Читать книгу Viruses: More Friends Than Foes (Revised Edition) - Karin Moelling - Страница 36

Early one morning, about thirty years ago, during my summer vacation in the Provence in France, I tried to contact my co-worker Jutta in Berlin. “Jutta, they are reporting accidents in a newspaper and the death of a technician working with HIV in US laboratories. Stop working with HIV, throw everything directly into the steam autoclave and kill all the virus samples immediately — this may be life-threatening.” She did not want to! “Can’t I finish the experiment first? I will be careful!” This was the typical reaction of a scientist. I remember, when we looked at a virus preparation of HIV in a centrifuge tube, it was turbid, from all the viruses that we had grown in the laboratory. We were playing with our lives without knowing it. I once gave a virus sample to the stewardess during an overseas flight to put into the refrigerator, next to food for passengers — it was in a capped tube and there was no danger.... Still! Jutta even ran an HIV test in the laboratory for a co-worker to determine his HIV status. What would have happened if he had been positive? Being HIV-positive was a death sentence in those days.

Infectious diseases are, worldwide, the most frequent cause of death. In Germany 60,000 people, and worldwide 80 million people, die of infectious diseases every year. HIV contributes 2 million cases of death per year. A similar number of people become newly infected. By comparison, 8.2 million people die of cancer worldwide each year. At the end of the 1970s infectious diseases were thought to be under control by antibiotics. This optimism vanished with the appearance of HIV/AIDS and turned into fear and pessimism. Even panic arose, as reported during times of the terrible Plague of Justinian in the Eastern Roman Empire around 541. For HIV everything was unknown: spreading, infection routes, diagnosis, and the course of the disease. It was a lucky coincidence that just at that time novel technologies for understanding diseases were becoming available: molecular biology and gene technology. The age of molecular cloning, recombination of DNA fragments of genes, the highly sensitive polymerase chain reaction (PCR) for detecting very small amounts of genetic material by amplification in the test-tube became available. All that was ready to go into research and ended up in one of the most incredible success stories of medicine, such as had never been experienced before. The only element still missing today is a vaccine. This is the conclusion after 35 years of intensive research. The virus was sequenced in almost no time; one could grow and amplify virus production in the laboratory, which enabled researchers and pharmaceutical companies to screen for drugs and to develop reliable diagnostic tests and methods for screening blood supply. In the meantime more than 30 drugs have been approved for anti-HIV therapy. Recently, a rapid diagnostic test has become available to test the HIV status of a potential sexual partner before entering a male sauna; it is fast, albeit not entirely reliable. Self-testing leads to fewer infections. Today nobody should die of AIDS in the Western world, with health insurance to cover the expenses of therapies — which still amount to about 20,000 dollars per year. The challenge is to support the poor, even in rich countries. The approach of suppressing multi-drug-resistant HIV infections by three drugs, “HAART” (highly active anti-retroviral therapy), the “triple therapy” has become a concept for other infectious diseases and also for cancer — if there are enough drugs available. HIV infection then allows the patient to lead an almost normal life, with a life expectancy similar to that of an uninfected person, i.e., about 75 years in the Western world. In the Third World the survival time is about 11 years after diagnosis, often with only a double therapy (ART, anti-retroviral therapy) and late beginning of treatment. In the Western world a normal family life can be led, with uninfected children being born. “Therapy as prevention” is the motto, indicating that no infection should occur if a patient adheres strictly to the therapeutic regimen. Pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) were launched in 2012 and have enjoyed great success, leading to an “almost-healing”. Depending on the drugs the “morning-after-pill” has to be taken within hours or a day. Thus, healthy people can stay healthy, while therapy of infected people is at the same time a prophylaxis for the uninfected partners. This may be the best we shall have for quite some time, until a vaccine (perhaps) becomes available one day. Complete removal of the virus from a person‘s body, a cure, is not yet possible but is a new ambitious goal. The virus changes and persists in reservoirs where it is inaccessible to therapies. However, the viral load (VL) is reduced by the triple therapy from a billion particles to about 20 per milliliter of blood. This is the limit of detection in diagnostics based on the highly sensitive PCR gene amplification method mentioned above.

