AIDS & HIV
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HIV (3D-rendered image) |
In early 1981 doctors began to see patients with strange symptoms in hospitals across New York City and San Francisco. Young men were showing signs of rare diseases that were very unusual for their age. In July 1981 the New York Times reported the outbreak of a rare form of cancer specifically among gay men called Karposi's Sarcoma. Over the next months and years doctors saw increasing numbers of gay men who were having serious difficulties in fighting off a number of common infections and cancers.
Doctors soon discovered a commonality among these men: they were lacking CD4+ cells which are essential for maintaining a healthy immune system. One year later the Centers for Disease Control had enough evidence to make the link between the illness and blood, and they named the disease AIDS (Acquired Immune Deficiency Syndrome). Over the next few years it became evident that the cause of AIDS was infectious, but it wasn't until 1984 that a virus named HIV (Human Immunodeficiency Virus) was shown to be the cause of AIDS.
To read more about this history of HIV and AIDS see the history pages on the AVERT website, which includes a timeline which highlights some of the most important developments.
> Control of HIV through anti-retroviral medication
> Current priorities for HIV research
> Other approaches to vaccination
> STEP and Phambili vaccine trials
> Why did the MRK-Ad5 vaccine fail?
The HIV retrovirus is an RNA based virus. When HIV infects cells in the body its viral RNA is recognized by the cell which then produces the complementary DNA strands. Over time this HIV DNA becomes integrated into the DNA of the host cell to become a provirus. From this point on whenever the cell replicates the HIV DNA is also replicated. The cell can remain dormant for a long time, but when it is activated it produces new viral particles which go on to infect other cells.
This chain reaction leads to the body initiating an immune response which includes the production of antibodies which are specific to the HIV virus. Whilst infection with HIV immediately begins to infect and damage cells in the body there is a long asymptomatic period (average of 10 years) between infection and the development of any symptoms. During this time the level of the virus in the blood drops to a low level, but people remain infectious.
Over time however the virus targets cells in the immune system which leaves the body susceptible to infections. The HIV virus specifically targets CD4+ T cells which are important components of the human immune system. The virus attaches itself to the outside of the T-cells before infecting them. This leads to apoptosis and the immune system becomes progressively weaker until the patient picks up an infection or cancer and is considered to be suffering from AIDS1.
AIDS is the term used to describe the condition where a person's immune system has been damaged by HIV to the extent that their bodies are no longer able to fight infection and other illnesses. It is important to note that people do not die of AIDS; they die from the other conditions, illnesses and infections that their bodies can no longer fight off due to their weakened immune systems.
The fact that the immue response to the HIV virus can be slow means that it can take up to six months for the body to produce significant quantities of antibodies. This hasmade the initial search for a test difficult.
The transmission of HIV to chimpanzees in the lab gave the first animal model of HIV. This was crucial to the development of blood tests allowing both diagnosis and the screening of blood donations. The test uses a technique commonly used in other areas of immunology which can detect the presence of a specific antibody. Called ELISA, it involves taking diluted blood serum and applying it to a plate with antigens attached. The test is sensitive enough to detect whether the blood contains HIV antibodies (which bind to the specific HIV antigens on the plate) even when they are at low levels. The ELISA method quickly became accepted worldwide as an effective way to screen for HIV. A negative ELISA test is sufficient to show that HIV is not present in a sample, but a second test is used to confirm a positive result from the ELISA test.
Whilst most people produce enough HIV antibodies to be detected by the ELISA test within 6 to 12 weeks, it can sometimes (in rare cases) take up to 6 months. Because of this 'window period' between infection and the production of antibodies there is the risk of the test showing a false negative result. Therefore it is recommended that a person who thinks they may have been infected with HIV is tested twice, once three months after exposure, and again after around six months.
Control of HIV through anti-retroviral medication
Whilst there is currently no cure for AIDS, there are treatments which aim to slow the progression from infection with HIV to AIDS. Retroviral therapies, usually used in combination are frequently used which has led to a reduction in deaths associated with HIV infection in the developed world.
