HIV and AIDS: an overviewAIDS despite its publicity and global impact remains a disease that is widely misunderstood not only by the layman, but also within the scientific community. AIDS, or Acquired ImmunoDeficiency Syndrome is defined clinically as the appearance of antibodies to the Human Immunodeficiency Virus, called HIV for short, associated with a fall in the number of CD4+ T-lymphocytes, a type of white blood cell, and the appearance of indicator diseases that are otherwise rarely encountered in the population, such as Karposi's sarcoma.
How is HIV transmitted ? HIV is passed by the exchange of body fluids, primarily blood and seminal fluid, there is NO clear evidence to suggest that HIV is transmitted via saliva. This explains the incidence of HIV infection in blood transfusion patients and hemophiliacs receiving HIV-infected factor VIII, those sharing infected needles, transmission via homosexual and heterosexual intercourse and the passage of HIV from mother to newborn child.
I will briefly answer the questions: WHAT IS HIV ? WHAT IS ITS MECHANISM OF ACTION ? WHICH TARGET CELLS DOES HIV INFECT ? HOW DOES HIV DEVASTATE THE IMMUNE SYSTEM ? WHAT STRATEGIES DO WE HAVE TO DEFEND OURSELVES ? HOW WIDESPREAD IS THE PROBLEM ? and WHAT ARE THE CONSEQUENCES FOR OUR SOCIETY ?
Firstly let us recap on the history of AIDS. AIDS was first recognised in the San Francisco homosexual community in 1981, and HIV-1 was first isolated in 1983 by a French team, and in 1984 was shown to be the infectious agent that caused AIDS. In 1986 the drug AZT was introduced and approved after clinical trials in 1987 as the magnitude of the AIDS pandemic became apparent. In 1988 AIDS was found to be spreading in the heterosexual population in New York and by 1992 over half a million people had been claimed by the global AIDS epidemic. Recently we learnt that AZT was not demonstrably effective in delaying the onset of AIDS in HIV infected individuals.
HIV is the name given to a closely related family of `retroviruses' that cause profound immune dysfunction over time. HIV-2 is found predominantly in West Africa, whilst HIV-1 is more common elsewhere. It is now believed that HIV infection alone is the primary cause of AIDS. All retroviruses share a common structure and means of reproduction, and are unique in carrying their genetic information in the form of RNA rather than DNA, although HIV differs from other retroviruses in killing the cells that it infects.
HIV primarily infects cells of the immune system that express the CD4 `co-receptor' protein on their surface. These include T4-lymphocytes or T-cells, the so-called `helper cells' of the immune system, monocytes and macrophages, which are the scavenger cells of the immune system displaying the infectious agents as antigens on their cell surface for T-cells to see, and dendritic cells which are found around the body and in the lymph nodes which are the sentinels of the immune system and alert T-cells as to the presence of an invading microorganism.
The anatomy of HIV is elegantly geometrical. The outer coat is made up of a layer of cell membrane taken from the last infected cell and is studded with protein `spikes' which are composed of glycoprotein 120 and glycoprotein 41 which are the viral docking proteins for the cellular CD4 co-receptor protein. This membrane layer, essential for viral entry into the host cell, envelopes the core proteins which encase the retrovirus's genetic material which is stored in the form of RNA. Also present are the proteins essential to viral reproduction; which include reverse transcriptase, an integrase and a protease. Shown below is an electron micrograph of HIV particles at different stages of their development inside a macrophage.
This slide shows the life cycle of HIV, which begins when virus particles attach via the gp120 to the CD4 receptor on the host cell membrane, symbolised by the horse shoes. This binding triggers the glycoprotein 41 to fuse the viral membrane with the host cell membrane, thus drawing the viral core into the host cell, whilst leaving the viral coat proteins behind in the cell membrane. The viral core then breaks down as reverse transcriptase (purple) produces a double-stranded DNA copy (blue) from the viral RNA (red). The viral DNA then enters the nucleus, where the viral integrase protein allows it to become incorporated into the host chromosomes. The host cell proteins then bind to the DNA and initiate the transcription process, in which DNA is copied into a messenger RNA in which form it can be read by cellular machinery and translated into viral proteins. Initially only short viral RNA molecules leave the nucleus, encoding regulatory proteins such as tat and rev which act to promote the synthesis of viral RNA. After 24 hours, longer RNA molecules leave the nucleus and encode the virus's enzymes and structural proteins. These proteins assemble into new viral cores containing new RNA which then bud from the host membrane, thereby releasing many new virus particles.
There are many theories that attempt to explain how HIV causes AIDS, and they are not mutually exclusive, but all require an understanding of the immune system and the biology of HIV. As we have seen HIV infects and kills CD4 receptor bearing helper T-cells. The viral gp120 coat proteins that HIV leaves behind causes uninfected T-cells to fuse with infected cells resulting in the formation of giant cell syncytia which die and thus deplete T-cell numbers.