Football and retroviruses are icosahedrons. Retroviruses can cause AIDS by immune suppression but once built the human placenta, so that we do not need to lay eggs.

Cell with nucleus and mitochondrium (former bacterium), DNA is the genome, RNA is the messenger for protein synthesis.

This dramatic reduction of the viral load raised the question as to whether someone treated successfully would be infectious at all. That would mean that precautions during sexual intercourse would no longer be necessary — so ran the argument. Interestingly it was Switzerland where this was discussed first, where people are more safety-oriented than in any other country. The proposal set off a worldwide debate, but was finally accepted. Consequently, one would no longer have to inform a partner about one‘s status, one’s own HIV infection. But adherence and the patient’s compliance are strict prerequisites — and severe limiting factors.

35 years of HIV research were celebrated in 2013 with a symposium at the Institut Pasteur in Paris. There the Nobel price laureate for the discovery of HIV, Françoise Barré-Sinoussi invited researchers from around the world. A noted non-participant at the meeting was Luc Montagnier, head of the department where the discovery was made, who shared the Nobel prize (2008). It was interesting to learn that Montagnier has meanwhile completely abandoned research and evidence-based therapeutics against HIV infections and turned his interest towards “alternative medicine” with natural plant extracts. This is not generally accepted.

The first electron micrograph of the virus was shown again, a historical slide. Already in the initial picture one could see that the virus changes its internal structures owing to the action of the viral protease: the virus matures after it has left the cell. This step is prevented by protease inhibitors — one can see the effect of the drug. The immature virus is no longer infectious. This electron-microscope picture was of historical importance, because Robert C. Gallo, at that time at the National Institute of Health in Bethesda, published it as his own picture. Françoise showed me the two pictures on her pinboard. Protests from the scientific community finally resulted in the declaration that there had been a mistake, pictures had been confused, the “wrong” one was published in error. Some co-workers then emigrated to other countries. The journalists, however, did not want to let go. Gallo had received the virus from Luc Montagnier, who generously gave samples of it to other researchers. Out of a mixture of viruses prepared in Gallo’s laboratory a viral candidate grew up, which however, turned out to be Montgnier’s isolate. Virologists normally do not mix virus isolates — on the contrary, they isolate individual clones — however, mixing and masking is what had happened. The French and the US governments finally reached a compromise according to which both sides would share the patent royalties. After all, Gallo had identified a very important growth factor (called Interleukin IL-2), which allowed propagation of the virus in cell culture, an important contribution to the development of a diagnostic test. Only HIV has such a fast mutation rate that no two virus isolates in the world are identical. A few point mutations, which were different in the “Gallo virus isolate”, were the basis for a defense by the lawyers, but did not prove an independent isolate. For ten years Gallo was under attack. This cost him the Nobel prize in spite of three excellent papers in the Journal Science shortly after the discovery of the virus. Furthermore, Gallo discovered the human T-cell leukemia virus HTLV-1, which is endemic in Japan and only distantly related to HIV. A friend of Gallo`s described him as a football player: you lose — ok — try again. So Gallo came to the Paris celebration. The show must go on. All the participants in his annual meeting at the Institute of Human Virology (IHV) in Baltimore celebrated an “almost-Nobel-prize-party” with a Ms Kennedy as event manager. The participants paid.

Has enough been achieved with the developments in therapy? Interestingly, new drugs seem still to be required, even though there is not a single virus or disease against which we have so many different pills. Most successful turned out to be the rather late developed integrase inhibitors. A new drug in 2015 prevents the release of the virus from host cells — not replication, as prevented by most other drugs. A very unusual approach is that of persuading the virus to leave its hidden reservoir that no medicine can reach. The battle cry is “purge the virus”, or “shock and kill” the virus, first to produce more viruses and afterwards treat them all. Making the infection worse before making it better — that sounds a bit risky.

The pills have dropped in price significantly in Africa, thanks to the commitment of Bill Clinton, down to several hundred dollars per year. However, this has the side effect that the pharmaceutical industry is not enthusiastic about developing new drugs. The pills in Africa, heavily subsidized, were smuggled to other countries, thus undermining their pharmaceutical markets. Today the pills have two colors, light and dark blue, depending on their origin, so that one can trace them back to the source. Are they equally good? I do not know.

