Helen Carter

The Science of HIV & AIDS in the UK

The biology and impact of the world's worst pandemic

In the UK the plight of AIDS today gets much less attention from the public and the media than it did back in the 1980’s and early 1990’s. This often leads to the misconception that AIDS is no longer a problem in this country; in reality, the increasing prevalence of HIV in the UK proves that this is simply not true.

Worldwide, accepted definitions, facts and figures on HIV and AIDS include:

• Acquired immune deficiency syndrome (AIDS) is a collection of symptoms and infections that result from specific damage to the immune system by the human immunodeficiency virus (HIV).

• HIV is transmitted through the direct contact of a mucous membrane, or the bloodstream, with a bodily fluid containing HIV.

• The late stage of the condition leaves individuals prone to opportunistic infections and tumours.

• Whilst antiretroviral treatments for AIDS and HIV exist to reduce the mortality and morbidity of HIV infection to date there is no known cure; even access to these antiretroviral treatments is not routine in all countries.

• Researchers believe that sometime in the 1930’s a form of simian immunodeficiency virus jumped to humans who butchered or ate chimpanzee bush meat in the Democratic Republic of Congo. The virus became HIV-1, the most widespread form found today.

• The world’s first known case of AIDS has been traced to a sample of blood plasma from a man who died in 1959. During the 1970’s HIV continued to spread undetected around the world and hence the pandemic began. Today an estimated 40 million people are living with HIV worldwide.

• As of January 2006, the Joint United Nations Programme on HIV/AIDS and the World Health Organization estimate that AIDS has killed more than 25 million people since it was first recognised on June 5^th, 1981.

• The stigma associated with HIV/AIDS is severe and extends to providers and volunteers involved with the care of HIV infected patients. AIDS exerts its toll also on societies, devastating their economies, decimating their labour forces and orphaning children.

• Thus, it is one of the most destructive pandemics in recorded history, surpassing even the Black Death. By 2015 it is estimated that 60 million people will have died of AIDS.

• In 2004 the global spending on AIDS was $6.1b. Estimated global AIDS spending required in 2007 for prevention and care is $20b. Less than 3% of all money spent on AIDS goes towards developing a vaccine for the disease.

• In February 2007 a study published in the Lancet showed that male circumcision could dramatically reduce the risk of HIV infection. The randomised control trial showed that circumcised men were 60% less likely to pick up HIV. This means that if all of the 2.5 million men in KwaZulu-Natal province had been circumcised, 37,000 new HIV infections could have been prevented in 2007 alone.

The history of HIV / AIDS in the UK
The first recognised case of AIDS in the UK was recorded in December 1981, when doctors at Brompton Hospital in London reported the case of a 49 year old homosexual man who had died ten days post referral. He was suffering from a rare infection that almost always occurs in individuals with severely weakened immune systems. Doctors believed that the condition might be linked to similar cases that had been occurring amongst gay men in the US.

Throughout the 1980’s the number of newly diagnosed HIV infections per year in the UK rose steadily. The figure plateaued during the 1990’s, averaging about 3,000 cases per year, but then increased dramatically after 1999. By 2005, the annual number of newly diagnosed infections was more than 7,500, and an estimated 63,500 people over 15 years of age were living with HIV in the UK, 20,100 (32%) of whom were believed to be unaware of having been infected. Since the pandemic began there have been 17,161 known UK HIV deaths.

The science bit...
HIV is a retrovirus, meaning that it uses a chemical relative of DNA, called RNA (ribonucleic acid), as its genetic material. It primarily attacks components of the human immune system, including T lymphocytes and other white blood cells that carry "CD4" receptors on their surfaces. HIV enters its target cells by binding to both the CD4 molecule and a chemokine "co-receptor", of which there are two forms, CCR5 and CXCR4. Once inside the cell the virus makes a DNA copy of its genome and then uses an enzyme it carries with it, called integrase, to insert this copy into the cell’s own DNA. Either immediately, or after a period of dormancy known as latency, the virus then hijacks the cell and turns it into a virus factory. The newly produced viruses leave the infected cell, destroying it in the process, and move on to invade other CD4+ cells, which are mainly T lymphocytes. These are the cellular linchpins that help to marshall the other components of the body's immune system. As their numbers dwindle the ability of the body to mount an effective immune response to combat other invaders, including bacteria, viruses and fungi, is progressively weakened. This means that HIV kills by slowly destroying the immune system and leaving the infected individual vulnerable to infection by so called "low grade" or opportunistic bugs.

