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HIV – will there ever be a cure?

What is HIV?

The human immunodeficiency virus (HIV) is a retrovirus composed of Ribonucleic Acid (RNA) and reverse transcriptase (an enzyme) encased within a capsid which lies inside a lipid bilayer with attachment proteins (glycoproteins). HIV causes Acquired Immune Deficiency Syndrome (AIDS) which leads to a severe illness and potential death due to a weakened and vulnerable immune system. It does this because it infects CD4 T-lymphocytes; these are white blood cells that recognise harmful microorganisms and stimulate an immune response.1

HIV diagram

Fig. 1: HIV diagram

HIV diagram20

Copyright, www.quia.com .

HIV can be passed on through bodily fluids e.g. through shared needles or sexual intercourse, but not sweat or urine. The first symptoms of HIV include a body rash, fever, sore throat, swollen glands, tiredness, muscle pain and joint pain. As the virus spreads, more serious symptoms including weight loss, skin conditions, chronic diarrhea, recurrent illnesses, and night sweats often occur. That’s why undergoing an hiv antibody test can be quite an essential.1  

Statistics and facts

  • Over 103,000 people are living with HIV in the UK2
  • 17% of people with HIV in the UK are undiagnosed2
  • About ⅔ of people living with HIV are men and ⅓ are women2
  • Over 60% of people living with HIV and accessing care are aged between 35 and 54, but there are significant numbers both of young people and older people now living with HIV2
  • 17.1 million do not know they have the virus2
  • 15.8 million people living with HIV globally are accessing antiretroviral therapy2
  • Around 22 million people with HIV do not have access to treatment2
  • The number of new HIV infections has declined globally by 35% since 20002
  • 1.2 million AIDS-related deaths in 20142
  • 17 million people were accessing antiretroviral therapy3
  • 36.7 million [34.0 million–39.8 million] people globally were living with HIV3
  • 2.1 million [1.8 million–2.4 million] people became newly infected with HIV3
  • 1.1 million [940 000–1.3 million] people died from AIDS-related illnesses3
  • 78 million [69.5 million–87.6 million] people have become infected with HIV since the start of the epidemic3
  • 35 million [29.6 million–40.8 million] people have died from AIDS-related illnesses since the start of the epidemic3
  • HIV is most dominant in Sub-Saharan Africa4
Map showing the abundance of HIV

Fig. 2: HIV map

Map showing the abundance of HIV21

Copyright, http://www.who.int/gho/hiv/en/ .

  • There are 2 main types of HIV which can be identified using Enzyme-linked Immunosorbent Assays (ELISAs). These types are split into groups and subtypes:
HIV types and strains

Fig. 3: HIV types

HIV types and strains22

Copyright, www.avert.org .

  • HIV originated from a type of chimpanzee in Central Africa which had the simian immunodeficiency virus (SIV). It is believed that SIV then mutated into HIV5
How does HIV proliferate?

Once HIV has invaded the body it starts by attacking the T-cells (T lymphocytes), a white blood cell that initiates cell-mediated immunity. Its attachment proteins (gp120 and gp41) bind with either CD4, CCR5 or CXCR4 receptors making the T-cell respond by allowing in the virus. The virus leaves behind its lipid bilayer along with the attachment proteins in the cell membrane and then the capsid disperses, releasing the RNA and reverse transcriptase enzyme. This enzyme copies the RNA into a Deoxynucleic Acid (DNA) template then copies the DNA to form a double helix. Integrase (another enyzyme) carries the DNA of the HIV into the nucleus and cleverly inserts it in the T-cells genomic DNA. During transcription and translation this DNA is replicated into messenger Ribonucleic Acid (mRNA) and transported out of the nucleus. The mRNA is decoded by ribosomes and binds transfer Ribonucleic Acid (tRNA) which deposit amino acids. These amino acids form polypeptide bonds and become viral proteins. The proteins and the replicated RNA form the virus which buds off the T-cell cell surface/plasma membrane and attacks other CD4 T-cells. The protease inside edits some of the proteins to make them functional – this is called maturation.

HIV replication

Fig. 4: HIV replication

HIV replication23

Copyright, colgateimmunology.blogspot.com.

Why is it taking such a long time to find a cure?

HIV is a complex, cunning virus that invades T-cells, important cells of the immune system that normally detect and destroy viruses, , also its antigens easily mutate due to sloppy replicating by reverse transcriptase when the RNA is copied into DNA so that the body cannot recognise it. This means that it is extremely difficult to create a vaccine for.

Current treatment

Antiretroviral drugs treatment

Antiretroviral drugs (ARVs) combined with HIV Prevention programs work by inhibiting viral enzymes such as reverse transcriptase, integrase and protease. They slow down, but do not stop, the progression of HIV. However, HIV can become resistant to these so 3 or more must be used at once. The 6 drug classes are:

  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  • Nucleoside reverse transcriptase inhibitors (NRTIs)
  • Protease inhibitors (PIs)
  • Fusion inhibitors (blocks HIV envelope from fusing with T-cell membrane)
  • CCR5 antagonists (CCR5s) (also called entry inhibitors)
  • Integrase strand transfer inhibitors (INSTIs)
Antiretroviral drugs inhibiting HIV replication

Fig. 5: Antiretroviral Therapy (ART)

Antiretroviral drugs inhibiting HIV replication24

Copyright, https://aids-hiv.wikispaces.com/Antiretroviral+Therapy.

