Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif.

The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, cholesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41-MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane-dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants.

[Robert Koch was right. Towards a new interpretation of tuberculin therapy]. / Robert Koch tenía razón. Hacia una nueva interpretación de la terapia con tuberculina.

At the centenary of Robert Koch's Nobel Prize award, tuberculosis treatment with tuberculin, which was announced in Berlin in 1890, is still considered a failure. Nevertheless, there is now sufficient information supporting the idea that tuberculin therapy was widely used until the second half of the twentieth century; thus, the impact of this treatment should be studied and related to the decrease in tuberculosis-related mortality recorded in that period. Moreover, tuberculin therapy has inspired at least two new immunotherapies; these, however, were directed toward precisely the opposite effect: suppression of the Koch phenomenon. Thus, inoculation of Mycobacterium vaccae polarizes the immune response towards the Th1 type; and inoculation of RUTI avoids local immunodepression after short-term chemotherapy without inducing toxicity. For this reason, Robert Koch's work on antituberculosis therapy should be reread and proper recognition given to his contribution in this field.

Robert Koch tenía razón. Hacia una nueva interpretación de la terapia con tuberculina / Robert Koch was right. Towards a new interpretation of tuberculin therapy

Con motivo del centenario de la concesión del premio Nobel a Robert Koch, se vuelve a considerar un fracaso el tratamiento de la tuberculosis con tuberculina anunciado en Berlín, en 1890. Sin embargo, hoy en día hay información suficiente para suponer que esta terapia fue ampliamente utilizada hasta la segunda mitad del siglo xx, por lo que se debería estudiar su contribución en el declive de la mortalidad por tuberculosis experimentado en este período. Además, la terapia con tuberculina ha inspirado al menos dos nuevas inmunoterapias, aunque buscando precisamente el efecto contrario: la supresión del fenómeno de Koch. Así, la inoculación de Mycobacterium vaccae polariza la respuesta inmunitaria hacia el tipo Th1; y la inoculación de RUTI evita la inmunodepresión local después de una quimioterapia de corta duración, sin inducir toxicidad. Por esta razón, es necesaria una relectura de la contribución de Robert Koch a la terapia contra la tuberculosis, y un justo reconocimiento de su labor (AU)

At the centenary of Robert Koch's Nobel Prize award, tuberculosis treatment with tuberculin, which was announced in Berlin in 1890, is still considered a failure. Nevertheless, there is now sufficient information supporting the idea that tuberculin therapy was widely used until the second half of the twentieth century; thus, the impact of this treatment should be studied and related to the decrease in tuberculosis-related mortality recorded in that period. Moreover, tuberculin therapy has inspired at least two new immunotherapies; these, however, were directed toward precisely the opposite effect: suppression of the Koch phenomenon. Thus, inoculation of Mycobacterium vaccae polarizes the immune response towards the Th1 type; and inoculation of RUTI avoids local immunodepression after short-term chemotherapy without inducing toxicity. For this reason, Robert Koch's work on antituberculosis therapy should be reread and proper recognition given to his contribution in this field (AU)

The live Mycobacterium tuberculosis phoP mutant strain is more attenuated than BCG and confers protective immunity against tuberculosis in mice and guinea pigs.

The Mycobacterium tuberculosis phoP mutant strain SO2 has previously been shown to have reduced multiplication in mouse macrophages and in vivo using the mouse intravenous-infection model. In this study we demonstrate that the M. tuberculosis SO2 is highly attenuated when compared with the parental M. tuberculosis MT103 strain and also more attenuated than BCG in severe combined immunodeficiency disease (SCID) mice. Complementation of the M. tuberculosis SO2 with the wild-type phoP gene restored the virulence of the strain in the SCID mice, confirming that the attenuated phenotype is due to the phoP mutation. In Balb/c mice subcutaneously vaccinated with either M. tuberculosis SO2 or BCG, the proportions of CD4+ and CD8+ populations measured in the spleen were significantly higher in the M. tuberculosis SO2 vaccinated group. In addition, the proportion of antigen-stimulated CD4+/CD8+ cells expressing IFN-gamma was significantly higher in the M. tuberculosis SO2 vaccinated group when compared with the BCG group. Balb/c mice subcutaneously vaccinated with the M. tuberculosis SO2 strain were also protected against intra-venous challenge with M. tuberculosis H37Rv at levels comparable to mice vaccinated with BCG, as measured by reduced bacterial counts in lung and spleens. Guinea pigs subcutaneously vaccinated with the M. tuberculosis SO2 strain were protected against aerosol challenge with M. tuberculosis H37Rv delivered at different doses. A high dose aerosol challenge of M. tuberculosis SO2 vaccinated guinea pigs resulted in superior levels of protection when compared with BCG vaccination, as measured by guinea pig survival and reduction in disease severity in the lung.