1986 saw the first clinical trial of an anti-retroviral medicine called AZT more commonly known as Retrovir and Retrovis. AZT had been studied for retroviral research in mice before the AIDS epidemic began, and experiments had shown it to have activity against retroviruses at doses which were non-toxic in animals2. The activity of AZT against HIV was soon confirmed in animals, and in 1987 it became the first anti-retroviral to be licensed by the FDA as a treatment for AIDS and HIV, offering hope to thousands. Soon other anti-retroviral drugs followed, which were more effective and less toxic than AZT. Unfortunately the virus quickly developed resistance to all of these compounds which is why treatment with combinations of drugs is now the norm. Read more about AZT on our medical timeline.
A major advance came with the development of drugs that inhibit the activity of HIV-1 protease, an enzyme that is necessary for the formation of virus particles. Saquinavir entered clinical trials in 1991, and in 1995 became the first protease inhibitor to be approved by the FDA. During pre-clinical testing, in vitro studies had shown it to have potent anti-HIV activity, while animal tests indicated that it had an acceptable toxicity profile and that clinically relevant doses could be achieved by oral dosing3. Other protease inhibitors soon followed. The publication of the 3-D structure of the HIV-protease, determined by X-ray crystallography in 1989, guided the development of Indinavir which proved to be more potent than Saquinavir. Over 150 lead and intermediate compounds were tested during the development of Indinavir, and once again studies of oral bioavailability and toxicity in animals played a key role in identifying the compound that was taken into clinical trials4. Indinavir quickly became a standard component of highly active antiretroviral therapy (HAART) that has greatly reduced AIDS related mortality in developed countries.
By 1996 the combination therapy, consisting of cocktails of anti-virals taken together, had increased life expectancy enormously. Combined with early diagnosis and treatment life-expectancy was longer than ever before for those with HIV. While these drugs are not a cure, and need to be taken for life, the development of around 20 anti-virals which are effective against HIV is considered one of the great medical successes of the late 20th Century.
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Most patients now take a combination of around 3 anti-retrovirals each day to control HIV. © istockphoto/Angel Rodriguez |
Anti-retroviral treatment has now turned HIV into what many consider to be a chronic, but manageable disease. In 2006 Stefano Vella, director of drug research and evaluation at the Institute Superiore di Sanita in Rome and former president of the International AIDS Society said: "Today, I can tell my patients with HIV that they can have a normal life expectancy." In February 2007, however, a study of more than 26,000 people who took anti-retroviral drugs showed that 'normal' life-expectancy was over-optimistic. Although mortality rates had progressively fallen since 1996, the life expectancy of a 20-year-old starting treatment in 2005 was 58 years5. In a more recent study life-expectancy was found to vary between social groups, but on average remained at 2/3 the normal life-expectancy of the general population for each country6. While anti-retroviral drugs can allow HIV-positive people to lead full and active lives, it remains unlikely that they will live past middle age with current treatments.
It is now known that there are two strains of HIV: HIV-1 and HIV-2. There are also over 11 naturally occurring strains of a virus called SIV (Simian Immunodeficiency Virus), which affects different species of monkeys. HIV and SIV are both lentiviruses, named due to the slow course of disease progression, often remaining unnoticed for years before causing any symptoms.
SIV is similar to HIV and both are particularly prone to mutation, so single individuals will pick up variations in the RNA structure of the HIV they carry over their lifetime. The amino acid structure of an individual HIV-1 protein has around 95% similarity with the same viral protein isolated from another individual.
HIV-1 shares the highest degree of similarity (85%) with the chimpanzee strain of SIV. It is believed that HIV-1 mutated from this strain of SIV before jumping species to infect humans. HIV-1 can therefore infect chimpanzees; however the virus does not usually cause AIDS. This discovery initially dashed hopes of a non-human primate model for this disease. Although there have been instances of chimpanzees developing AIDS7, these are very rare, and since the early 1990's scientists have moved away from the chimpanzee as a model of HIV infection.
