This essay was written by Brian Thomas and was first published in the 1996 Mill Hill Essays.
“Fresh air can seriously damage your health“. A most unlikely Government Health warning but, for the patient with Acquired Immunodeficiency Disease Syndrome, AIDS, air-borne infection presents a constant threat of pneumonia and death. Nearly all will die of diseases caused by microbes that are everywhere in the environment, and harmless to the normal, healthy individual. It could almost be said that air, water and food carry death to anyone infected with the Human Immunodeficiency Virus, HIV – the causative agent of AIDS. The World Health Organisation estimates that, by the end of the decade, ten million people will have died from AIDS-related disease, and a further forty million will be infected by HIV. This is an epidemic of plague proportion, and the majority of its victims will be from the poorest countries of sub-Saharan Africa and South East Asia.
In an individual with AIDS the protective immune system has collapsed. As a result, the individual becomes susceptible to infection by a variety of environmental microbes. These microbes present no problem to the healthy individual, but can be fatal to the AIDS patient. For instance, Pneumocystis carinii – a fungal like organism, is a major cause of pneumonia-related death in AIDS patients in the developed world. Few doctors would have encountered this infection in their normal practice before the start of the AIDS epidemic in the 1980s.
Indoor swimming presents a hazard of infection from Mycobacterium avium – an organism that is found in soil, water and fresh vegetables, and is distantly related to the causative agent of Tuberculosis. Before the AIDS epidemic established itself, only twenty-four cases of Mycobacterium avium infection had ever been reported in the medical literature. In 1985 it was considered to present no health risk, even to AIDS patients. By 1990, over twelve thousand clinical cases, often fatal, had been reported in the United States alone. This bacterium infects the lungs as an aerosol, but is more commonly ingested with food or water, and the severe weight loss it causes contributes to death from other infections.
Viral, bacterial, fungal or protozoan organisms that are everywhere in the environment, and present no health risk to the general population, cause AIDS-related death. Household pets are a risk factor: cats often harbour a single cell protozoan parasite called Toxoplasma gondii; and while blood tests indicate that many of us have been exposed to this parasite without any ill effect, it has a devastating effect on AIDS patients.
The infections that afflict AIDS patients in the developed world are also life-threatening to transplant patients whose immune systems have been deliberately suppressed by drugs administered to prevent rejection of their new kidney or heart. Here again, Pneumocystis carinii is a frequent cause of pneumonia.
Because AIDS patients are most at risk from environmental hazards it is not surprising that differences exist in the pattern of AIDS-related diseases seen in developed and developing countries. In the developed world, the rate of progression to full-blown AIDS, following infection with HIV, takes between five and ten years. In developing countries, on the other hand, progression is far more rapid, due to differences in life style, diet and hygiene, and to a more hostile environment. The chief killer in these countries is Tuberculosis and this may, in turn, present a global threat once more from strains of Mycobacterium tuberculosis that are resistant to current drug treatment.
How does HIV wreak such havoc, and open the door to these opportunistic infections? HIV targets and destroys the command centre of the immune system, as effectively as a cruise missile attack. It targets particular blood cells – the CD4 T lymphocytes, so named because of the presence of a protein called CD4 on their surface. The main function of CD4 T cells is to regulate the activity of other cells in our immune system, such as those which produce antibodies, by releasing “hormone-like” substances called lymphokines. Interferon, for example, the first lymphokine to be discovered forty years ago by Dr. Alick Isaacs at the National Institute for Medical Research, plays a major role in recovery from viral infections. The CD4 T cells, by producing lymphokines, are like command centres that initiate the immune attack on infectious pathogens. Destroy these centres by infecting them with HIV and the enemy, opportunistic infection, takes all!
Why does HIV target CD4 T cells? Viruses, unlike other microbes, lack some of the essential biological machinery to reproduce themselves. They must enter, and hijack this machinery from an uninfected cell, a sort of Trojan Horse strategy. However, the surfaces of our cells present an effective barrier to all microbes, and for this reason viruses have evolved a postal address system to gain entry. The exterior coats of different viruses attach to specific regions on the surfaces of their target cells and are then literally invited in by the cells. The use of a different postal address accounts for the life style of different viruses by limiting the range of tissues that they infect: Polio virus infects cells of the gut, and occasionally of the nervous system to cause paralysis, Hepatitis virus only infects liver cells. The particular type of tissue that viruses attack is determined by the postal address on the surface of the cells which make up that tissue.
The address for HIV is the CD4 protein. All regulatory T cells of the immune system display CD4 proteins on their surface, and are therefore targets for HIV attack and extinction. A human cell that lacks the CD4 address can not be infected with HIV and as a result, novel therapeutic strategies that interfere with this postal delivery system could provide protection from virus attack.
Our first line of immune defence against viral infection is to produce antibodies that bind to the virus, which in turn prevent the virus binding to its address. Once inside a target cell it is too late for this kind of protection. The aim of a successful vaccine, therefore, should be to stimulate the immune system to produce antibodies against the virus coat, before virus infection. The potential for success of such a vaccination programme is amply confirmed by the global eradication of small pox, and the continuing decline in the incidence of poliomyelitis.
What are the prospects for an effective vaccine against HIV? It is unlikely that a “conventional” vaccine approach – immunisation with the virus coat protein – will afford long term protection to high risk groups. This is because the virus is able to escape the attention of the immune system, by changing its coat continually. As a result, HIV-positive individuals from the same community, or even household, harbour a variety of very similar viruses. An effective vaccine would therefore have to contain a cocktail of HIV virus coat proteins from the different viruses in circulation. A similar problem exists for Influenza vaccines. The Influenza viruses are also able to change their coats, and this requires continuous world-wide monitoring of circulating viruses in order to ensure that this year’s vaccine is “up-to-date”. However, the huge extent of coat protein variation seen with HIV makes the problem of effective vaccine production by conventional methods seem insurmountable.
Even so, there is some considerable optimism amongst AIDS researchers that new kinds of therapy might be developed in the near future. Much of this optimism is fuelled by recent findings that a very few individuals, despite repeated exposure by sexual intercourse with HIV positive partners, are free of HIV infection . Their CD4 T lymphocytes are resistant to HIV infection and it now appears that, in addition to the address protein, CD4, target cells must also display another, co-address protein known as CCR-5 on their surfaces in order for HIV to gain entry. This is somewhat analogous to a letter requiring both an address and a postal code. Those people who are resistant have an alteration to the CCR-5 protein on the surface of their CD4 T cells. Because the resistant individuals are in good health and do not seem to require the co-address protein CCR-5 for their immune system to work effectively these exciting findings offer the possibility of developing new drugs which might knock out the co-address, and at the same time leave the immune system intact. Or will the ease and speed with which HIV can alter its coat and acquire drug resistance defeat all attempts at therapy? Hopefully, not!