HIV: a new hope
Two articles describing a new promising method of treatment and prevention of HIV infection from different sides:
Genetically modified viruses as a cure for HIV
The human immunodeficiency virus (HIV) is known for its ability to purposefully penetrate the cells of the immune system. The destruction of immune cells infected with HIV leads to acquired immunodeficiency syndrome (AIDS). To enter a cell, HIV must bind to special receptor proteins on its surface. One of the most important target proteins, especially in the early stages of infection, is a receptor called CCR5 [1-5]. How important is this receptor for the virus to successfully infect cells?
Each of us has two copies of the CCR5 gene – one from dad, the other from mom. A mutation called delta-32 in one copy of such a gene significantly slows down the development of AIDS, delaying the development of the disease for several years [6]. Mutations in both copies make a person resistant to HIV. In 2008, the first case of a complete recovery of an HIV-infected patient was documented in Germany. Then a 42-year-old patient who suffered from two fatal diseases at the same time, namely AIDS and leukemia, received a bone marrow transplant from a donor with a delta32 mutation in the CCR5 gene. Before the transplant, the patient's old bone marrow was destroyed as part of cancer therapy. As a result, the patient was cured of both fatal diseases [7]. However, the risk of death as a result of such an operation is very high, so this method of combating HIV infection is not fully justified.
In 2015, a group of scientists led by Professor Michael Farzan published an article in the journal Nature about a promising method of treating and preventing HIV infection [8]. A new molecule called eCD4-Ig has been developed, similar to antibody molecules and capable of interacting with HIV. There is a small fragment in this molecule that is able to tightly bind to the part of the viral particle that recognizes the CCR5 receptor, and this disrupts the ability of the virus to penetrate the cells of the immune system.
The beauty of this molecule is that it is a protein engineered by genetic engineers. The gene encoding this protein can be transferred by genetic engineering to a neutralized virus (not HIV, but another virus, much safer). Such a virus is injected into the patient, his DNA enters some cells and instructs them to produce eCD4-Ig molecules. The patients for such gene therapy in the study were four monkeys.
These monkeys, as well as monkeys from the control group, were infected six times with a virus related to and very similar to HIV, which is capable of infecting many primate species.
The eCD4-Ig molecule was actively produced in all monkeys that were subjected to gene therapy. None of the monkeys protected by the eCD4-Ig molecule were infected, but all unprotected monkeys were infected.
Now the development is at the stage of preclinical testing. This means that many more years will pass before we get a ready-made HIV drug based on the use of genetically modified viruses, because clinical trials on other model animals and on humans are still to come. It is expected that the drug will be able to both prevent HIV infection and treat it by replacing existing antiviral drugs.
Despite the existence of some strange people who still claim that HIV does not exist or it does not cause AIDS, as well as opponents of genetic engineering, drugs and vaccines, technological progress continues and modern medicine finds new approaches to the treatment of those diseases that for many years seemed incurable.
For more information about the problem of HIV infection and HIV dissidents, you can read the review "HIV hoax - hoax".
List of literature:
1. de Silva E, Stumpf MP: HIV and the CCR5-Delta32 resistance allele. FEMS Microbiol Lett 2004, 241(1):1-12.
2. O'Brien SJ, Moore JP: The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS. Immunol Rev 2000, 177:99-111.
3. Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C et al: Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996, 382(6593):722-725.
4. Galvani AP, Novembre J: The evolutionary history of the CCR5-Delta32 HIV-resistance mutation. Microbes Infect 2005, 7(2):302-309.
5. Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E et al: Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 1996, 273(5283):1856-1862.
6. Huang Y, Paxton WA, Wolinsky SM, Neumann AU, Zhang L, He T, Kang S, Ceradini D, Jin Z, Yazdanbakhsh K et al: The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med 1996, 2(11):1240-1243.
7. Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K, Schneider T, Hofmann J, Kucherer C, Blau O et al: Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009, 360(7):692-698.