These must be taken every day for the rest of a patient’s life for maximum survival. 67 Unfortunately, as with most drugs, there are some side effects such as nausea, fatigue and diarrhoea.8

PrEP and PEP

Pre-exposure prophylaxis (PrEP) is a prevention method for people who are at very high risk of contracting HIV. Truvada is the drug which is made up of two medicines and is a nucleoside reverse transcriptase inhibitor (NRTI). When it is taken every day it has been found to reduce the risk of contracting HIV by about 90%. However, it is more effective when combined with other prevention methods. There are some side effects such as nausea caused by this drug. There has been recent debate about this drug as the NHS is unkeen to provide it for free but the High Court ruled that the NHS should provide it. It is currently available in the UK.9

Post-exposure prophylaxis (PEP) is a prevention method using antiretroviral medicines (ARV) and must be used within 72 hours after being infected with HIV in order to be effective (the sooner, the better). However, it is not 100% effective. It should be taken for 28 days.10

Immune checkpoint blockers

Usually associated with cancer immunotherapy, immune checkpoints are negative regulators of T-cell activation, T-cell replication, and effector functions including cytokine production. Antibodies blocking immune checkpoints have been hypothesised to disrupt the resting status of T cells and hence wake dormant infected T-cells. This helps other strategies to recognise and eliminate all of HIV infected T-cells in the body.11

Immune checkpoint blockers

Fig. 6: Immune checkpoint blockers

25

Copyright, http://www.pharmaceutical-journal.com/news-and-analysis/feature/immune-checkpoint-inhibitors-bring-new-hope-to-cancer-patients/20067127.article .

Potential cures

The Berlin Patient

Timothy Ray Brown is supposedly the only man to be cured of HIV. He was born in 1966 in Seattle, Washington and studied in Berlin. In 1995 he was diagnosed with HIV and used antiretroviral therapy to control it. Later in his life he was discovered to have acute myeloid leukaemia (AML). In 2007 he underwent stem cell transplantation after unsuccessful chemotherapy. His Berlin doctors chose an unrelated donor who screened positive for the homozygous CCR5∆32 mutation. This mutation changed the shape of the proteins on the T-cells’ membranes, therefore HIV could not bind and enter. Despite complications and undergoing a second transplant from the same donor in 2008, the outcome was a success. Therefore it is assumed that these CCR5 receptor mutations protect people from HIV infection.12

Timothy Ray Brown

Fig. 7: The Berlin Patient

Timothy Ray Brown26

Copyright, http://www.ibtimes.co.uk/timothy-ray-brown-worlds-only-person-cured-hiv-speaks-about-stem-cell-transplant-experience-1482179 .

The CCR5 mutation means that CCR5 doesn't appear at the cell surface therefore HIV cannot bind to the T-cell

Fig. 8: CCR5 mutation

The CCR5 mutation means that CCR5 doesn’t appear at the cell surface therefore HIV cannot bind to the T-cell27

Copyright, http://www.cell.com/trends/genetics/fulltext/S0168-9525(06)00124-7 .

Gene therapy

Scientists have come up with several methods of trying to find a way of getting the immune system to recognise HIV infected cells.

Calimmune are currently doing a study on a gene medicine called Cal-1 which blocks CCR5 receptors and hence HIV. This was inspired by the Berlin Patient. 13

The ‘Shock and kill’ strategy involves using Histone deacetylases (HDAC) (enzyme) inhibitors, immune-stimulant drugs that reactivate the reservoir cells, making them visible to the immune system.14

'Shock and kill' method

Fig. 9: ‘Shock and kill’ method

‘Shock and kill’ method28

Copyright, http://www.nature.com/nature/journal/v487/n7408/fig_tab/487439a_F1.html .

PD-1 inhibitors are antibodies that increase CD8 T-cell proliferation which help kill infected CD4 T-cells. These are also be used to treat cancer e.g. Nivolumab and Ipilimumab can cause the immune system to attack a person’s own organs and tissues.1914

Professor Lucy Dorrell of the Oxford University, together with Immunocore, has developed ImmTAVs which are two-headed proteins and a possible cure for HIV. One end consists of a genetically engineered T cell receptor that is affinity enhanced (made to bind to an antigen more strongly) to detect HIV proteins in an infected cell, even when they are present at very low levels. The other end is an antibody that binds to CD3, which is present on the CD8+ T-cells that kill virus-infected cells. The ImmTAV can therefore recruit a large number of CD8+ T cells and re-direct them to purge the HIV-infected cells.15

Could Clustered Regularly Interspaced Palindromic Repeats (CRISPR) be the answer?

Unfortunately not currently; cutting out HIV DNA using the Cas9 enzyme allows the DNA to mutate and produce new copies of HIV. Usually when DNA is cut, a base is deleted and the gene becomes deactivated but this did not work in the T-cells in a recent experiment. However, there are hopes that CRISPR can instead be used to modify T-cells to tackle the virus.16

Broadly neutralising antibodies (bNAbs)

Broadly neutralising antibodies (bNAbs) have been found in blood samples from some HIV patients whose immune systems can naturally control the infection. These antibodies may protect a patient’s healthy cells by recognizing a protein called the envelope spike (antigen), present on the surface of all HIV strains, and inhibiting, or neutralizing, the effects of the virus.17

Toll-like receptor (TLR) agonists

Toll-like receptors on immune cells are part of the natural or immediate immune response, but they promote adaptive immunity (cells that prevent pathogen growth), or recognition of and response to specific viruses and other pathogens. TLR7 activation leads to increased antigen presentation and enhanced activity of natural killer cells, antibody-producing B-cells, and CD4 and CD8 T-cells. These receptors can be manipulated in order to fight HIV.

Conclusion

Despite the lack of a definite cure for HIV, scientists across the world are carrying out research on HIV and with fast developing technology and more money being invested into research, there are likely to be great advances made in this field within the next decade.

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