There are still problems with resistance of the virus in patients undergoing therapy. The virus contains 10,000 nucleotides, and these mutate — about 10 mutations per replication round in about 24 hours. The reverse transcriptase, the enzyme for virus replication transcribing the viral RNA into double-stranded DNA, is highly error-prone. Therefore, many mutants accumulate and thus evade the treatment. There is always a swarm of different viruses in the patient, described as quasispecies. All the members of this swarm are related, but not identical. Some viruses are mutants, escaping from one therapy and therefore requiring another treatment, often a different combination of drugs. If one replaces one treatment regimen by another one, the original virus can grow up rather quickly, within weeks, which was surprising to scientists when it was first noticed. A triple therapy is used in the Western world, a quadruple therapy in a single pill is already forthcoming, and an injection shot that should last for three months is in preparation and initial testing. The volume to be injected is still rather large (4 milliliters) and hurts a bit.

What is the situation in the world? Is it as good as the results from research suggest? 37 million people are HIV-positive, 21 million are diagnosed as infected, 2 million new infections are estimated to happen per year (figures for 2013). UNAIDS, an organization of the UNO focusing on AIDS, regularly publishes these numbers. 1.5 million people died of AIDS in 2013, one-tenth as many as 10 years earlier. 15 million people with HIV were receiving a therapy, 22 million patients are still waiting. Treatment reducing the viral load, VL to an undetectably low level means that the person is no longer infectious and does not spread the virus. In the US this is achieved in 30% of the people, in Switzerland and the U.K. about 60%, and in Russia 11%. Almost a quarter of the newly infected people are females between 15 and 24 years of age. In Africa they have no chance to improve their living standards, and young females become prostitutes of “sugar daddies”. But the epidemic will not end if this continues. A new effort has been initiated to keep the girls at school by “cash incentives”, giving them money to prevent prostitution and allowing them to buy desired phones.

Similarly, male circumcision is promoted by cash payments ($12.50), which reduce the infection rates by about twofold. I remember when circumcision was first proposed, 30 years ago — it sounded like an emergency solution and a declaration of bankruptcy of all research then — and the audience burst out laughing. It is still performed as in Biblical times.

“Save the children” is the goal, save the next generation, after almost a whole generation has already been lost in Africa. No newborn child should become infected. In the Western world it is regarded as medical misconduct if an infection happens during delivery. Mother-to-child transmission (MTCT) is preventable if pregnant women can be reached by therapies and treated during childbirth. Reaching them all is still a problem. We can hardly remember the model proposed by George W. Bush, ABC: Abstinence, be faithful, (use) condoms. It is the biggest challenge for public health workers to translate knowing into doing — this is difficult enough to achieve with smoking or eating, let alone with sexual intercourse.

Worst of all — many infected people in the USA do not know that they are infected. The number amounts to 200,000 out of 1.3 million. One-half of new infections can be attributed to this. Unfortunately, newly infected people are especially highly infectious. A convincing new strategy is to treat as early as possible — but you need to know! Another serious problem is the lack of compliance. About half of the people who receive therapies do not take them regularly and remain infectious. Education is needed, as it has a strong protective effect against HIV infections.

Up to 2020 the hope is described by a rule of thumb, “90:90:90”, meaning: 90% of people infected should be diagnosed, 90% of these should be provided with antiretroviral therapy, and 90% should be below detectable viral load, VL leading to about 72% successfully treated. Then no infection of partners would occur and the pandemic could come to a halt. This has already been put into practice successfully in some countries (Botswana) in Africa in 2016. The goal is that HIV RNA should become undetectable, thanks to treatment. This ambition is to target the viral load, VL and make HIV undetectable in all people living with AIDS. Could then AIDS be overcome by the year 2030? That is a prediction. It should be possible in principle — it is mainly a matter of supplying antiviral therapies, learning, teaching, improving sanitary conditions and health-care systems — and that means money.