T-helper cells are thrown off balance by HIV, triggering the proliferation of antibody-producing plasma cells, but too few of the all-important killer T-cells.
HIV infects the dendritic cells of the periphery and lymph nodes, the sentinels of the immune system that alert T-cells to the presence of foreign proteins, or antigens. HIV `outwits' and `overwhelms' the immune system through its rapid mutation rate. HIV causes the immune system to attack itself by the release of gp120 and gp41 coat proteins, which bind to CD4-bearing cells evoking their destruction, and HIV infection is believed to trigger T-cell suicide, or programmed cell death.
The following slides help to explain how the immune system responds to and attacks invaders, and how HIV may evade and defeat it. An important component of the immune response takes place in lymph nodes which constantly sample the blood contents. B-cells and T-cells congregate in separate compartments of the lymph nodes and dendritic cells are found between them. Dendritic cells, macrophages and monocytes normally capture foreign proteins, or antigens, from invading micro-organisms and activate unstimulated T-cells by presenting these antigens with special proteins of the multiple histocompatability complex or MHC for short. These activated T-cells fall into three broad categories: killer T-cells which then leave the lymph node in search of infected cells where they encounter these antigens again and multiply to destroy the infected cells; TH1-helper cells that trigger the production of killer T-cells and TH2-helper T-cells that stimulate the B-cells that recognise the antigen by releasing signalling hormones called cytokines. The stimulated B-cells proliferate to produce plasma cells that release large quantities of antibody in the body that recognise and bind to the foreign antigen and direct further action by the immune system.
By reducing the number of CD4 receptor-bearing helper T-cells, particularly the TH1-helper T-cells that stimulate killer T-cells, the capacity of the immune system to control the virus appears to diminish. Recent evidence suggests that HIV infection of the dendritic cell population leads to a failure of the dendritic cells to recruit new T-cells in response to HIV infection.
HIV has two additional defense mechanism. The reverse transcriptase of the virus makes many mistakes when copying RNA to DNA, as it does not proofread its copy, making on average one or two mistakes per replication cycle. The structural diversity of the viral coat and core protein antigens constantly increases as the virus multiplies within the body, and the immune system is eventually overwhelmed as it cannot continuously recognise and respond to the ever increasing number of mutant forms and keep the virus in check.
The coat glycoproteins pose additional problems for T-cells. When free gp120 binds to CD4 receptors on T-cells it primes them, so that when they meet a range of further antigens instead of multiplying as normal, they die. This may mean that the viral gp120 coat protein mimics the so-called MHC molecules that present antigen to T-cells, scrambling the normal signals governing T-cell activation and proliferation.
The graph below shows how the amount of viral antigen, a measure of viral proliferation, and the number of helper T-cells varies in the blood stream over the course of HIV infection. During the initial stages of HIV infection the level of viral antigen in the blood increases rapidly as the helper T-cell count drops, but within 2-3 months the helper T-cell count appears to recover and viral antigen appears to have largely disappeared from the blood. The rapid decline in the number of T-cells which signals the onset of AIDS comes relatively late in infection. During this long incubation period of HIV the virus is multiplying rapidly in the lymph nodes where the T-cell-activating follicular dendritic cells are concentrated.
This may explain why T-cell function declines long before T-cell numbers fall dramatically following HIV infection.
There are four broad approaches that have been taken to combat the spread and infectiousness of AIDS. The first is to design drugs that interfere with viral replication by inhibiting proteins that are unique to the virus. The best known of these is AZT (or azidothymdine) which blocks the action of reverse transcriptase and thus stops viral reproduction by preventing the viral genetic information from being converted from the RNA to DNA form. However within months AZT-resistant forms of reverse transcriptase appear due to the high rate of HIV mutation, and all that remains are the side effects and costs of AZT. Other inhibitors are currently being tested for tat, a viral protein that speeds up the expression of the viral proteins, such as Ro 31-8959 at Hoffmann-La Roche and viral protease inhibitors.
Another approach is to manipulate the levels of the signalling hormones of the immune system to restore the balance of `killer' T-cell function. Injecting highly specific monoclonal antibodies that reduce the level of interleukin-4 increases the number of TH1-helper T-cells which in turn may enhance killer T-cell activity. Trials in Kenya have claimed that the oral administration of alpha-interferon reduces the level of HIV infection and increases the number of helper T-cells in patients.
A change in behavior would dramatically affect the spread of HIV, namely a reduced number of sexual partners and protected sexual intercourse.
One of the most important areas of AIDS research is the development of vaccines against viral coat proteins and whole-killed virus in order to block HIV infection in man and infection by the closely related Simian Immunodeficiency Virus (or SIV) in primates. Macaque monkeys have been successfully immunized both with vaccinia virus which had been genetically engineered to produce the SIV coat protein and by whole-killed SIV.
