Viruses: More Friends Than Foes (Revised Edition). Karin Moelling
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.
The Berlin patient and the Mississippi baby — cure HIV?
A unique therapeutic effect to cure a patient was achieved at the Charité Hospital in Berlin. A patient with HIV and a lymphoma was due to receive a bone-marrow transplant against the lymphoma. For that, a special donor was selected, one who was naturally resistant against HIV. The hope was that the “Berlin patient” would become resistant too and be cured — and this was indeed what happened. About 15% of Europeans are resistant to HIV infection because of a natural mutation in the surface receptor that the virus needs to enter the cell. (The receptor is a chemokine receptor CCR5 and the mutation is called CCR5delta32 because the molecule is shortened by 32 amino acids.) Some research was performed with survivors of the Black Death, to see whether they survived because of exactly this mutation in the Middle Ages. Graves were opened to sequence some of those survivors — however, the speculation appears probably to have been unfounded.
A bone-marrow transplantation and replacement of HIV-resistant lymphocytes was successful. So the lucky survivor Tom Brown was “functionally cured” since ten years — that is the description for someone whose viral load, VL is undetectable but may lead to a later remission. Even better would be a “sterilizing” cure without remission. Eight repeats of the same procedure failed subsequently. Repeats for AIDS patients cannot be easily performed because it requires almost a complete removal of the patient’s immune system — a risky procedure. Thus, this case is at best a model for novel therapeutic approaches. They are indeed pursued by either blocking or knocking out the receptor CCR5 (by silencer RNA), so that the virus cannot enter the cell. People can dispense with the receptor and live normally without it.
Another case of near-cure was the Mississippi baby. It was treated directly after birth (within 30 hours), which can be done because the therapies are not as toxic as they were. The baby was treated for 19 months with ART. Nineteen other babies were treated in the same way, by this so-called post-treatment control (PTC), which controls the virus. The control is, however, not complete, as the virus came back after four years in the Mississippi case. But another child has now been “functionally cured” for more than 12 years, so we may hope that the residual virus will stay under control for the person’s entire life. (At least five logs (100,000-fold) reduction of the viral load VL down to about 50 viral copies/ml is required.)
New approaches aim to cut out the integrated HIV with molecular scissors, which will easily be more possible with a brand new technology