New, promising vaccine against the most resistant HIV strains

A new study reports successful immunization against a stubbornly invincible "star of death" strain of an HIV-related laboratory virus (SIVmac239) and another strain strain. The new approach also provides long-term, single-dose protection, demonstrating that gene therapy could provide broad and sustained protection based on a modified form of CD4 protein that allows HIV to enter human cells.

According to UNAIDS statistics, more than one million people die from causes directly or indirectly related to HIV infection and nearly 200,000 infections by the virus in the child occur each year. It is notorious that the HIV virus first enters the immune cells carrying the CD4 receptor and then kills them, weakening the immune response to the infection. Many attempts have been made to neutralize the virus by preventing its binding to the CD4 receptor and thereby keeping it out of the cell. This is usually done by introducing one or more antigens of the HIV virus into the host organism to cause an immune response. Unfortunately, HIV reproduces very rapidly and mutates with equal rapidity, making the antigen used for vaccine production obsolete and the reaction time too slow.

The "death star" strain, in particular, has challenged all the vaccines developed so far. It is a simian immunodeficiency virus that infects monkeys and other primates. It has been used as a laboratory model for HIV because of its close similarity. HIV-related viruses can only multiply in primates and humans.

In response, a team of scientists from Scripps Research in Florida has developed an innovative technique: defeating the HIV virus using another harmless virus as a vector, in order to introduce into the host a gene that will produce a protein that will bind then neutralize the virus. HIV virus in the body.

The paper was published in the newspaper Translational medicine science July 24, 2019.

Mathew Gardner, PhD, and Christoph H. Fellinger, PhD, have worked closely with mentor Michael Farzan, PhD, co-chair of Scripps' research department on immunology and microbiology, at the University of Michigan. study. Image Credit: Scott Wiseman for Scripps Research

In the current work, the team used another non-disease-causing laboratory strain, namely an adeno-badociated virus (AAV) to express a modified gene product called eCD4-Ig. This modified protein contains two co-receptors of the HIV virus, namely CD4 and CCR5. In fact, CCR5 was discovered for the first time by the same team more than 10 years ago.

The AAV vector is inoculated into muscle in laboratory Rhesus macaques monkeys and in rapidly infected muscle cells. As a result, they began to show high levels of the eCD4-Ig receptor protein. When the animal was then exposed to the high dose SIVmac239 virus, the virus migrated to the muscle cells expressing these receptors and bound to them. As a result, it changes shape too early in the process, rendering it unable to further infection.

This elegant and elegant approach has protected the animal in the long run, while all infected control animals have died from SIV-related causes. AAV can therefore be used to produce a protective vaccine unlike all known vaccines, antibodies and biological drugs developed to date.

AAV is already well known for its ability to introduce therapeutic genes to treat diseases such as hereditary retinal disease and spinal muscular atrophy, for which it is FDA approved. Lead author Michael Farzan explains that the new study highlights the potential of AAV to develop many protective vaccines, and in particular to stop HIV infection using eCD4.

The vaccine is still in an early stage of development. For example, when the exposure burden increased by 2, 8, 16, and 32 times the original infectious dose, the immunized animals eventually died of infection. Even then, the number of viruses in their bodies was significantly lower at the peak point than in non-immune animals. The researchers also reported that viruses containing CD4 mutations preventing their binding had a survival advantage in this situation, with 75% of viruses in dying immune monkeys showing such changes. Other routes of protection against CD4-Ig were harmful to the virus and therefore were not selected. The virus therefore tends to escape the inhibition produced by the binding of eCD4-Ig by gene mutations, for example by taking advantage of a single amino acid that differentiates eCD4-Ig from the CD4 molecule in the monkey. This could be a mechanism of resistance and it will take a lot of work to bring the vaccine to maturity.

Farzan said, "We have solved two problems that have undermined studies on HIV vaccines up to now: the lack of response time and the lack of response width. No other vaccine, antibody or biological product protects against the two viruses for which we have demonstrated robust protection. "

The potential impact of the work of protecting people from the virus is immense, particularly because of the ability to provide long-lasting, single-dose immunity in places where access to medical care is limited and the rate of vertical transmission is high. is high. Farzan said, "We hope ultimately to prove that our approach is safe for those infected and at risk at a cost that makes it usable everywhere."