What is the natural history of HIV infection? What are the symptoms?
Most infections with HIV are initially "silent", meaning that a person may not notice that anything is wrong. Then, several weeks after infection, patients often develop a "seroconversion illness", which characteristically includes flu-like symptoms, lymphadenopathy (swollen lymph glands), fevers, loss of appetite and weight, diarrhoea and general lethargy and malaise. During this time infected individuals have very high levels of virus in the bloodstream (10 million viruses per millilitre of blood is not uncommon). The reason for this very high viral load is that the virus is able to replicate (grow) largely unchecked because the immune system has yet to mount an effective suppressive response, including the production of antibodies that can mop up viral particles. As a result the number of CD4+ T cells can fall to very low levels at this time, and the patient is highly infectious.

But then the immune system kicks in, and the virus largely retreats, hiding within lymphoid tissues and replicating only very slowly. The levels of virus in the blood stream become much lower, the patient is less infectious and feels well. Untreated, an infected individual usually remains "healthy" like this for 5 to 15 years.

Structure of the human immunodeficiency virus (HIV) viral particle.

However, the body’s immune system only has a limited ability to control HIV. The virus makes mistakes when it copies its genetic code. Roughly once in every 10,000 genetic letters that are copied the virus introduces the wrong genetic base. Since the genome contains about 9000 bases in total, almost every genome copied will contain an error. The result is that these genetic mistakes alter the appearance of the virus and so make it harder for the immune system to recognise and keep up, because it is trying to hit a moving target. Eventually, through this progressive shape-shifting, the virus takes on a form that the immune system cannot respond to, and at this point the pace of the infection begins to accelerate and the number of CD4+ T cells begins to fall.

When the CD4 count falls below a critical threshold (400 per microlitre of blood) the body is no longer able to defend itself. At this point an HIV-infected individual is said to have AIDS, and patients usually begin to develop opportunistic infections caused by organisms that would not normally affect healthy people. These include mycobaterial infections (caused by bacteria related to tuberculosis), the lung infection PCP (pneumocystis carinii pneumonia), oral and genital thrush, complications of CMV (cytomegalovirus), chronic diarrhoea and weight loss, toxoplasmosis, meningitis, dementia, and polyomavirus (JC virus), which is associated with a disease of the brain's white matter known as PML (progressive multifocal leucoencephalopathy). At this point patients are often prescribed prophylactic drugs to help ward off some of these infections including co-trimoxazole, which can slow down the progression of PCP.

Without treatment the median survival time after developing AIDS is only about 9 months. However, the rate of clinical disease progression varies widely between individuals from 2 weeks to 20 years. Many factors affect this rate of progression, including age, quality of health care and the presence of co-existing infections. An individual's genetic make-up also plays an important role because it's now becoming clear that some people are resistant to certain strains of HIV and although they become infected they do not seem to develop AIDS, or they do so only extremely slowly. There are even people who seem to be totally immune to infection with the virus. They carry a mutated cell surface marker called CCR5-delta-32, which prevents HIV from locking onto and invading their cells. Scientists hope that understanding what makes these people able to resist the virus may hold the key to future therapies to block infection amongst susceptible individuals.

Treatment
Whilst the number of people living with HIV is rising each year, the number of HIV infections that progress to AIDS has dropped dramatically since 1996. This is primarily the result of anti-retroviral therapies, which are available to slow the progress of the virus. These target essential components of the viral replication cycle and include reverse transciptase (RT) inhibitors, which interfere with the way the virus makes a complementary "cDNA" copy of its RNA genome, and protease inhibitors, which prevent the virus from cutting up the raw materials it needs to form new viral particles.

There are two types of drugs that block RT; these are known as nucleoside and non-nucleoside RT inhibitors. The nucleoside RT inhibitors are structurally very similar to normal DNA bases, but they lack a critical chemical group required to enable a DNA chain to grow. So when the viral RT inserts one of these altered bases into the copy that it's making of its genetic code, it can't finish the job because it cannot add the next genetic letter. An example of this type of agent is the drug AZT or zidovudine (azidothymidine). The non-nucleoside RT inhibitors, which include drugs like efavirenz and nevirapine, work slightly differently. They target the RT enzyme itself and bind to it, distorting its shape so that it cannot work properly. This stops the virus from replicating.

Protease inhibitors (PIs) only emerged more recently. They work by blocking the action of a protein-cutting enyzme carried by HIV, which is critical to the virus being able to assemble new infectious particles. If this enzyme is prevented from doing its job the virus cannot escape from the infected cell. An example of the PIs includes saquinavir, which is famous for being one of the first drugs produced by building a computer model of the shape of the viral enzyme and then designing a drug specifically to block it.

There are also agents known as fusion inhibitors, which are a newer type of drug that work by stopping HIV from binding with the CD4 receptors that it uses to enter cells. One being evaluated at the moment is called efurvatide.

