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At the end of 2008 it was estimated that there were 33.4 million people living with HIV worldwide. There were around 2.1 million new HIV infections that year. Since 1981 when AIDS first emerged 25 million people have died from the disease. Given the huge scale of this pandemic and its impact on society, it is extremely important to try to understand where the virus came from, how is it is evolving and what this means for the battle against AIDS in the future.
When simply asked 'Where did HIV come from?' people come up with many different answers because of differences in interpretation of the question itself and their own beliefs. Some answer 'monkeys', others say 'Africa', some mention various conspiracy theories and some go on to explain how HIV is spread. There are many theories about where HIV came from, however it is most widely accepted that it originated from a similar virus found in non-human primates known as SIV (simian immunodeficiency virus) in Sub-Saharan Africa. This paper will discuss how and when this zoonosis occurred, why HIV is highly pathogenic and how it became a pandemic. Also importantly how can learning about where HIV came from help us overcome the infection in the future?
Discovery of HIV
At the start of the 1980s most scientists and clinicians had seemingly become complacent because infectious diseases were largely under control. Disease such as smallpox, polio, typhoid fever and whooping cough had been almost eradicated. There was great confidence that any epidemic could be conquered. Then in 1981 AIDS appeared on the public health agenda.1
The Centres for Disease Control and Prevention (CDC) published a noteworthy article in the Morbidity and Mortality Weekly Report (MMWR) on June 5, 1981, describing cases of five young, previously well, sexually active, homosexual men who were all suffering from Pneumocystis jiroveci (Pneumocystic carinii) pneumonia, a fungal infection not normally found in healthy individuals. It was found that three of the five patients had "profoundly depressed numbers of thymus-dependant lymphocyte cells and profoundly depressed...responses to mitogens and antigens." It was clear that the function of the immune system was compromised in these individuals; however the writer only understatedly noted the occurrence of these infections in these men to be "unusual".2 By the time this article was published two of the men had died. After this clinicians were vigilant to report the emergence of any similar cases.1
In July of 1981 further cases of abnormally aggressive Kaposi's sarcoma producing blue to violet skin and mucous membrane skin lesions (normally a mild skin cancer affecting mainly old aged men of Mediterranean descent), as well as Pneumocystic jiroveci were observed in 26 young homosexual male and reported in the CDC's weekly bulletin. The article failed to comment on the patient's immune systems.1,3 However it is clear that the underlying cause was in fact a general immune deficiency which meant that common pathogens which the body is commonly exposed to but does not normally cause illness, could take hold. These are known as opportunistic infections.4
As the reports of these unusual cases continued to emerge, it appeared that this new disease only affected homosexual men, and scientists tried to investigate what behaviours exclusive to this community made them at high risk for contracting the disease. Some came up with theories blaming the use of amyl nitrate, some said that particular organisms such as the cytomegalovirus was more prevalent in homosexuals and others suggested that the immune system of homosexuals had been weakened by constant exposure to sexually transmitted diseases. The disease was being referred to as GRID (gay related immune deficiency). It was still not thought of as a transmissible disease.1
However in the next two years further reports came in of injection drug users, heterosexuals, transfusion recipients and haemophiliacs all suffering from immune deficiency. It was finally being understood that this disease was in fact transmissible and the patterns of spread suggested a virus may be responsible. The disease was given the name acquired immune deficiency syndrome (AIDS) on September 3, 1982. In 1983 it also became apparent that AIDS could be transmitted from mother to child. AIDS caught the public eye because this disease was not confined to one community and could affect anyone, it had presented unusually and some of those affected had died but the cause was still unknown!1
At this stage, fungi, chemicals and even possible autoimmunity to leukocytes were considered as causes of AIDS. HIV was discovered simultaneously in 1983 by French researcher Luc Montagnier and in 1984 by American researcher Robert C. Gallo. In a retrospective article on their discovery of HIV they noted that there were many clues from the AIDS cases that pointed towards the cause. Looking into this it can be seen that firstly the decrease in a subgroup of T cells which had the CD4 surface antigen was a biological marker that unified all the AIDS cases. This finding suggested that something was specifically targeting CD4 T cells. The Human T cell Lymphotropic Virus did just that. Furthermore animal models existed where lymphotropic retroviruses caused an AIDS like wasting syndrome as well as leukaemias and lymphomas. HTLV was also transmitted through blood and sexual contact as well as mother to child which was consistent with the epidemiology of AIDS. Lastly AIDS was reported in haemophiliacs who were given only filtered clotting factors which meant that the causative organism of AIDS had to be small enough to pass through the filters i.e. a virus.
