The first of December is World AIDS Day: a day to show support for those living with HIV, to commemorate those we have lost, and ultimately unite in the fight against HIV. To combat this pandemic though, we need to understand how the virus – and the wider virus group – reacts with the human body. In the following excerpt from Virus Hunt, Dorothy H. Crawford discusses the discovery and history of HIV and the retrovirus family.
HIV is a virus unlike any other. It works by stealth, silently entering the body and wiping out the very immune defences that have specifically evolved to fight such invaders. Without modern drug treatments it eventually kills virtually everyone it infects, but only after a period of ten years or so. At first it shows no outward signs of its presence and this is the key to its success. Those living with HIV, unaware of the virus within, get on with their daily lives and in so doing unwittingly spread the virus to others. The end game only begins when the immune system is so weakened that all manner of microbes can invade and flourish, thus causing the terrible symptoms of AIDS. So what is this virus and how does it work?
HIV belongs to the retrovirus family, a large and ancient group of viruses that infect many vertebrate species. These viruses are generally harmless in their natural hosts but if transferred to another species they may cause a variety of diseases ranging from cancer to anaemia and immune deficiency. When HIV was first identified in 1983 only two other human retroviruses had already been discovered. Both of these were identified by Robert Gallo and co-workers at the National Institute of Cancer, Bethesda, US, while hunting for viruses that cause human cancers. He concentrated on leukaemia, developing methods for propagating the malignant blood cells in culture with the help of growth factors and for detecting reverse transcriptase, an enzyme uniquely produced by growing retroviruses. In 1981 all his hard work paid off when he detected reverse transcriptase in a single culture of cells from a leukaemic patient. Gallo isolated human T lymphotropic virus (HTLV) I from the patient’s malignant cells and showed that this retrovirus causes the rare blood disorder, adult T cell leukaemia. This discovery was followed by the isolation of a second human retrovirus, HTLV II, but so far this has no disease associations. Gallo’s discoveries, and the technical advances that made them possible, set the scene for the isolation of HIV by Barré- Sinoussi and Montagnier shortly afterwards and for the identification of several related viruses that followed.
The history of retroviruses began over 100 years ago. In 1908 two Danish scientists, Wilhelm Ellermann and Oluf Bang, transmitted leukaemia from one chicken to another with a tumour cell extract that had been filtered to exclude whole cells and bacteria. This experiment did not cause much interest until 1911 when Peyton Rous, working in the US, reported similar tumour transfer using a cell-free extract of a solid tumour from a chicken. The reports predated the characterization of viruses and so, although work continued on these ‘filterable agents’, other scientists were skeptical of their very existence. Rous was only awarded the Nobel Prize for his seminal discovery in 1966, some fifty years after the event. In the meantime a ‘milk agent’ (now known to be mouse mammary tumour virus) that increased the incidence of cancer in pups from mothers with breast cancer was discovered by fellow American, John Bittner. Then in 1936 and in 1951 Ludwig Gross from New York published evidence of a mouse leukaemia virus. All these animal tumour viruses, at the time called oncoviruses, later turned out to belong to the retrovirus family, but this only became apparent after their remarkable method of replication was elucidated in the 1970s.
Retroviruses, in common with several other virus families, including those to which flu and measles viruses belong, carry their genetic material as RNA rather than DNA. But the retrovirus life cycle has a unique step that allows these viruses to colonize their respective hosts for life. Each virus particle contains two copies of the RNA genome along with the reverse transcriptase enzyme, which enables retroviruses to convert their RNA genome into DNA. During the unravelling of this replication cycle reverse transcriptase was discovered independently by American scientists Howard Temin and David Baltimore. The implications of this discovery appeared to belie the central dogma of molecular biology in which genetic information flowed exclusively from DNA to RNA to protein, and so it was initially met with disbelief. However, the evidence was overwhelming, and in recognition of this scientific breakthrough, Temin and Baltimore shared the Nobel Prize for Medicine in 1975.
When a retrovirus infects a cell, its reverse transcriptase converts the viral RNA genome into double-stranded DNA, and another enzyme carried in the virus particle called integrase then catalyses the joining, or integration, of the viral DNA copy into that host cell’s DNA chain. Now part of the cellular genome, the virus is protected from immune attack and remains there for the life of the cell, being replicated along with cellular DNA and passed on to daughter cells.
The integration process effectively archives retroviral genomes for the life of the infected cell, and if the virus gains access to germ cells then it will pass from one generation to the next ad infinitum. This latter scenario may seem rather far-fetched but when the human genome was sequenced it revealed a remarkable 96,000 retrovirus-like elements occupying around eight per cent of the entire genome. Nobody really knows what they are doing there but scientists speculate that they are fossils—the remains of ancient virus infections. Maybe some of them caused plagues like HIV/AIDS, and if so then perhaps in several thousand years’ time a fossilized HIV will be found fixed in the human genome.
Featured image credit: “balloons-sky-blue-balloon” by Mark-Krister. CC0 via Pixabay.