It was soon discovered that macaques are susceptible to SIV, and that the virus goes on to cause a fatal immunodeficiency syndrome in this species8. Researchers have also found that SIV is sensitive to similar drugs to HIV and they have exploited these similarities to develop and test many antiviral medications, particularly those used in prophylaxis. This is the use of drugs to reduce the risk of infection following accidental exposure to HIV, or to prevent the transmission of HIV from an infected mother to her baby during childbirth. Read more about prophylaxis here.
A disadvantage with SIV is that the sequence of its genes and proteins differ in places to that of HIV, which means that some HIV vaccines cannot be tested directly against SIV. To overcome that difficulty in the mid 1990's scientists developed SHIVs, genetically engineered viruses consisting of a SIV backbone and the HIV genes Env, Rev, Tat, and Vpu8. While early strains of SHIV failed to lead to AIDS in macaques, pathogenic strains such as SHIV 89.6p were eventually produced9.
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| Electronmicrograph of HIV-1 virions (green spheres) budding from a lymphocyte. © CDC/C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus |
The AIDS-like condition caused by SIV in macaques affects the nervous system in addition to infecting and damaging the T-cells of the immune system. HIV and SIV both infect cells through their interaction with the CD4 protein found on the surface of some T-cells, but infection also requires the virus to interact with another protein called a co-receptor. In most cases of early HIV-1 and SIV infection the co-receptor used is CCR5, but in some HIV-1 isolates, particularly those obtained late in the course of infection, another co-receptor named CXCR4 is used9. Several of the SIV strains, and more importantly SHIV strains such as SHIV 89.6p, also use CXCR4 as their co-receptor, a difference that was not initially seen as important, but vital for future HIV vaccine development.
There were initial concerns that SIV in the macaque model would not behave like HIV in humans. Part of the reason for this speculation was that studies showed an immediate and rapid decline in the levels of T cells in the gut mucosa of macaques infected with a CCR5-binding strain of SIV. After only a week the T cell count in the gut mucosal tissue appeared to be only half that of uninfected macaques. This was not thought to happen in humans, suggesting that SIV was significantly different to HIV10. However, when scientists examined mucosal tissue in human studies it was realised that T cells in the guts of many patients also decrease after HIV infection11, 12. This was a very important discovery as for the first time it became clear that SIV and HIV could quickly destroy large populations of CD4+ T-cells. Researchers subsequently showed that the virus targets CD4+ cells that are in an activated state, which include those cells that are particularly common in the mucosa where they form part of a defensive barrier against infection. This knowledge has greatly improved scientists understanding of how HIV infection eventually leads to the collapse of the immune system13.. The observation that sexually-transmitted HIV and SIV initially target T-cells of the mucosal tissue has also had significant implications for vaccine research, and vaccines are now under development that aim to block this initial onslaught14.
HIV-2 is a less common form of the virus, and has far fewer similarities with the chimpanzee strain of SIV. HIV-2 is like the SIV strain found in sooty mangabeys, and its structure has greater similarities to this SIV virus than to HIV-1.
Primate studies have also helped to increase our understanding of HIV in the area of natural resistance to infection or progression to AIDS. Epidemiological studies have identified individuals termed long-term nonprogressors and elite controllers who don't develop AIDS despite having been infected with HIV for many years without treatment. While some of these cases are attributed to mutations in the CCR5 gene that inhibit HIV infection of T-cells, viral resistance is also associated with particular variations in a subset of genes known as the human leukocyte antigene (HLA) genes that are part of the major histocompatibility complex (MHC) of immune system genes. Similar variations were found in the HLA genes of chimpanzees, where they increase resistance to AIDS by improving the ability of T-cells to recognize and destroy the virus15. This is not a phenomenon confined to humans and chimpanzees, several MHC variants, for example Mamu-A*01, Mamu-B*17, and Mamu-B*08, are associated with greater resistance to SIV and SHIV in Rhesus macaques16. This is therefore a factor that scientists need to take into account when selecting animals for experiments.
Current priorities for HIV researchConcerns include halting the spread of the epidemic, and ensuring access to anti-retroviral treatments, which are still very expensive, making them difficult to obtain in poorer countries. In developed nations the greatest threat to people with HIV is TB, which is becoming increasingly common and resistant to treatment.
