Membrane-proximal external region of HIV could be used to design vaccines

UPV/EHU-University of the Basque CountryNov 30 2012

Beatriz Apellaniz, PhD holder of the UPV/EHU-University of the Basque Country, has studied in her PhD thesis HIV regions that could be used to design a vaccine. The researcher has focussed her research on a specific region of the surface protein of the Human Immunodeficiency Virus (HIV), which is responsible for the Autoimmune Deficiency Syndrome (AIDS), one of the diseases with the greatest human morbidity and mortality.

This region, known as the MPER (Membrane-proximal External Region) is one of the domains that is responsible for the fusion of the virus with the cell that it is going to affect, and it is of particular interest, since, as Doctor Apellaniz explains, there are known to be infected people whose immune systems are capable of generating antibodies that target this region in particular.It has been demonstrated that these antibodies could halt the infection in its early stages, which is what a preventive vaccine is seeking to do.

Apellaniz adds that it is a region that does not mutate easily:"Although HIV mutates very quickly, this specific region is very well preserved, so it is a good starting point for designingvaccines or treatments that would not become less effective as HIV goes on mutating."

So the thesis Functional and structural characterization of peptides derived from HIV-1 gp41 membrane-proximal and transmembrane domains. Implications for anti-HIV inhibitor and immunogen development has set out to characterise the MPER and to study a way of inhibiting it,and thus prevent the virus from penetrating the cell it was intending to infect, or to imitate it in order to trigger the generation of antibodies by the immune system.This strategy is known as reverse vaccinology and consists of studying, on a molecular level, which regions and structures recognise the antibodies in the virus before going on to design a vaccine that can trigger the generating of various neutralising antibodies in all individuals.

The cholesterol percentage, one of the keys

Although cholesterol is not a very popular molecule for those people who have elevated cholesterol, it is essential for the organism and, in this case, is one of the keys in the research carried out by Apellániz.

In fact, the amount of cholesterol in the membrane of the virus is extremely high and the MPER is found in this cholesterol-rich membrane. As the researcher herself points out, "according to laboratory work done previously and one of the conclusions of the study, cholesterol is needed in the membrane so that this HIV region can position itself in a specific way to favour the generation of neutralising antibodies.So a possible vaccine that we are proposing in the laboratory would be one that includes the MPER in membranes with a high cholesterol content.In fact, depending on the lipid composition, this HIV region is inserted into the membrane to a greater or lesser extent and adopts different structures.If for example a lot is inserted, it may remain hidden and the antibodies may not recognise it.That is why we are trying to find a way of making this region more exposed."

So the researcher has discovered that a high concentration of cholesterol encourages the MPER to remain exposed and allows a response to be made by the immune system.Apart from that, Apellaniz has pointed out that the characterisation of the lipid composition is also useful in the design of drugs that stop the virus infecting the cell by inhibiting the union of the MPER with the membrane.

These studies, which have led to the publication of seven papers in journals with a high international impact, have been carried out using models that imitate the membrane of the virus, and using the peptides developed and the lipids selected they have immunised rabbits which have generated neutralising immune responses.So the author has concluded that "with some variation, this region would constitute a potential bull's-eye for the development of vaccines."