The hypothesis that the cause of AIDS was a retrovirus was proved correct however that it was a close relative of HTLV was wrong although early investigation using molecular and immunologic probes favoured similarity to HTLV-1. Using interleukin-2 and anti-interferon serum a new virus was isolated from T lymphocytes extracted from a lymph node biopsy from a patient with lymphadenopathy. This virus was different from HTLV-1. In 1986 the virus that had been previously named HTLV-III/LAV (lymphadenopathy associated virus) was now called HIV (human immunodeficiency virus). Further examination of HIV showed it had more genetic similarity to retroviruses that cause different chronic infections in animals. These viruses are collectively known as lentiviruses.4,5
Identifying the cause of AIDS was challenging because unlike other viral diseases which have caused epidemics in the past or more recently such as SARS and 'swine flu', AIDS is characterised by clinical signs that appeared years after infection and by then patients had many other infections presenting difficulty in isolating the cause. The discovery of the cause of AIDS had an important positive effect as it became possible to develop an effective test to detect the virus. By 1985 the test was in use and proof of its effectiveness was that over the next five years only four cases of AIDS were linked to transfused blood.1,5
HIV Virology and Immunology
HIV is a lentivirus of the retrovirus family. Retroviruses are enveloped viruses which contain their genetic information in the form of single stranded RNA which can be replicated in a host cell via the enzyme reverse transcriptase to produce double stranded DNA. The viral DNA can then be incorporated into the host DNA by a virally coded integrase enzyme. The retroviral DNA is then referred to as a provirus. HIV can be transmitted via semen, vaginal secretions, blood and breast milk. HIV infects CD4 T-cells, macrophages and dendritic cells. 6
The HIV genome consists of 9747 nucleotides coding for 9 genes.1
3 structural genes: Gag - nuclear proteins
Pol - viral enzymes (reverse transcriptase, integrase,
Env - envelope proteins
6 regulatory genes: nef, tat, rev, vif, vpu, vpr
The envelope of HIV is a lipid bilayer produced by budding. It encodes the Glycoprotein 120 (gp120) and Glycoprotein 41 (gp41). Gp120 mediates target recognition of CD4 and gp41 mediates fusion. After gp120 binds to CD4, it breaks away exposing the hydrophobic tip of gp41 which is then 'buried' deeply in the lipid membrane of the target cell. The virus particle is drawn close to the cell surface, facilitating fusion. Co-receptors are also required for entry of the virus into the host cell. The most well known are chemokine receptors: CCR5 which predominates on macrophages and CXCR4 which works mainly on T lymphocytes. Some HIV strains have a preference for T-cells (T-tropic) while others replicate in macrophages (M-tropic). The importance of this difference in usage of co-receptors is that M tropic strains dominate early on in HIV infection. It is postulated that HIV may undergo genetic shift to change its co-receptor allegiance which means that more co-receptors can be used later on in infection allowing greater viral replication and further depletion of CD4 cells allowing more rapid progression to AIDS. 1,4,6
Once inside the host cell a complementary DNA strand is produced from viral RNA by reverse transcriptase. A second complementary DNA strand is synthesised and the cDNA product is transported to the cytoplasm. Integrase cleaves the cDNA, inserts it into the host genome and repairs the insertion sites. The provirus can now lie dormant during the latent stage of HIV infection or start actively producing other virus.1,6 A key aspect to this process is the incredible rate at which new virions are produced. Different studies have shown that somewhere between 1010 and 1012 virions are produced each day in an infected individual. HIV also has a high mutation rate as reverse transcriptase has no proof reading mechanism. Approximately one mutation occurs for each virus produced.4
Combining the remarkable rate of replication and mutation means that HIV is a rapidly evolving virus, approximately one million times faster than the human genome. Although many mutations may render the virus genome nonviable some new quasi-viruses may be produced that are fully functional which can go on to infect a new host.4 There will be rapid selection of the virus with the survival advantage and there may be several strains present within one host, one which may be resistant to drug therapy.