Doctors have also recently been testing a new agent called raltegravir, which is an "integrase inhibitor". This prevents the virus from inserting a copy of its genetic material into the host cell genome. In a recent trial published in the Lancet doctors randomly allocated 179 patients with end-stage HIV / AIDS to receive either the active drug or a placebo. After 6 months the patients receiving raltegravir showed a 98% drop in the levels of virus in the bloodstream, compared with only 45% in the placebo group. The next step will be to test raltegravir in combination with other HAART regimen drugs in healthier patients who are not approaching the end-stages of their disease. It may make a considerable difference to the rate of disease progression.

So there are lots of drugs with which we can now combat HIV; but there's a problem. Because the virus frequently makes mistakes when it copies its genetic material it rapidly develops forms of the virus that are resistant to the action of these drugs. To slow down the rate at which this happens, rather than use them singly, a cocktail of drugs is used, often one from each of the three classes (nucleoside RT inhibitors, non-nucleoside RT inhibitors and protease inhibitors). This is known as HAART or Highly Active Antiretroviral Therapy (HAART) and it has dramatically reduced the evolution of viral resistance and prolonged the time during which an HIV-infected individual remains healthy and symptom free. However, it's worth emphasising that, whilst drugs help to control the spread of HIV to uninfected cells, unfortunately there is no treatment available at present that can eradicate HIV once integrated into a host.

Side effects...
This means that individuals using HAART have to take medication every day for the rest of their lives, and this often causes severe side effects. When individuals first start treatment they may suffer headaches, hypertension or general malaise (feeling unwell), although these usually improve or disappear with time. Other side effects can include diarrhoea, nausea, fatigue, anaemia, lipodystrophy, skin problems, neuropathy, mitochondrial toxicity, dyslipidaemia and bone problems. Whilst most people who take anti-HIV medications have some side effects it must not be assumed that everyone gets every side effect that has ever been written down.

Another problem with combating HIV is that a number of different strains of the virus can arise due to differences in selection pressures as the virus encounters different individuals, different drugs and different routes of spread. This can result in resistance to multiple anti-retrovirals and frequently occurs through a process called recombination. It occurs because each HIV virion carries two complete RNA genomic strands, meaning that homologous recombination can occur when a cell is coinfected with two different but related strains. The two strains may then exchange genetic material, including drug resistance traits. The process of recombination also therefore poses theoretical problems for the development of a safe vaccine against HIV.

The situation is also made worse by the fact that increasing numbers of patients are found to be carrying resistant forms of the virus at diagnosis, even before any drug therapy has been administered. Indeed, in 2004 an estimated 9% of new HIV diagnoses were found to be drug resistant strains, presumably acquired from individuals who had already received treatment. If patients then acquire additional strains of the virus with different resistance profiles the process of recombination can yield multiply-resistant viruses. In a case described recently in the Lancet this resulted in an individual producing a strain of the virus that was resistant to every available anti-retroviral agent. The patient in question also progressed to AIDS and died within six months of becoming infected.

The main ways HIV is transmitted in the UK
The three main transmission routes of HIV are sexual contact, exposure to infected body fluids or tissues and from mother to foetus or child during the perinatal period. It is possible to find HIV in the saliva, tears and urine of infected individuals but there are no recorded cases of infection by these secretions and the risk of infection is negligible. Breast milk, however, is known to be a significant risk factor for mother to child transmission of HIV. Studies have shown that if no anti-infection precautions are taken then 15-20% of new born babies will be infected, but if they are also breast-fed this proportion rises to over 50%. As a result HIV-positive mothers are advised not to breastfeed their babies.

A reported 754 HIV-infected children had been born in the UK to infected mothers as of the end of December 2006. Aware of the increasing risk posed by HIV to newborns and care-workers, in 1999 the UK Government introduced routine antenatal testing for HIV amongst all pregnant women. In those found to be positive, the use of antiretroviral treatment can greatly reduce the chances of a mother passing the infection to her baby. Since 1996 the increased use of such treatment has caused the rate of mother-to-child transmission to fall substantially.

Early media coverage of AIDS in the UK focused on injecting drug users. During the early 1980’s it was a big problem, but in 1986 needle exchanges began to operate across the UK, providing clean needles and giving drug users information and support. These schemes were largely effective in reducing the prevalence of HIV among certain members of this population. However, while they account for a small proportion of people living with HIV in the UK, the prevalence of HIV among injecting drug users has risen significantly in recent years (from 1:110, in 2002, to 1:62, in 2006). This rise has been attributed to an increase in the use of drugs outside of London where needle exchange schemes and information about HIV are harder to access.

Government policy in the UK
According to the latest Government legislation, NHS treatment for HIV is free to everyone who is living in the UK legally. This means that people who are living in the UK without due authority (such as illegal immigrants and failed asylum seekers) must pay for any HIV treatment they receive.

