Negative modulation of suppressive HIV-specific regulatory T cells by IL-2 adjuvanted therapeutic vaccine

Abstract

The potential benefit in using IL-2 in immunotherapy for cancer and autoimmunity has been linked to the modulation of immune responses, which partly relies on a direct effect on Tregs populations. Here, we revisited the role of IL-2 in HIV infection and investigated whether its use as an adjuvant with therapeutic vaccination, impacts on HIV-specific responses. Antiretroviral therapy treated-patients were randomized to receive 4 boosts of vaccination (ALVACHIV/Lipo-6T, weeks 0/4/8/12) followed by 3 cycles of IL-2 (weeks 16/24/32) before treatment interruption (TI) at week40. IL-2 administration increased significantly HIV-specific CD4+CD25+CD134+ T-cell responses, which inversely correlated with viral load after TI (r = -0.7, p <0.007) in the vaccine/IL-2 group. IL-2 increased global CD25+CD127lowFoxP3+Tregs (p <0.05) while it decreased HIV- but not CMV- specific CD39+FoxP3+CD25+CD134+Tregs (p <0.05). HIV-specific Tregs were inversely correlated with IFN-γ producing specific-effectors (p = 0.03) and positively correlated with viral load (r = 0.7, p = 0.01), revealing their undesired presence during chronic infection. Global Tregs, but not HIV-specific Tregs, inversely correlated with a decrease in exhausted PD1+CD95+ T-cells (p = 0.001). Altogether, our results underline the negative impact of HIV-specific Tregs on HIV-specific effectors and reveal the beneficial use of IL-2 as an adjuvant as its administration increases global Tregs that impact on T-cell exhaustion and decreases HIV-specific CD39+Tregs by shifting the balance towards effectors.

Regulatory T cells (Tregs): A major immune checkpoint to consider in combinatorial therapeutic HIV-1 vaccines

“…In a more recent work, we showed that therapeutic vaccination, of HIV-1-infected patients under therapy (cART), using ALVAC-HIV and Lipo-6T followed by 3 cycles of subcutaneous interleukin-2 (IL-2), decreased CD4 C CD25 C OX40 C CD39 C Foxp3 C HIV-1-specific Tregs thus shifting the balance towards effectors, while peripheral bulk CD4 C CD25 hi CD127 low FoxP3 C increased significantly. 6 Moreover, we have been able to demonstrate that increased bulk Tregs frequency impacts on T-cell exhaustion while decreased HIV-specific Tregs impact on the balance towards effectors. This demonstrates the need for assessing different subsets of Tregs as each population is provided with its specific phenotype and/or function, playing thus different roles in HIV-1 infection.…”

“…23 These results were explained by the expansion of CD4 C CD25 C FoxP3 C Tregs. 24 However, unlike IL-2 therapy alone, the use of IL-2 as an adjuvant to vaccines highlighted more positive effects by decreasing HIV-1-specific CD4 C CD39 C FOXP3 C CD25 C CD134 C Tregs as mentioned above, 6 emphasizing thus the promising character of this cytokine in combinatorial therapeutic strategies for HIV-1 C patients. Il-7 therapy was seen as an alternative strategy to IL-2 therapy.…”

“…In this context, recent advances have been made in HIV-1 infected patients, where both subsets (bulk and antigen-specific) have been simultaneously measured and compared in the same patients. 6 These aspects will be highlighted below.…”

Vaccinal effect of HIV-1 antibody therapy

“…One approach might rely on counteracting immunosuppressive immune responses already established in infected subjects. To this end, inhibition of Tregs-mediated immunosuppression has been attempted by several therapeutic approaches aiming at their modulation and/or depletion [68][69][70][71]. It is noteworthy that treatment intensification (5-drug ART) in HIV-1-infected patients has been recently associated with reduced frequencies of Tregs and broad HIV-1-specific CD8 + T cell responses [72].…”

Dendritic Cells in HIV/SIV Prophylactic and Therapeutic Vaccination

“…Moreover, recent therapeutic vaccines have aimed to induce broad immune responses rather than single antigen-specific responses to combat viral escape mutants and suppress the viral rebound [79]. For example, ALVAC-HIV vaccine expressing portions of HIV env, gag, pol, and nef genes, and Lipo-6T (tetanus toxoid class II-restricted universal CD4 epitope combined with 2 Gag, 2 Nef, and 1 Pol peptide) immunization followed by IL-2 enhanced CD4 and CD8 T cell responses, improved viral control and reversed CD4 exhaustion [80][81][82]. The peptides in the Lipo-6T vaccine component were modified by addition of a lipid tail in the C-terminal region to improve antigen presentation.…”