HIV infection depletes CD4 T-cells through 3 main mechanisms:
Direct killing of infected cell by the virus
Increased rates of apoptosis in the infected cell
Killing of infected CD4 T-cells by CD8 cytotoxic lymphocytes
When the CD4 T-cell count is depleted below 200 cells/mm3, cell mediated immunity is lost and the individual is therefore more susceptible to opportunistic infections. Although B-cells produce 'neutralizing' antibodies 4-12 weeks after HIV infection (seroconversion) they are ineffective at clearing the virus. These antibodies are directed against gp120 however the virus evades the immune system for several reasons. Gp120 is heavily glycosylated which protects the epitope. The high rate of mutation also means HIV has a highly variable structure. The epitopes can change escaping detection by the immune system. Furthermore the integration of the virus into the host genome means that cells that are not killed are permanently infected. This ability to elude the immune system makes HIV a very successful virus.7,8
Worldwide there are 2 main types of HIV circulating the human population, these being HIV-1 which is responsible for the vast majority of infections and is globally distributed and HIV-2 which is less infectious and mainly affects a small population of people living in West Africa or who originated from this area. HIV-1 can be divided into three distinct groups known as 'M' (major), 'O' (outlier) and 'N' (non-major and non-outlier). The difference in their geographic distributions makes them useful in mapping out the epidemiological history of HIV. The M group is further divided into 11 subtypes denoted A to K which also have different endemic regions. Group M accounts 90% of HIV-1 infection worldwide. The most common subtype worldwide is C. To see such great genetic diversity of the virus in group M is predictable given than group O and N are geographically confined to West Africa giving them less opportunity to spread and N is even rarer than O. HIV-2 can also be divided into denoted subtypes A to G. However like groups N and O of HIV-1 they show little geographical differentiation, because they again are found in West Africa with little scope for spread.1,4
As well as the high rate of mutation, HIV is able to freely undergo recombination where it can occur between viruses of the same subtype and even viruses from different species of primates. These recombinations can also produce active HIV infection. It is likely that the incidence of recombination is underestimated due to difficulty of their detection. Recombination also makes it very difficult to reconstruct an accurate history of HIV and affects estimates of divergence of subtypes.4,9
A study published in Nature in 2009 investigating 'Adaptation of HIV-1 to human leukocyte antigen class I' has shown evidence that the virus is adapting to CD8 T-cell responses. Particular HLA molecules (HLA-B27, HLA-B51 and HLA-B57) are associated with successful control of HIV infection and slow disease progression. In populations with high prevalence of these favourable HLA molecules and high transmission rates, high rates of HIV mutations are seen, allowing the virus to resist control of infection. As the epidemic continues the relationship between these specific HLA molecules and slow disease progression will disappear meaning HIV has the advantage.10
Combining all these factors together, the high replication rate, the ability to escape detection by the immune system by undergoing mutation at a rapid rate, and the ability to form recombinants as well as adapt to the immune system, makes HIV a rapidly evolving virus, highly successful virus. Clearly classifying HIV into subtypes will become more difficult as the epidemic spreads, and more wide spread sampling will be needed. The resultant great genetic diversity of the virus also has several implications for public health. The likelihood of resistance to antiretroviral therapy is increased, the rate of disease progression may differ and it is important to investigate if these new strains of HIV produce differences in clinical manifestation of the infection. It also complicates vaccine development. The rapid mutation of HIV also makes it very difficult to identify which strain was the first to infect humans and give an accurate estimate of the time when the cross-over from primates to humans occurred.
We must investigate the origin of HIV to try to understand these properties of the virus and why the non-human primate equivalent does not appear to cause an AIDS like illness in the majority of their natural hosts.
The origin of HIV
HIV is a zoonosis i.e. the infection crossed from animals to human. In a simple explanation, the following conditions are required for zoonosis and further spread of the pathogen amongst humans:
A near host animal population
An infectious pathogen in the host animal that can cross to humans
Interaction between humans and the host animal for transfer of the pathogen to occur. Many individual exposures may be require before the pathogen can take hold in the human
The pathogen must have the capability of spreading amongst humans. This can occur through mutations.
A mechanism which allows the pathogen to spread rapidly and therefore prevents it from 'dying out' by either killing the human host or development of immunity in the majority of populations.11
For obvious reasons, the source of HIV was searched for among the primate lentiviruses as they are our closest ancestors. SIVs have been identified in over 30 species of primate in Sub-Saharan Africa, each species having its own form. The method to finding out which species of primate gave rise to HIV involved extensive study of different SIV sequences to produce a phylogenetic tree (figure 2)12. The tree shows the evolutionary relationship among the various SIV and HIV strains that had a common ancestor.
