TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs

Abstract

Activation of HIV-1 reservoirs and induction of anti-HIV-1 T cells are critical to control HIV-1 rebound after combined antiretroviral therapy (cART). Here we evaluated in humanized mice (hu-mice) with persistent HIV-1 infection the therapeutic effect of TLR3 agonist and a CD40-targeting HIV-1 vaccine, which consists of a string of 5 highly conserved CD4+ and CD8+ T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol fused to the C-terminus of a recombinant anti-human CD40 antibody (αCD40.HIV5pep). We show that αCD40.HIV5pep vaccination coadministered with poly(I:C) adjuvant induced HIV-1-specific human CD8+ and CD4+ T cell responses in hu-mice. Interestingly, poly(I:C) treatment also reactivated HIV-1 reservoirs. When administrated in therapeutic settings in HIV-1-infected hu-mice under effective cART, αCD40.HIV5pep with poly(I:C) vaccination induced HIV-1-specific CD8+ T cells and reduced the level of cell-associated HIV-1 DNA (or HIV-1 reservoirs) in lymphoid tissues. Most strikingly, the vaccination significantly delayed HIV-1 rebound after cART cessation. In summary, the αCD40.HIV5pep with poly(I:C) vaccination approach both activates replication of HIV-1 reservoirs and enhances the anti-HIV-1 T cell response, leading to a reduced level of cell-associated HIV-1 DNA or reservoirs. Our proof-of-concept study has significant implication for the development of CD40-targeting HIV-1 vaccine to enhance anti-HIV-1 immunity and reduce HIV-1 reservoirs in patients with suppressive cART.

A pathogenic role of plasmacytoid dendritic cells in autoimmunity and chronic viral infection

“…Blocking IFNAR during chronic HIV-1 infection in humanized mice led to complete rescue of T cell number, reversion of T cell immune exhaustion, and anti-HIV T cell activity. Most importantly, anti-IFNAR mAb has rescued anti-HIV T cell immunity (Zhen et al, 2017;Cheng et al, 2018b). Consequently, HIV-1 reservoirs, as measured by both cellassociated HIV DNA and cells with infectious HIV-1, are reduced in the IFNAR-blocking mice.…”

Data and Text Mining Help Identify Key Proteins Involved in the Molecular Mechanisms Shared by SARS-CoV-2 and HIV-1

“…Toll-like receptors 3 (TLR3) and 7 (TLR7) play an important role in the innate immune response against HIV-1 and SARS-CoV-2 [ 67 , 68 , 69 , 70 , 71 ]. The polymorphism rs3775291 of the TLR3 receptor is associated with protection against HIV-1 [ 67 , 68 ].…”

“…The polymorphism rs3775291 of the TLR3 receptor is associated with protection against HIV-1 [ 67 , 68 ]. TLR3 agonists increase the anti-HIV immune response induced by vaccination [ 69 ]. TLR7 agonists increase the anti-HIV-1 immune response, the activation of HIV-1 expression, and the inhibition of HIV-1 replication, which may help to treat latent infections [ 70 ].…”

The Use of Toll-Like Receptor Agonists in HIV-1 Cure Strategies

“…Of the TLR agonists investigated ex vivo as described above, only agonists of TLR3, TLR7, and TLR9 have progressed into clinical testing as potential LRAs in the field of HIV-1 cure research. However, TLR3 agonist testing quickly progressed from small animal models into clinical trials in advanced cancer disease and its LRA potential has not been assessed in NHPs (64)(65)(66)(67). The majority of the preclinical work concerning TLR9 agonists have similarly been conducted in the field of cancer treatment and is thus beyond the scope of this review but has been described elsewhere (68).…”