8. Gardner M. et al, AV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges.
A new approach to HIV
I had no idea they were working on something like this at all. And their results are well worth writing about.
In order to understand exactly what has been done, you should first refresh how exactly HIV enters the cell.
The virus has a shell protein. In general, it is very variable (very often mutates), but it has a "pocket" that is responsible for binding to the CD4 protein on the surface of the lymphocyte. After binding to CD4, the virus envelope protein changes its shape and another "pocket" opens on it, which allows it to bind to another protein on the surface of the lymphocyte – CCR5 (some HIV variants at this stage bind not to CCR5, but to CXCR4, but they are relatively rare). Binding to CCR5 once again changes the shape of the envelope protein and starts the actual process of introducing the virus into the cell.
Scripps researchers have created an eCD4-Ig molecule that tricks the virus by mimicking both parts of binding to the cell.
They transplanted a piece of CD4 protein onto an antibody so that this antibody became able to bind to a "pocket" on the surface of the virus envelope protein designed to bind to CD4. In response to this binding, the shell protein, as expected, changes its shape and opens a "pocket" for binding to CCR5. But a piece of CCR5 protein is attached to the synthetic molecule, which binds to this "pocket". As a result, this molecule binds tightly to the virus envelope protein and prevents it from binding to the corresponding receptors on the surface of lymphocytes.
As I have already said, the envelope protein as a whole varies greatly from one variant of HIV to another, but this molecule attacks two sites that are very important for the virus and therefore practically do not change. As a result, it is effective against a wide variety of HIV variants. And due to the fact that it binds in two different places, this binding is very strong and the molecule is effective even at very low concentrations.
But that's all in theory. How well does it work in practice? In cell culture, the results are very impressive – as expected, it acts in very low concentrations on a variety of HIV variants. It also performed very well on the mouse model, but we are more interested in the results on macaques, as they are closer to human ones.
Instead of injecting this protein intravenously, the researchers used a new technology to deliver genetic material. The human-safe Adeno-associated virus (English Adeno-associated virus, AAV) has been modified so that instead of delivering its genome, it carries genes encoding the eCD4-Ig protein. It is injected intramuscularly, it delivers these genes to muscle cells, which begin to synthesize the eCD4-Ig protein and synthesize it for many months (sometimes several years). This approach is both cheaper and more reliable than injecting large doses of synthesized and purified protein every couple of weeks.
The macaques modified in this way were then tried to infect with a variant of VIO (monkey immunodeficiency virus) carrying the HIV envelope protein. The virus was injected directly into a vein. Results:
The control group monkeys who received placebo are shown in red, the macaques who received eCD4–Ig are shown in blue. Panel a) tracks the percentage of uninfected macaques (the blue lines remain at 100%, which indicates that no macaques have been infected). In panel b), the concentration of the virus in the blood is monitored (the blue lines remain at zero, and the red ones jump up at the moment of infection). Unfortunately, the number of macaques in each group is small – only 4 per group. But overall the results look very good.
What's next? First, we need to repeat the experiment with a large number of macaques and test not only intravenous administration of the virus, but also sexual transmission. Then it makes sense to see what happens if this molecule is injected into already infected macaques – whether it will effectively suppress the virus. And most importantly, we need to redesign the structures so that they can be introduced to people and begin testing the safety of this approach. A couple of things can go wrong. Firstly, this molecule carries parts of the signaling proteins of the immune system and, in principle, may have some negative effects. Secondly, it is still a synthetic molecule that does not exist in nature and an immune response can be developed in the body to it. If everything is fine with security, then it will be possible to test for effectiveness later.
In general, everything looks very impressive and there is a good chance that the method will work both for HIV prevention and treatment (possibly in combination with standard medications). If everything goes without problems, then the security data will most likely be received in the next two years. In terms of effectiveness in treatment – in 3-4 years, in terms of effectiveness in preventing infection – in six to seven years.
Portal "Eternal youth" http://vechnayamolodost.ru25.02.2015