Notably there is a large distance between HIV-1 and HIV-2 on the tree. This clearly shows they share more in common genetically to SIVs found in different primate species than they do with each other
HIV-1 is closely related to SIV from chimpanzee species P.t.troglodytes
HIV-2 is closely related to SIV from sooty mangabeys
Groups M, N and O must have originated from three independant transfers of the virus from chimpanzee to human because these lineages are spread out among the SIVcpz nodes.4,12
Five factors are considered to validate zoonotic transmission of primate SIVs. These are:
Similarities in the organization of the viral genome
Prevalence of the virus in the natural host
Possible routes of transmission.13
Due to the lack of a complete set of data on all African primate SIVs, we cannot be completely confident when trying to predict the exact ancestry of HIV. However there is good evidence provided in the early 1990s to suggest that HIV-2 evolved from an SIV found it sooty mangabey monkeys (SIVsm).14 Firstly HIV-2 and SIVsm are very closely related molecularly. Secondly some subtypes of HIV-2 are more closely related to SIVsm than they are to each other. This also indicates that there have been multiple transfers of the virus from monkey to human, giving rise to the 8 subtypes of HIV-2.4 Furthermore some studies have shown the rate of SIV in sooty mangabays to be as high as 40%.15 This increases the likelihood of a transfer from an infected monkey to a human. A credible explanation also exists of how the virus transferred from monkeys to humans. Sooty mangabeys are found in West Africa which coincides with the geographical distribution of HIV-2. They are often kept as pets or eaten as bush meat, providing an opportunity for body fluid contact between monkey and human through bites, scratches and butchering of meat, allowing the virus to transfer. The virus may have taken advantage of people with already weakened immune systems allowing the virus to gain a foothold.4
The discovery of the primate ancestor SIV of HIV-1 however, seemed to be less certain at first. HIV-1 is most similar to SIVs found in chimpanzees (SIVcpz) in a species called Pan troglodytes troglodytes. Although there were similarities to the linkage of HIV-2 to SIVsm, some factors seemed to weaken the link between HIV-1 and SIVcpz. For the argument: mixes of HIV and SIVcpz strains were found through genome studies, which suggests that the 3 groups of HIV-1 -M, O and N arose from at least three independent transfers of the virus from ape to human. Also the natural range of P. t. troglodytes coincides with areas in West-Central Africa where groups M, O and N are endemic. There was even an explanation for how the virus was able to transfer to humans, again through contact with bush meat and keeping chimpanzees as pets. However the issue was the low prevalence of SIVcpz infection in wild chimpanzees.16 This meant there was a very small natural reservoir for the virus. However this low level of prevalence could be due to the fact that very few studies of SIV infection in wild populations have been carried out therefore the true prevalence is uncertain. Some considered whether both humans and chimpanzees could have acquired the virus independently from another species. However this is quite unlikely as many other primate species have been surveyed for SIV strains that closely resemble HIV-1 and none have been as closely related as SIVcpz from P.t.troglodytes.4
Further evidence to support the origin of HIV-1 from P.t.troglodytes came from a more recent study in 2006 of 599 faecal samples from 378 chimpanzees (P.t.troglodytes) and 213 gorillas in the wild forests of Cameroon.17 The samples were tested for HIV-1 cross-reactive antibodies. 40 of the 378 chimpanzee samples were positive, giving further proof that SIVcpz from P.t.troglodytes is the ancestor of HIV-1. The study also pointed to the origin of group M in southeasten Cameroon and group N in south central Cameroon. Also quite unexpectedly 6 of the gorilla samples were positive for HIV-1 cross-reactive antibodies. The SIV most closely related to group O comes from a gorilla.17 and therefore it is possible that the gorilla was an intermediate host of HIV between chimpanzees and humans.18
Other research published in 2003 has shown that the SIV found in P,t,troglodytes is in fact a hybrid of two SIVs which naturally infect red-capped mangabeys and the greater spot nosed monkey. The mechanism by which the chimpanzees acquired the virus is thought to be through killing and eating these smaller species of monkey.19
When did HIV originate?
From retrospective studies, the oldest sample of HIV collected to date is from 1959 which came from a sample from a man living in what is now known as Kinshasa, Democratic Republic of the Congo. There are very few other preserved samples that predate the early 1980's. Nevertheless, this hasn't stopped researchers from trying to put a date on the origin of HIV-1 Group M (responsible for 90% of infections worldwide). In 2000 Korber et al dated the origin of the most recent common ancestor of HIV-1/M at 1931 [1915-1941], 20 long before the first cases of AIDS were recognised. The estimate also tells us that for most part of its evolutionary history, HIV must have only spread at low levels in closed population groups before circumstances changed enabling a pandemic to occur.