The need for a vaccine to protect populations is clear, and difficulties in controlling the spread of HIV, particularly in sub-Saharan Africa, combined with the high cost of anti-retroviral drugs, have driven the need for an HIV vaccine.
Another important area of research is prophylaxis. This is the use of drugs to reduce the risk of infection following exposure to HIV. Information on HIV prophylaxis is available here.
There are currently over 30 potential HIV vaccines in development around the world. Despite the optimism that a vaccine would be possible in the early days of HIV research15, it was soon realised that developing a vaccine would pose more technical difficulties than anticipated.
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| ©istockphoto/José Carlos Pires Pereira |
The problem is that the HIV virus is unlike any virus studied before, because its generic material is encoded in RNA the virus is able to mutate rapidly. This characteristic helps it to evade the body's immune response, as antibodies are only able to recgnise specific regions of the viral surface. As vaccines work by stimulating the production of antibodies, this is a significant problem. The viral envelope of HIV is also very flexible, and changes shape as it attaches to T-cells, making it difficult for antibodies to bind to the virus and stop the process. However, the past 25 years of research have given several leads as to ways to overcome these problems and produce an effective HIV vaccine. One such lead relies on the fact that there are regions of the virus which are very stable and do not tend to mutate.
Evidence that human antibodies can neutralise HIV in animal models16 , the fact that some people have immune responses which are able to control the virus for years without developing AIDS, and the demonstration that some vaccines are effective against SIV in macaques17 indicate that developing an effective vaccine is possible.
Approaches to vaccine development
Many approaches have been investigated in the search for a successful HIV vaccine. One approach is to develop a Live-attenuated vaccine, which involve the use of forms of the live virus which have been altered, either genetically, by mutating specific points on the RNA, or by other means, rendering them unable to cause disease. This type of vaccine gives a closer simulation of natural HIV infection than inactivated viruses, and generates good immune responses. Attenuated SIV vaccines have had mixed success in protecting macaques against the disease in challenge studies, where they are exposed to SIV after inoculation. In some studies animals were successfully protected18, but not in others19. Unfortunately live-attenuated SIV vaccines themselves caused AIDS when given to infant macaques, and long-term follow up of adult macaques showed that here too the live vaccine sometimes eventually caused AIDS20 , making this approach unsuitable for human trials. Disappointing as this was, it did at least provide further evidence that it was possible to stimulate an immune response that could prevent SIV/HIV infection.
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X-ray crystallographic image showing the broadly neutralizing antibody b12 (green ribbon) in contact with a critical target (yellow) for vaccine developers on HIV-1 gp120 (red). © NIH |
Other approaches to vaccination
With live-attenuated vaccines appearing unpromising a variety of other vaccination techniques have been studied21. The classical approach to vaccine development is to use an inactivated form of the virus or part of the virus, such as the viral envelope protein, to induce a humoral immune response, generating antibodies which will recognise the virus and prevent an infection from establishing itself in the body. The outer envelope protein of the virus, gp120, was an obvious target and a purified form was developed to be used as a vaccine. AIDSVAX, an early gp120 subunit vaccine, was able to block low-dose infection in chimpanzees by the atypical CXCR4-binding HIV strain HIV-1 IIIB, and was taken into human clinical trials. Unfortunately AIDSVAX failed to protect in the clinical trails8, a failure that was predicted by its earlier failure to prevent infection of macaques by a pathogenic CCR5-binding SIV strain (see: Why did the MRK-Ad5 vaccine fail?). Efforts to develop subunit-based vaccines have continued, but the results against CCR5-binding SIV strains have mostly been disappointing, with a best partial protection against homologous SIV strains21.
