Two research teams have developed antibodies that stop HIV from infecting cells, meaning they can completely remove HIV from the body. Unfortunately, a new strain of HIV has been discovered in Cuba that causes death no later than three years after infection. This strain does not respond to known drugs, but it is known how it is infected.
An international research team led by prof. Michael Farzan from The Scripps Research Institute (TSRI) made a discovery that will greatly facilitate the prevention of HIV infection, both of HIV-1 and HIV-2 variants. Although strains of the HIV-1 variant were discovered relatively early, this type has always been a big problem for clinicians and virologists; with most of his strains, modern therapies have failed to neutralize him.
Meanwhile, as stated in Nature, prof. Farzan, the new protein therapy he proposed, blocks one of the basic mechanisms of viral transmission, not only HIV-1 or HIV-2, but also the simian acquired immunodeficiency virus – SIV.
All variants of HIV, like SIV, attack the immune system’s primary immune cells – CD4 lymphocytes. After attaching to a cell, the virus injects its genetic material – single-stranded RNA – which the cell processes to produce new viruses. Attachment in almost all HIV or SIV viruses involves the use of coreceptors by the virus, i.e. proteins located on the surface of the CD4 cell membrane. This is usually the CCR5 protein.
Farzan’s team studied people with CCR5 deficits who were not HIV-positive. As it turned out, HIV-1, HIV-2 and SIV viruses could not attach to cells with this type of CCR5 mutation, and it posed absolutely no threat to its carrier. It also found that even normal CCR5 can be blocked by proteins that make small aden-like viruses – which have an affinity for infectious adenoviruses but do not cause any disease or tissue degeneration.
A vaccine was developed on their basis. Intramuscular injection of aden-like viruses causes tissue to rapidly produce proteins that block two key areas of the CCR5 coreceptor, thereby preventing HIV or SIV from entering the cell. The new viral vaccine was tested with positive results in in vitro cell cultures taken from humans and monkeys. The in vitro mouse model tests were also successful. During the tests, it turned out that the viral vaccine is active even with high concentrations of HIV or SIV viruses, but its duration will be limited – up to eight months.
Work is currently underway to improve the vaccine. During the research, a significant new threat emerged, caused by a mutation of the HIV virus.
An international team of scientists working under the leadership of prof. Anne-Mieke Vandamme, has identified a new and most dangerous mutation in HIV to date. Previously known strains, after infection, caused a slow decline in immunity even in the absence of treatment and the occurrence of full-blown AIDS after a longer period of time, ranging from 7 to 10 years. Treatment and partial eradication of HIV (which can never be completely removed from the infected body) made the patient almost completely safe and could live for decades with only the treatment regimen.
However, in the case of the newly discovered strain of the virus, the situation is different – from the moment of infection to the onset of full-blown AIDS, a maximum of three years passes, and the new strain does not respond to antibody therapy drugs that block the coreceptors that HIV has used to enter cells. This is because infection occurs through a completely different cellular pathway.
As the Italian team of prof. Lucia Lopalco, the standard pathway for viruses to enter cells is through the use of the CCR5 coreceptor protein. Hence, many people with abnormal CCR5 simply do not get HIV. But it is possible to ‘switch’ some viruses to another coreceptor protein – CXCR4. HIV strains that infect using both CCR5 and CXCR4 proteins are extremely dangerous. Until now, CCR5 has always been primary, i.e. even in these strains, the protein was always searched first, and only in some cases the virus was able to infect it later with the CXCR4 coreceptor protein.
Meanwhile, researchers in Cuba tested blood samples from 73 patients diagnosed with HIV infection, 52 of whom already had AIDS to varying degrees.
It turned out that people with AIDS contain enormous amounts of the virus and the RANTES molecule in the blood of people with AIDS. RANTES is a specific protein by which the human immune system blocks CCR5 co-receptors. If infection were to come this way, the virus should not be in the bloodstream, because RANTES would block the coreceptor and prevent it from entering the cells. Meanwhile, the concentration of the virus was enormous. After examination, it turned out that the culprit is a new strain for which the primary pathway to infection is the CXCR4 coreceptor protein. Moreover, it does not react to any molecules that block the CCR5 protein, which means that it does not use this cellular pathway at all. When examining its composition, it was found that it contains a protein – protease D – that facilitates its multiplication, hence such a short period from infection to full disease. Four different strains of HIV have so far been found in Cuba, making the country an area where mutations can easily develop.
Informed about this discovery, the team of prof. Farzan, is currently working on a coreceptor protein derived from adeno-like viruses that can block the CXCR5 pathway in the same way as CCR4 blockade. As prof. Farzan, a solution that will block both cellular pathways can be expected in the short term.
Meanwhile, a team of scientists from the US National Institute of Allergy and Infectious Diseases decided to attack HIV from the side of the virus itself. Researchers found that two proteins – gp41 and gp120 – contained in the viral envelope strengthened the area where the virus neutralizing antibody could stick to the HIV envelope. Scientists have developed such an artificial protein using other viruses. A protein called 35O22 uses the viral envelope proteins gp41 and gp120 and sticks to the virus exactly where they are. In vitro tests showed that 35O22 eliminates 62 percent. all strains of HIV and SIV and that a very small amount of this antibody is enough to completely neutralize the virus. Blood tests of HIV-infected people have shown that this antibody is the most effective ever used. Currently, tests on a mouse model are starting to demonstrate effectiveness directly in the body. If their course is positive, expect the first trials of the new 35O22-based drug in about 1-2 years.
Immune drugs represent the most promising avenue for developing treatments for HIV infection. The most important thing, however, will be the prevention of infections and the detection of new patients. The “dark number” of infected people who do not know about their disease may even be up to 30 percent. in Western Europe, and in Central Europe – up to 40-50 percent.
Text: Marek Mejssner