The method used to estimate the time of origin of the virus is based on how extensively different strains have mutated by analysing different viral sequences from samples acquired over a few decades. By observing the changes in nucleotides, a molecular clock is calibrated which tells us the rate of evolution of the viral sequence. Using this rate of evolution and statistical models of evolution the researchers extrapolated backward to the start of the epidemic to estimate when the most recent common ancestor of HIV-1/M existed.18
Although a relaxed molecular clock technique was used to account for the fact that different lineages of the HIV-1/M phylogeny may evolve at different rates, this method of estimating the virus' age has several problems and therefore may have a large error. The effects of recombination are not taken into account which can greatly affect the estimate.4 Preferably, excluding all recombinant viral sequences would give a better estimate. Also the viral strains studies are collected at different times of host infection and therefore some may have already undergone mutation in the host, which also reduces the accuracy of the estimate. Ideally samples should be collected during seroconversion for more fair comparison between the viral sequences. Many of the old samples may not be in as good a condition as the new as RNA degrades quickly and therefore this may have reduced the quality of the genetic material studied so that only small fragments could be obtained. Furthermore although not possible seeing as the oldest sample obtained is from 1959, using older viral sequences which have had less time to mutate would give a more accurate estimate.
In 2008, another study pushed back the date of origin of HIV-1/M in humans to 1908 [1884-1924].21 In this study viral sequences were obtained from a paraffin-embedded lymph node biopsy taken in 1960 from a woman living in what is now known as Kinshasa, Democratic Republic of the Congo. This is the second oldest sample studied. The viral sequences of this specimen were compared with the 1959 sample and there seemed to be a 12% difference between them. This suggests that a common ancestor of the strains must have existed earlier than 1931 as previously estimated. This estimate may be more accurate because two of the oldest samples were studied, however there is likely to be some error due to the reasons mentioned above.
The date 1908 of when HIV-1/M first appeared amongst humans coincides with the appearance of cities in the area. This would have increased the number of potential sexual contacts for infected individuals, allowing the spread of the virus.
The Contaminated Oral Polio Vaccine Theory
This controversial theory proposed by Edward Hooper in 1999 suggested that HIV was the result of contamination of an experimental oral polio vaccine with SIV that was tested on about a million people in Belgian Congo, Ruanda and Urundi in the 1950s. The contamination according to Hooper occurred when chimpanzee kidney cells infected with SIV were used to cultivate the polio virus and people that were given the vaccine therefore became infected with HIV.22
However this theory is very unlikely for several reasons:
The polio virus was cultivated in cells from Asian macaque monkey not chimpanzees.
A sample of the vaccine was tested for genes associated with HIV or SIV and none were found
Chimpanzees from the region where the apparent cells were taken from do not have the SIV that is closely related to HIV-1/M
The evidence from genetic analyses estimates the time of origin of HIV-1/m to 1908. This predates the 1950s when the oral polio vaccine was being tested and therefore HIV had infected the human population long before.1,23
However to truly disprove this theory, a HIV infected tissue-sample needs to be found which predates the vaccine trials.
Differences between SIV infection in primates and HIV in humans
Intriguingly SIV infection does not seem to cause an AIDS like illness in their natural hosts, the exception being Asian macaques which were infected by an SIV from a different African species and therefore the macaque is not the natural host of the virus, and chimpanzees. Investigating the avirulence of SIVs can help us to understand how HIV might evolve or perhaps how we can harness this advantage that primates seem to have.
It is hypothesized that individuals infected with HIV initially stimulate a strong immune response to the virus, whereby genetic diversity of the virus increases through natural selection due to host immune system pressure. The viruses are suppressed by the immune system until it has been sufficiently weakened by extensive CD4 T-cell depletion, at which point the viral loads increase, genetic diversity decreases as selection pressure from the host has decreased and AIDS appears.
The role of viral evolution in the development of AIDS is however more complex than the above hypothesis and still remains unclear. Studies in larger numbers of patients have not shown a clear correlation between HIV variants and disease status.
SIVs replicate and mutate at the same rate as HIV, and although they do not cause disease, high viral loads are seen in infected primates. However the virus seems to provoke a weakened immune response. There may be several reasons for this. SIV strains appear to show tropism for CCR5 co-receptor and do not use the CXCR4 co-receptor. This may account for the slow progression of infection in primates as we know that use of CXCR4 co-receptor by HIV is associated with more rapid progression to AIDS in humans.4
The nef (negative regulatory factor) gene of the virus has been shown to have 2 roles. Early on it was shown that the Nef protein helped the virus evade the immune system, thereby allowing the virus to persist and multiply. However more recently a study has shown that the Nef protein may also have a protective meaning that the function and numbers of CD4 T-cells is conserved in the primate host which also provides and explanation for why the majority infected with SIV do not progress to AIDS.24 This function of the Nef gene seems to have been lost through evolution in the lineage that gave rise to HIV.
