Intrastructural help

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Intrastructural help ( English intrastructural help , ISH ) is in immunology and virology a form of reciprocal interaction between B and T cells of the immune system, with the result of an increased immune reaction to viruses. It is researched in particular with regard to immunotherapy and vaccine development.

history

Intrastructural aid is an effect between B and T cells that was first described in 1979 for the influenza virus . It has been observed that T cells specific for influenza virions can promote the stimulation of influenza specific B cells and thus trigger a potent humoral immune response . This principle was later applied to the Rabies virus, and raccoons were protected from a fatal infection with the Rabies relative Lyssa virus. Furthermore, it was shown for hepatitis B that after previous contact with the core antigen HBcAg, ISH can also trigger an immune response against the surface antigen HBsAg.

The principle of intra-structural aid is advantageous because relatively constant structural antigens can be used for T-cell priming in order to generate a humoral immune response against very variable surface antigens. For this reason, the principle was also applied to the extremely variable HI virus.

background

One of the approaches to a protective HIV- 1 vaccine is through neutralizing antibodies . These antibodies will be found in 10-25 percent of HIV-1 infected people. Only a few of these people (only 0.8% of HIV-1-positive individuals worldwide) are able to suppress the viral load to a level below the detection limit and are called "elite controllers" or "long term non-progressors". Most of the HIV vaccination studies carried out could not induce protective neutralizing antibodies, but some protective effects of polyfunctional antibodies could be observed. These Fc-dependent effects appear to play an important role in disease control. In contrast, the results from the adenovirus-based STEP study indicate a higher susceptibility to disease due to vaccine-induced high levels of non-neutralizing polyfunctional antibodies and T-helper cells . Antibodies of the subclass IgG1 , which were mainly induced by vaccination , had relatively little functionality in mouse models. For this reason, one of the goals is to improve the quality of the immune response by inducing polyfunctional antibody classes such as e.g. B. IgG2A to increase. However, according to the findings from animal studies, cytotoxic T cells are imperative for a protective vaccine. Although this has not yet been found in any clinical study on humans, it can be assumed that it can reduce the viral load in the early phase of the infection . Therefore, a current goal is to prevent uncontrolled T-cell proliferation and to modulate the humoral immune response towards highly efficient polyfunctional monoclonal antibodies.

HIV vaccine research

One of the main aspects here is the precise modulation of the immune response after activation. This implies a good quality and quantity of neutralizing antibodies, but low levels of T-cell stimulation in order to avoid the aforementioned increased susceptibility and disease progression. First in vitro and immunization experiments that were carried out with the Simianes immunodeficiency virus showed a ten to 50-fold increase in Env -specific antibodies in treated mice compared to exosome -vaccinated mice. This was also verified for HIV in the mouse model with adoptive transfer experiments. Experiments on non-human primates also showed increased Env antibody titers after a “group-specific antigen” (gag) pre-immunization. It can be assumed that these results are transferable to humans, since HIV-1 patients with neutralizing antibodies showed an increased number of gag-specific T cells, but at the same time had comparable levels of Env GP120 -specific T cells. These findings point to the involvement of the intra-structural help in neutralizing ability.

Individual evidence

  1. ^ SM Russell, FY Liew: T cells primed by influenza virion internal components can cooperate in the antibody response to haemagglutinin. In: Nature . Volume 280, Number 5718, July 1979, pp. 147-148, PMID 317881 .
  2. ^ Russell, SM, Liew FY & Liew, FY T cells primed by influenza virion internal components can cooperate in the antibody response to haemagglutinin. Nature 280: 147-148 (1979).
  3. ↑ Dietzschold, B. et al. Induction of protective immunity against rabies by immunization with rabies virus ribonucleoprotein. Proc. Natl. Acad. Sci. USA 84, 9165-9169 (1987)
  4. ↑ Milich, DR, McLachlan, A., Thornton, GB & Hughes, JL Antibody production to the nucleocapsid and envelope of the hepatitis B virus primed by a single synthetic T cell site. Nature 329: 547-549 (1987).
  5. ↑ Hraber, P. et al. Prevalence of broadly neutralizing antibody responses during chronic HIV-1 infection. Wolters Kluwer Heal. AIDS 28: 163-169 (2014).
  6. ↑ Migueles, S. a & Connors, M. Long-term nonprogressive disease among untreated HIV-infected individuals: clinical implications of understanding immune control of HIV. JAMA 304: 194-201 (2010).
  7. ↑ Montefiori, DC et al. Magnitude and breadth of the neutralizing antibody response in the RV144 and Vax003 HIV-1 vaccine efficacy trials. J. Infect. Dis. 206, 431-41 (2012)
  8. ↑ a b Bournazos, S. et al. Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 158, 1243-1253 (2014)
  9. ↑ Costa, MR et al. Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001. J. Virol. 90, 10362-10378 (2016).
  10. ↑ Buchbinder, SP et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomized, placebo-controlled, test-of-concept trial. Lancet (London, England) 372, 1881-93 (2008).
  11. ↑ Temchura, V. & Überla, K. Intrastructural help. Curr. Opin. HIV AIDS 12, 272-277 (2017).
  12. ↑ Nabi, G. et al. GagPol-specific CD4 + T-cells increase the antibody response to Env by intrastructural help. Retrovirology 10, 117 (2013).
  13. ↑ Storcksdieck called Bonsmann, M. et al. Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells. J. Immunol. 195, (2015).
  14. ↑ Liang, X. et al. Vectored Gag and Env but Not Tat Show Efficacy against Simian-Human Immunodeficiency Virus 89. 6P Challenge in Mamu-A * 01 - Negative Rhesus Monkeys. 79: 12321-12331 (2005).
  15. ↑ Liu, J. et al. Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys. Nature 457: 87-91 (2009).