Most scientists consider it unwise to use whole-killed HIV to vaccinate humans, but as the next slide shows that both the viral coat protein and CD4 molecules have been used in an attempt to develop vaccines against HIV. Injecting gp120 and 41 together into HIV patients before the onset of AIDS increases the number of antibodies against the viral coat proteins and appears to reduce the decline in CD4 helper T-cell counts. This strategy aims to block viral entry into the cell by smothering the viral coat proteins with antibodies. More promising still is the injection of recombinant CD4 molecules into monkeys which leads to the production of antibodies against the host's CD4 receptors and blocks SIV and HIV entry into cells and leads to reduced levels of virus in the blood without apparently affecting T-cell function.
The incidence of new cases of HIV infection in the U.S. between 1991 and 2001 has actually fallen from 59,000 to 25,000 (from a background infection incidence rate of 323 in 1981). The relative incidence of infection amongst males was generally much higher than in females, probably indicating early transmission by homosexual activity, except in Africa where transmission appeared to be sexually indiscriminate. The incidence of new HIV infection in homosexual and bisexual men declined markedly after 1984, whilst the number of new cases amongst the heterosexual community increased in the UK/US populations.
There were 100,000 diagnosed AIDS cases in Western Europe by the end of 1992, and 19.5 million HIV infections worldwide, most of which led to full-blown AIDS. There have been 13.2 million AIDS orphans worldwide since the commencement of the epidemic (UN AIDS figures 1999).
As many as 120 million HIV infections were predicted worldwide by the year 2000, although UN figures now suggest a more conservative estimate of 42.5 million (1999), with the largest spread originally predicted in Asia. The epidemic in Thailand showed an `exponential' growth rate where casual sex, prostitution and drug use are common.
The potential impact of AIDS upon a community is well illustrated in Uganda, where 80% of deaths in rural areas in the 13-44 age group are due to AIDS, and 20% of adults in the capital Kampala were infected with HIV (1993).
These statistics raise many important questions for our society. Should we give AZT and other drugs to AIDS sufferers irrespective of their cost or effectiveness, especially when the side effects are severe and the clinical benefits are uncertain. Does the pharmaceutical industry have an unhealthy profit motive in AIDS, at the expense of thorough trials and health costs? Experts suggest that by providing the underdeveloped world with $3 billion of health care we might halve the projected number of HIV infections by the year 2000. Assuming that AZT is not given to AIDS sufferers and only half of AIDS patients receive health care, it is estimated that AIDS will cost the South African economy £9 billion by the year 2000.
Moral issues are still more contentious. In Islamic North Africa and the Middle East the number of individuals infected by HIV is currently at around 75,000 compared to 8 million in sub-Saharan Africa. Is AIDS as the Muslim world suggests a Western problem brought about by drugs, homosexuality and promiscuity. Is the Catholic Church's ban on contraception counterproductive in a world where people make mistakes and HIV is prevalent?
Whilst 1% of the US population bears two copies of the delta 32 mutation which appears to make them resistant to HIV infection, and other mutations which confer resistance may indeed be found (e.g. the Cystic Fibrosis associated CFTR gene deltaF508 (typhoid) and the sickle-cell anaemia hemoglobin gene (malaria)), the existence of such resistance markers do not defer the need for a vaccine. Genetic diversity appears to be the last line of a species' defense against parasitic infection, as mutations, recombination events and polymorphisms ensure that sufficient individual variation occurs to make the complete obliteration of a population extremely unlikely. The high price for such resistance through genetic variation and mutation is the incidence of inherited diseases such as Cystic Fibrosis, thalassaemias and sickle-cell anaemia.
Vaccine development has since become a major focus of scientific and economic attention with promising results. It might be noted that resistance genes have since been discovered, most notably the delta 32 mutation within the CCR5 HIV entry co-receptor, an alteration which confers complete apparent resistance to HIV entry and infection within the 1% of the U.S. population who carry two copies. These individuals appear to be homozygous for this delta 32 mutation which may have originated within survivors from the bubonic plagues which ravaged the European continent from 1347 to 1666. However the incidence and frequency of this gene appear initially to be insufficient to explain the high (circa 20%) survival rates amongst infected HIV populations, in essence supporting the existence of other resistance mechanisms, such as the 'auto-vaccination' by HIV isoforms made less virulent through mutations that occur within the virus itself.
In addition to HIV infection via blood and exchanges of infected fluids through sexual contact, a third route of transmission may have been overlooked. Just as malaria, encephalitis, Yellow Fever and the West Nile Virus are propagated through mosquito bites and a mammalian/avian vector, so it may well be that the high incidence of HIV infection rates in South-East Asia, Equatorial Africa and Florida (which paradoxically has 18.5 percent of residents aged 65 or older, the highest proportion in the U.S.) may correlate with mosquito distributions as shown below. An RT-PCR analysis of the presence of HIV markers within ingested blood from mosquitoes in these areas may be necessary to test this hypothesis.
 Global Adult prevalence of AIDS |
 United States Adult Incidence of AIDS Cases |
 Distribution of Dengue Fever and Carrier Mosquito |