Although evidence exists for the role of the Nef gene and M-tropic and T-tropic strains in the progression of HIV to AIDS, there are still many other factors which must affect the interaction between the virus and the host immune system which are responsible for the development of AIDS. Although viruses of higher virulence appear in hosts due to virus evolution, this alone cannot be held responsible for the development of AIDS and this area requires much research to fully understand why HIV leads to AIDS.30
Not many studies of SIV infection in wild chimpanzees have been carried out in the past and therefore it was thought that SIV did not cause AIDS in chimpanzees, as is the case with other primates and their natural HIV. However in 2009 a study which followed 94 chimpanzees in 2 communities in a Tanzanian National Park over 9 years showed that SIVcpz infected chimpanzees has a 10-16 fold death risk, infected females are less likely to give birth and have fewer offspring. The fact that humans and chimpanzees are affected is not surprising seeing as we are 98.5% genetically similar to chimpanzees.
As we know chimpanzees acquired SIV more recently that other primates through cross-species transmission from monkeys which they hunted. We also know that only 2 sub-species of chimpanzee have been infected by SIV, the other 2 sub-species are found in different regions of Africa and therefore infection of SIV must have occurred after these subspecies were separated geographically. Perhaps chimpanzees have therefore not had enough time to adapt to the virus like other primate species have. The fact that an AIDS like illness has only been seen in a small group of chimpanzees in Tanzania could also possibly indicate that other chimpanzees found in other regions have adapted to SIV infection so that they do not suffer from AIDS.25
Further studies are needed to monitor SIV infection in wild chimpanzee populations in different regions of Africa although this is easier said than done due to the 'ethical and socio-behavioural constraints' of studying wild animals.'26 However this will allow us to investigate whether differences exist in manifestation of SIVcpz infection between chimpanzees and identify what viral or host factors may be causing these differences. This may help us understand the progression of HIV to AIDS and could lead to the development of new therapeutics and preventative strategies which could help us as well as affected chimpanzees.
It seems that that evolutionary virus-host adaptation over hundreds of years has decreased the virulence of SIV and has allowed maximum survival of the primate even in the presence of high viral loads. This means infected primates can continue transmitting the virus to other individuals.27 Whether or not HIV will progress in this way in humans is still unknown.
How did HIV spread amongst the population?
As we now know HIV was circulating in humans in Africa long before AIDS was recognised however why is this the case? A reasonable explanation for this is that initially HIV prevalence was very low because of the lack of opportunity to spread from small local populations. Also even if AIDS had developed in some people, it may have been wrongly diagnosed as one of the many other infections that the individual would have been suffering from, seeing as no one had even heard of AIDS. Another possible reason may be that HIV had not developed the characteristics that make it as virulent as it is today.4 However, studies to examine virulence have provided conflicting results, with some showing increasing virulence of HIV whereas others suggest stable or decreasing virulence. This may relate to differences in assessment of virulence, some using immunological or virological measures which may not give a proper indication of the virulence of HIV as a whole.4, 28
HIV spread across the globe through the following ways:
Global travel meant that migration of infected individuals from one population to another could provide opportunity for introduction of the virus.
Increasing 'risk behaviours' such as non-use of barrier contraceptives, having multiple sexual contacts and prostitution
Blood/blood product transfusions prior to availability of tests to check for HIV positivity.
Sharing of contaminated needles by drug users and use in parts of the world for patients where clean needles were unavailable.
Vertical transmission from mother to child before antiretroviral therapy was available.1,23
Since direct contact of body fluids is needed to transmit HIV, it is a relatively poorly transmitted pathogen in comparison to other pathogens of zoonotic origin which have caused pandemics in the past such as Spanish Influenza, the Plague and more recently swine flu (H1N1). There are many other zoonotic diseases however not all have established a pandemic and some have a cure or a vaccine to prevent disease unlike HIV. Despite the relative difficulty in transmitting the virus, HIV has managed to establish a pandemic. This may be because of the long latency period between initial infection where no symptoms of disease are experienced and the appearance of opportunistic infection at which point the person will already have AIDS. Therefore the individual would have had the opportunity to pass on the virus unknowingly before preventative measures could have been undertaken. HIV infected individuals are also at increased risk of contracting other zoonotic infections due to the immunosuppression caused. As we know HIV was transmitted from primates to humans through direct body fluid contact when humans hunted chimpanzees and sooty mangabeys for bushmeat and kept them as pets. However there are many other modes of transmission of pathogens from animal to human. The threat of zoonotic infections has promoted the importance of preventative strategies as we never know when a new infection may emerge that could be more deadly than all the pandemics we have faced so far. The table below shows some of the preventative measures used to prevent transmission of pathogens from animals to humans.