This measure aimed to tackle health tourism, the process whereby people migrate to a country in order to take advantage of better healthcare services there. However, denial of treatment to people in these situations can effectively be a death sentence, especially if they are then deported to countries where no treatment is available.

There are certain 'notifiable diseases', for which a person will always receive treatment in the UK regardless of their legal status, in order to prevent the rapid spread of epidemics. HIV, however is not on the notifiable diseases list. If a woman has no legal right to be in the UK then she will only receive medication to stop her baby being born HIV positive if doctors decide it is an 'emergency'.

Financial costs to the UK health system

• The cost of managing a patient with HIV is around £16,000 a year.

• The total cost of treatment and care in 2002/03 was estimated to be £345m.

• In 2000 it was estimated that the average lifetime treatment cost for an HIV positive person was between £135k and £181k.

Why is HIV / AIDS still on the increase in the UK?
There is currently no vaccine or cure for HIV or AIDS. The only known methods of prevention are based on avoiding exposure to the virus, male circumcision which is discussed below, and antiretroviral treatment administered directly after a highly significant exposure. This is known as post exposure prophylaxis (PEP) and comprises a 4 week drug schedule, the side effects of which are very unpleasant.

Another reason people are still dying of AIDS is due to many being diagnosed with HIV at a late stage of infection. In 2005 more than one third of adults diagnosed with HIV had a CD4 count lower than the recommended threshold for starting treatment. At this stage treatment is much less likely to work. This late diagnosis is alarmingly common, highlighting the need for greater awareness and for people to access testing services as soon as possible if they think they may have been exposed to HIV.

What is next?
Billions of pounds are spent every year worldwide on caring for and treating individuals with HIV/AIDS and on resources to prevent further spreading of the virus. However, ultimately it is a cure that is required to combat this pandemic. A vaccine to prevent HIV infection, as an alternative method to current therapies, may still be many years away. Not only might such a vaccine have to prime antibodies to attack HIV (the way most vaccines work) but it might also need to increase T cell production. Vaccine trials have been undertaken in South Africa, Kenya, the USA and Thailand, though most have yet to yield promising results. Controversial vaccines made from the blood of HIV carriers have been tested in Nigeria and Thailand. Other developing avenues for treatment of HIV positive individuals include gene therapy, targeted radiation therapy and nanotube technology to block the invasion of HIV into target cells. In April 2007 researchers even identified a component naturally present in human blood (a protein derived from alpha-1-antitrypsin) that can block HIV entry into cells.

In the absence of a vaccine researchers have turned to other approaches to try to combat the virus. A promising discovery, confirmed earlier in 2007, was that male circumcision can dramatically reduce, by 60%, the chances of acquiring HIV. The first clues that circumcision might be beneficial in halting the spread of HIV came after researchers noticed much lower prevalences of HIV infection amongst communities in which males were routinely circumcised. This hypothesis was tested recently in a series of randomised control trials in which HIV-negative volunteers seeking the procedure were randomly assigned either to undergo circumcision immediately or to wait for a period of time first. The patients were then followed up with regular HIV tests. The trial had to be stopped prematurely on ethical grounds when a large excess of HIV cases were found in the group of individuals asked to wait before undergoing the procedure. Scientists think that the foreskin represents a significant portal of entry for the virus because it is relatively enriched in cell types targeted by HIV, it provides an environment in which the virus can persist for an extended period thus maximising the risk of infection, and the mucosa of the foreskin can develop tiny fissures during intercourse and these facilitate viral entry and infection.

In response to these findings, the WHO / UNAIDS have recommended that it should be considered as an effective preventative measure. According to Kevin de Cock, director of the World Health Organisation's AIDS department, "This is an extraordinary development...Circumcision is the most potent intervention in HIV prevention that has been described". And according to Marie-Louise Newell of the University of KwaZulu-Natal in South Africa and Till Barnighausen of the Harvard School of Public Health "if all of the 2.5 million men in KwaZulu-Natal province had been circumcised, 37,000 new infections could have been prevented in 2007".

But none of these strategies can be effective without education, particularly about safe sex. One in ten girls aged 16-19 in the UK is infected with chlamydia, which can only have been acquired through unsafe sex. This is clear evidence that large numbers of young people are placing  themselves at direct risk of HIV, probably because they are from a generation who never saw the "grim reaper" television adverts of the 1980s when AIDS first hit the headlines. HIV is a very real threat and still very much a life sentence. Unless people can be made aware of this then the problem will only continue to get worse.

- June 2007

About the Author

Helen Carter is an immunologist at the Department of Pathology, Cambridge University, where she's trying to figure out how T cells work. She did her PhD at the Wellcome Trust Biocentre in Dundee and she is the head of the Cambridge regional group of the British Society for Immunology, which tries to promote Immunology to scientists and non-scientists alike.