Live recombinant, or DNA, vaccines have also been developed, in which another virus is used to transfer genes from HIV or SIV into cells. The infection in these cells can then be 'recognised' by the immune system, leading to an immune response. In contrast with the humoral response stimulated by subunit vaccines, live-recombinant vaccines stimulate cytotoxic T- cells, a type of lymphocyte which lacks the CD4 receptor HIV uses to enter the cell, and so cannot be infected by HIV21. The normal role of these cells in the body is to control a viral infection and kill virus-infected cells before they divide. There is good evidence that these cells control HIV during the first stages of infection, preventing the development of AIDS, often for many years. Animal studies in macaques have shown that the ability of vaccines to stimulate cytotoxic T-cells has an impact on the spread of the infection, reducing viral load. Cytotoxic T-cells only attack cells which contain the virus, so they do not prevent infection, but they do reduce the impact of the virus on the immune system, and a low viral load can prevent transmission, reducing the spread of disease.
STEP and Phambili vaccine trials
The search for a vaccine against HIV faced setbacks when a vaccine developed by Merck, MRK-Ad5, was withdrawn from phase II b clinical trials in October 2007. This vaccine had already undergone a full development process, using non-animal and animal-based tests, and the first stages of trials in humans. Though it did not stimulate production of protective antibodies it had stimulated cytotoxic T-cells strongly in animal studies, and it was hoped that it would therefore reduce viral load in people who became infected with HIV, and perhaps even lower infection rates. The second set of phase II trials were designed to test how effective the vaccine would be. Two separate trials were run, one, known as STEP, took place in America and Australia, while a separate trial, 'Phambili', took place in South Africa.
Over 90% of the volunteers in the STEP trial were male, while volunteers in the Phambili trial were more evenly split between men and women. These trials were smaller than a usual phase III clinical trial, with analysis taking place after the first infections with HIV were seen in people who had received the candidate vaccine. This precaution was designed to reduce the risk to those taking part, and it was this analysis that raised concerns over safety.
An independent Data and Safety Monitoring Board (DSMB) studied the trial and concluded that the vaccine did not either prevent HIV infection, or reduce the amount of the virus in those who became infected. The DSMB recommended that no further immunisations were made in either trial.
By November both trials had been 'unblinded', so that the volunteers who took part were told whether they had received the trial vaccine or a placebo. Initial analysis of the STEP study showed that of 741 people who received a single dose of the vaccine 24 became infected with HIV. This was compared with 762 people who received the placebo, of whom 21 became infected with HIV. Although this result was not statistically significant, further analysis was carried out, and an increased likelihood of infection was found in relation to a particular group of male volunteers.
The MRK-Ad5 vaccine consisted of 3 HIV genes, carried into the body using a common cold virus, adenovirus-5, as a vector. The key HIV genes carried by the virus were hoped to be sufficient to give immunity to HIV, allowing the body's T-cells to identify and kill cells containing the virus, without either the HIV genes or the adenovirus which carried them being able to cause disease.
However, male volunteers who already had strong immunity to adenovirus-5 prior to vaccination seemed more likely to become infected with HIV once they had received the vaccine (21 out of 392 men who had high levels of antibody to adenovirus, 9 out of 386 in the control group). The reason for the increased risk may have been unrelated to the vaccine, but since HIV infects immune cells, it was possible that the immune response generated by the adenovirus when they were vaccinated may have been responsible. New vaccines which do not use adenovirus-5 are now being developed.
For now, trials of vaccines using this vector will have strict selection criteria for volunteers, requiring a low level of immunity to adenovirus-5. Adenovirus-5 immunity is most common in Africa, where around 80% of people have a high level of antibody to the virus in their blood.
Why did the MRK-Ad5 vaccine fail?
The MRK-Ad5 vaccine was fully developed, and extensively studied in non-human primates before human trials began. Macaques were given a vaccine similar to MRK-Ad5, and were then infected with SHIV 89.6p, a hybrid SIV, genetically engineered to contain genes from HIV. The SHIV hybrid-virus retains key properties of HIV, but can cause disease in macaques like SIV. While monkeys which received the vaccine were not protected against infection with SHIV they did have lower viral loads than those which did not receive the vaccine and did not develop AIDS. A small group of the STEP volunteers who became infected did have a smaller than usual viral load in their blood, but the sample size was very small and since the trial ended early it is not known whether this is a significant finding.