Although effective treatment for HIV exists which has greatly increased the life expectancy of infected individuals, as yet there is still no cure for HIV and efforts are being gathered towards producing a vaccine, however so far this is proving to be very difficult. Treatment for HIV is based on anti-retroviral drugs such as HAART (highly active anti-retroviral therapy). In areas where it is widely available, the development of HAART for HIV infection and AIDS has reduced the death rate from this disease by 80%, and increased the life expectancy for a newly diagnosed HIV-infected person by 20-50 years.6 As new treatments continue to be developed and because HIV continues toÂ evolveÂ resistance to treatments, estimates of survival time are likely to continue to change. Without antiretroviral therapy, death normally occurs within a year after the individual progresses to AIDS.Â Most patients die from opportunistic infections orÂ malignanciesÂ associated with the progressive failure of the immune system. HAART is also successful in preventing mother to child transmission in pregnant women.
There are 3 classes of drugs used: protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs). These all work in different ways to inhibit viral replication. Research is now being carried out to improve treatment by decreasing side effects of the drugs, simplifying drug regimens to improve adherence, and determining the best sequence of regimens to prevent drug resistance. Otherwise preventative strategies are encouraged such as use of barrier contraceptives, implementation of the needle exchange programme, educating people about how HIV can be transmitted, and regular HIV testing in high risk occupations. At the end of 2007 it was suspected that in the UK there were 77,400 people living with HIV, over a quarter of whom were unaware of their infection.6 Therefore efforts must be increased to identify individuals infected and therefore implement prevention strategies to reduce risk of transmission as well as start treatment before the disease progresses. Despite there being treatment available for HIV, only a vaccine is thought to be capable of halting the pandemic. This is because a vaccine would cost less, thus being affordable forÂ developing countries where the majority of HIV infections are found and would not require daily treatment.29
There are several types of vaccines being experimented with:
Peptide vaccines made up of small proteins from the virus
Recombinant subunit protein vaccines made of proteins found on the surface of HIV such as gp120, gp140 and gp160
Live vector vaccines - genes encoding HIV proteins are inserted into a vector which transmits the genes to cells in the body
DNA vaccines - copies of a small number of HIV genes are inserted into plasmids which produce proteins very similar to HIV
Vaccine combination - any 2 vaccines are given one after the other to produce a stronger immune response
Psuedovirion vaccine - a non-infectious vaccine which closely resembles HIV but does not contain all HIV proteins30
The use of whole-killed and live attenuated HIV have not progressed to clinical trials owing to an unfavourable benefit/risk ratio, which is further supported by experimental evidence from humans and simian models.31
The production of a vaccine could have several outcomes in terms of controlling HIV infection:
Sterilizing Immunity - This would result in complete immunity from HIV infection with no HIV detectable at any time and no transmission of the virus to others.
Long-term controlled Infection - This vaccine may slow the progression of disease in an infected individual so that the viral load would be very low or undetectable and the CD4 count would remain high. HIV would not progress to AIDS and transmission of the virus to others would be prevented or greatly reduced.
Altruistic Vaccine - This vaccine would have little benefit to those infected however it would help prevent transmission of the virus to others. The viral loads would remain low in infected individuals so that they stay healthier for longer. Vaccination of uninfected individuals would prevent or reduce the risk of transmission.30
There are several reasons why the production of a vaccine for HIV is very difficult:
The high mutation rate of HIV and the resultant great amount of genetic diversity that exists between HIV-1 and HIV-2, the different groups and subtypes as well the different strains found in one infected individual means that a vaccine would have to elicit an immune response that produced antibodies which could neutralise a great diversity of HIV isolates. The global distribution of different subtypes suggests that different geographical regions may need each need a different vaccine and this could be very difficult and time consuming
Venereal and haematogenous transmission of the pathogen means that a vaccine would have to produce mucosal immunity to contain a sexually transmitted virus and systemic immunity to contain a virus due to blood transmission. Also to combat both free virions and viruses inside cells, antibody mediated immunity and cell-mediated immunity, respectively, would have to be elicited by the vaccine.
The high level of replication despite strong immune responses raises the possibility that no vaccine would be able to elicit an immune response capable of completely clearing the virus and therefore progression to AIDS will still occur.
