the generation gap

Twenty years of HIV and AIDS

In 1980 the terms HIV and AIDS did not even exist. Twenty years on, 16.3 million people have died after being infected with HIV, and a further 33.6 million people are infected with the virus.

In 1981, a drug technician at the Centers for Disease Control in the USA noticed an unusually high number of requests for a drug used to treat a rare form of pneumonia, Pneumocystis carinii pneumonia (PCP). The occurrence of PCP seemed at first to be limited to gay men in Los Angeles, but later that year the first cases appeared in drug addicts. Meanwhile, a rare cancer, Kaposi’s sarcoma, had begun occurring in gay men in New York.

During the first half of the 1980s, it became clear that these new outbreaks of disease were arising in patients whose immune systems were severely weakened, leaving them vulnerable to otherwise rare opportunistic infections. Cases of this new condition - acquired immune deficiency syndrome (AIDS) - began to be reported in other countries around the world, and the virus believed to be responsible – human immunodeficiency virus (HIV) – was isolated. Within a few years, HIV had spread from the gay community and intravenous drug users to the heterosexual population – and swept through North America, Latin America, Europe, Africa and Asia, recently emerging as a significant problem in Russia. By the end of 1999, just 20 years after its recognition, the World Health Organization estimated that 33.6 million people were HIV positive and 16.3 million people had died AIDS-related deaths worldwide.

Anatomy of a virus

How does HIV undermine the immune system to such a devastating degree? Like all viruses, HIV commandeers host cells, turning them into ‘factories’ churning out virus particles. HIV is a retrovirus, its genetic material being composed of RNA. When it infects a cell, an HIV enzyme – reverse transcriptase – copies the RNA into double-stranded DNA, which is then spliced into the host DNA. This new integrated DNA (the HIV provirus) manufactures viral proteins and RNA copies of the virus genome. Finally, proteins and RNA are brought together to form new HIV particles, which bud from the cell and go on to infect other host cells. Many viruses are deadly, but HIV is a particularly insidious pathogen: it takes over a subset of white blood cells, T helper cells – the very cells that protect us from infection.

The start of HIV infection, known as the ‘acute phase’, is characterised by rapid viral replication and a dramatic drop in the T helper cell count. However, three weeks into this acute phase, other parts of the immune system start to gain some control over the virus. In particular, cytotoxic (killer) T cells start destroying infected T helper cells. Although this activity fails to eliminate the virus, by six months the rate of viral replication has reached a lower, relatively steady state. The next, prolonged, ‘chronic stage’ lasts an average eight to ten years, during which the number of T helper cells gradually declines until the immune system becomes so depleted of T helper cells that other infections set in.

Fighting back

Medical interventions against HIV have taken two forms. Most effective to date have been the antiretroviral drugs, which block viral replication within infected cells at different stages in the life cycle of the virus. Nucleoside analogues (of which AZT was the first example) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) prevent DNA copies of HIV RNA being made. Protease inhibitors intervene later in the life cycle by preventing a protease enzyme from cleaving newly made HIV proteins.

However, forms of the virus resistant to antiretroviral drugs quickly emerge, which is why AZT on its own was only effective in the short-term. Combination therapy – known as highly active antiretroviral therapy (HAART) – has helped overcome this obstacle. Regimens based on two or more nucleoside analogues or NNRTIs, together with a protease inhibitor, interrupt two separate stages of HIV replication simultaneously, reducing the likelihood that resistant forms will arise.

HAART can knock HIV down to undetectable levels in the blood, and since the mid-1990s, has significantly prolonged lives in the West – enabling people literally to get up from their deathbeds and return to normal life. The downside is that the long-term toxic effects of these drugs on the body is not known – and patients have to adhere to a strict, often inconvenient and uncomfortable regimen.

There have also been attempts to create antibody-inducing vaccines to neutralise the virus. However, extensive variation in the surface structures of HIV present considerable difficulties for vaccine development. Moreover, it is now generally accepted that a vaccine that only induces antibodies against HIV has little chance of success. Most work is now focused on vaccine strategies that stimulate both cell-mediated immunity (T cell) and humoral (antibody) responses. However, a genetically engineered version of the HIV surface antigen gp120 is currently in phase III (large-scale) clinical trials in the USA and Thailand.

As the old maxim goes, prevention is better than cure, and the ideal intervention would be to target high-risk behaviour and prevent transmission of the virus in the first place. However, attempts to influence human behaviour have often become entangled in complex social and psychological factors. Attitudes vary widely from country to country, and interventions are only likely to be successful if they take due regard of the specific cultural and behavioural factors affecting the spread of disease in a particular community.

The origins of HIV

It is now generally believed that HIV-1 (the more common virus type) has its origins in a virus affecting a subgroup of chimpanzees, Pan troglodytes troglodytes, which were once common in west-central Africa. Its less common relative HIV-2 is thought to come from sooty mangabeys.

Both HIV-1 and HIV-2 cause AIDS, although HIV-2 is still relatively restricted geographically to West Africa. Both have genetic subtypes identified. HIV-1 subtypes can be grouped into M (major group), N (minor group) and O (outlier group). Group M accounts for the great majority (99 per cent) of HIV-1 infections worldwide, and is itself subdivided into ten subgroups, A–J, on the basis of genetic relatedness.

How the original viruses crossed the species barrier from monkey to human is far from clear. Some researchers maintain the jump could have occurred when infected monkeys were hunted by humans for meat. Another, more recent theory suggests that HIV could have been transmitted to humans through infected oral polio vaccines distributed in central Africa during the 1950s. This contentious idea was expounded by journalist Edward Hooper in his book The River: A journey back to the source of HIV and AIDS, and is soon to be put to the test, when three laboratories will independently analyse the remaining, refrigerated samples of the vaccine. However, a recent mathematical model of the evolution of HIV in humans, developed by Bette Korber in New Mexico, suggests that the viruses jumped to humans sometime between 1910 and 1930, arguing against Hooper’s theory (though not entirely eliminating it as the margins of error are very broad).

Whatever its origin, the human impact of the HIV epidemic has been devastating. By the end of 1999 HIV had orphaned 11.2 million children worldwide. In sub-Saharan Africa, life expectancy, which had risen from 44 to 59 between the 1950s and early 1990s, has dropped again to just 45 years – and economic advances made in recent decades are being undone as huge swathes of the labour force sicken and die.

The epidemic is now reaching new territories. In the former Soviet Union, HIV infections have grown explosively in the past year or so. In addition, it has also had a profound impact on other epidemics, such as tuberculosis (TB). One-third of the increase in TB cases over the last five years can be attributed to the HIV epidemic, and UNAIDS estimates that TB is now the cause of death for one out of every three people with AIDS.

Although in the West behavioural interventions and antiretroviral drug therapy have slowed both the rate of HIV transmission and the speed of disease progression, these are by no means watertight cures. In other parts of the world, especially southern Africa where 13.7 million people are now infected with HIV, the disease is a disaster on a continental scale. The need to tackle the AIDS epidemic on all fronts – with new vaccines and medical interventions, and campaigns to reduce transmission – grows more urgent by the day.

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