The decision to proceed to clinical trials with MRK-Ad5 was criticized at the time by scientists who raised concerns about the reliability of SHIV 89.6p as a model of HIV infection, since the manner in which it infects cells of the immune system differs from that seen with HIV infection10. When SHIV 89.6p infects CD4+ T-cells it uses a co-receptor on the T-cell called CXCR4, whereas as mentioned above in most cases HIV-1 uses another co-receptor named CCR5. CXCR4 mediated infection causes a rapid and virtually complete loss of CD4+ T-cells from the peripheral blood and lymphatic tissues, while CCR5- binding strains of HIV and SIV rapidly deplete T-cells in the gut mucosa and the peripheral T-cells are depleted much more gradually. Most importantly MRK-Ad5 failed to prevent infection or have an impact on disease progression in macaques exposed to SIVMAC239, a strain of SIV that uses CCR5 and whose course of infection closely matches that seen in the majority of HIV cases25,26. It is now clear that SHIV 89.6p is something of a sheep in wolf's clothing, and lacks sufficient stringency for the evaluation of vaccine candidates.
With evidence building for the last decade that it is not the best experimental model, why did SHIV 89.6p became such a popular model for HIV-infection? Part of the answer seems to be its similarity to HIV, as mentioned earlier this allowed HIV vaccines to be tested against it without modification. However, a large part of its popularity does appear to be down to the fact that it was possible to create vaccines that completely block it, in contrast to the situation with pathogenic CCR5-binding SIV strains where protection was at best partial. However, it would be wrong to discard SHIV 89.6p entirely; a minority of HIV cases are due to infection with CXR4-binding strains - such as HIV-1 IIIB mentioned earlier - and SHIV 89.6p is a useful model for the development of treatments for these cases.
Following the failure of the STEP, discussion about future research has focused on the continued need for research and funding into the development of an HIV vaccine. The consensus among virologists is that research should focus on the basic discovery which makes vaccine development possible, and the development and use of better animal models. It is notable that with the exception of the live-attenuated vaccines - which have serious safety concerns - very few vaccine candidates have shown significant protective efficacy against pathogenic strains of SIV, such as SIVMAC239, that best replicate HIV infection in humans17. Another concern is that where vaccines, including live attenuated vaccines, did work, they only gave high levels of protection against homologous SIV or SHIV strains, where the strain used to make the vaccine was identical to the later challenge strain. Given the diversity of HIV, and its ability to mutate quickly, vaccines will need to protect against a wide range of HIV strains. Finally, some rhesus monkeys are more easily able to control SIV infection due to particular variations in a set of immune system genes known as the major histocompatibility complex (MHC), which is why a vaccine can protect one group of monkeys against a particular SIV strain, but fail to protect another group against the same strain.
There is now a broad recognition within the HIV vaccine research community that faced with understandable pressure to get candidate vaccines into clinical trials, and disappointing results from tests performed against stringent SIV strains, the bar for progression to human clinical trials was set too low. Among several recommendations16, 26, 27 there is general agreement that before proceeding to clinical trials a candidate vaccine should:
- Demonstrate efficacy against stringent challenge viruses such as SIVMAC239 and SIVMAC251
- Demonstrate efficiency in rhesus monkeys that lack MHC alleles associated with efficient virologic control (Mamu-A*01, Mamu-B*17, Mamu-B*08)
- Demonstrate efficacy against both homologous and non-homologous SIV challenge
- Target virus effectively during early infection of mucosal tissues
- Induce both an antibody mediated and T-cell mediated immune response
There is still an urgent need for new treatments to control HIV, and it is clear that more basic research needs to be done. One approach that has been studied extensively for the past decade is the prime-boost strategy, which involves immunization with a DNA vaccine followed a few months later by a boost immunization with a subunit based vaccine, with the objective of stimulating a stronger immune response that involves both the antibody and T-cell arms of the immune system.
Revised June 2010
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Research Fields: Infection and Immunity, Disease characteristics, Drugs & toxins(yes - 3 items)Animals Used: Mouse, Primates(required - 2 items)