Most vaccines contain either killed pathogens or live attenuated forms, however it is very difficult to experiment with such forms in HIV as killed HIV does not retain its antigenicity and live viruses pose a safety issue.1,32
Several potential vaccine candidates are in different phases of clinical trial. Specifically, potential vaccines that can induce neutralizing antibodiesÂ active against a broad range of HIV primary isolates; cytotoxic T cell (CTL) responses in a vast majority of recipients and strong mucosalÂ immune responses are being sought. In particular evidence from trials in primates has shown that a vaccine given before SIV infection that produces potent CTL response has not ellicted immunity from AIDS however has controlled the viral replication following infection and thereby slowing disease progression allowing a long period of disease-free survival. The production of such a vaccine for humans seems more easily achievable and could have enormous benefit as it would reduce the transmission of HIV and slow the progression of disease particularly in regions of the world where antiretroviral therapy is unavailable. 30,31,32
In 2004, the STEP study began. This was a phase II randomized, multi-centre, double-blind, placebo-controlled study in 3000 HIV-seronegative high-risk volunteers.Â It tested a vaccine called V520 which was designed to stimulate HIV-specific cellular immunity, which prompts the body to produce T cells that kill HIV-infected cells. The vaccine contained a weakened adenovirus which served as a vector for 3 genes of HIV-1 subtype B. The trial was discontinued in 2007 as the results showed that the vaccine was not effective and that it actually made some recipients at higher risk of acquiring HIV-1.33
The most recent study with more promising results was the phase III trial of a vaccine called RV 144 in Thailand which began in 2003. It is the largest AIDS vaccine trial ever to be carried out. It was a Â randomized, multicenter, double-blind,Â placebo-controlled trial, that that evaluated the efficacy of four primingÂ injections of a recombinant canarypox vector vaccine plus two booster injections of a recombinant glycoproteinÂ 120 subunit vaccine based on strains of subtype B and E which are endemic to Thailand. The vaccine and placebo injectionsÂ were administered to 16,402 healthy (HIV negative) men and women between theÂ ages of 18 and 30 years that were at heterosexual risk for HIV infection. 8197 volunteers were given the vaccine and 8198 were given the placebo. The volunteers were then followed up every 6 months for three years with the primary end points being HIV-1 infection and early HIV-1 viraemia. The results published in October 2009 showed 74 volunteers out of the placebo group became infected whereas 51 out of the vaccinated group became infected with HIV-1 therefore vaccine efficacy was 31% (7 subjects were excluded from analysis as they had HIV-1 infection at baseline). However the vaccine did not affect the viral load or the CD4-count in subjects who were subsequently diagnosed with HIV-1.34 These results show the vaccine was modestly effective at reducing the risk of infection; however the numbers were very small and therefore could have been due to chance. The trial would need to be repeated perhaps in greater number and in other parts of the world where different subtypes of HIV-1 are endemic to see whether the vaccine truly reduced the risk of infection. Additional research is needed to understand how this vaccine was able to reduce the risk of infection.
Although we may be closer to producing a vaccine than we were 25 years ago when HIV was discovered, still much research needs to be done. Perhaps we need to better understand the virus itself and the interaction between the virus and the immune system in primates before we can move towards searching for a cure in humans. If we investigate further to discover factors which enable SIV infected primates to avoid progression to AIDS we may be able to produce vaccines based on these factors.
From the evidence presented we can see that HIV-1 and HIV-2 most likely originated from chimpanzees and sooty mangabeys respectively. HIV-1 group M (responsible for 90% of infections) originated in Cameroon and from here spread across the world. The properties of HIV make it a highly virulent pathogen; however its poor transmission means that action can be taken to prevent spread of infection. Since there is no cure available, strategies for prevention are very important and their use should be encouraged by healthcare organisations. Education about HIV is also important to encourage testing in high risk individuals so that the infection can be picked up at an early stage and managed appropriately with antiretroviral therapy.
From finding out where HIV came from, we can try to understand why its counterpart in non-human primates does not cause disease and how HIV might evolve. We can also look for genetic factors that will put us at an advantage so that at least infection does not mean progression to AIDS. By studying the evolution of HIV and finding which parts of the virus have remained the same we may get closer to producing a vaccine.
Searching for the origin of HIV also teaches us a valuable lesson that disease can occur many years after infection with an unknown pathogen and therefore makes us more vigilant to look out for other pathogens which may produce a disease course similar to that of HIV to AIDS, particularly those which have originated from animals.35 Therefore the importance of preventative strategies for zoonotic infections cannot be stressed enough particularly due to the emergence of several zoonotic infections that have caused devastation in the human population in the past.