufferers and they are able to lead an almost entirely normal life, but they have to take the drugs for the rest of their lives.

Antiretroviral drugs are administered in combination with other drugs, and can be combined into one pill, which is known as combination therapy. The combination of a variety of drugs that target different aspects of HIV is known as Highly Active Antiretroviral Therapy (HAART). It consists of drugs that target different things, such as virus-specific enzymes, or DNA replication. HIV can quickly become resistant to a single drug due to its high mutation rate, so using a combination of drugs decreases the chances of resistance arising. It also increases the chances of the treatment being effective over long periods of time.

 

 

Figure 2: Thanks to new treatments, families can lead almost normal lives.

HAART has been shown to be effective, but it relies heavily on patients taking their medication correctly and regularly. Even if a patient only misses a couple of doses, it severely reduces the chances of the treatment working. Patients can experience severe side effects due to the antiretroviral drugs. Common side effects include: nausea, diarrhoea, skin rashes and extreme tiredness. However, not all patients experience side effects and the outlook for patients living with HIV is very positive. 

 

Further Reading

World Health Organisation HIV Section: www.who.int/topics/hiv_aids/en/

Chapter 1 of HIV Management In Australasia, a great basic introduction to HIV:  http://www.ashm.org.au/images/Publications/Monographs/HIV_Management_Australasia/HIV_Management-Chapter_1.pdf

 

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