A Crucial Role for Infected-Cell/Antibody Immune Complexes in the Enhancement of Endogenous Antiviral Immunity by Short Passive Immunotherapy

Abstract

Antiviral monoclonal antibodies (mAbs) represent promising therapeutics. However, most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization, namely the modulation of the endogenous immune response. As induction of long-term antiviral immunity still remains a paramount challenge for treating chronic infections, we have asked here whether neutralizing mAbs can, in addition to blunting viral propagation, exert immunomodulatory effects with protective outcomes. Supporting this idea, we report here that mice infected with the FrCasE murine retrovirus on day 8 after birth die of leukemia within 4–5 months and mount a non-protective immune response, whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses. Interestingly, the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity (ADCC) mechanism. In addition, it forms immune complexes (ICs) with infected cells that enhance antiviral CTL responses through FcγR-mediated binding to dendritic cells (DCs). Importantly, the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties, allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb. Thus, our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment. They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses. They also indicate that targeting infected cells, and not just viruses, by antibodies can be crucial for elicitation of efficient, long-lasting antiviral T-cell responses. This must be considered when designing antiviral mAb-based immunotherapies.

Cutting Edge: An Antibody Recognizing Ancestral Endogenous Virus Glycoproteins Mediates Antibody-Dependent Cellular Cytotoxicity on HIV-1–Infected Cells

“…With respect to the relatively low frequency of HIV-1-infected TM-expressing cells, the unexpectedly strong cytotoxic ability of HA-137 might be explained by the greater amount of Ab used in the killing assay compared with the surface staining experiment. The increased killing might also be explained by a paracrine cytokine production from other cells that interacted with cICs, such as dendritic cells or macrophages (12,13). Taken together, our results show that HA-137 binds HIV-1-infected cells, forming cICs that induce a polyfunctional and cytotoxic NK cell response that is able to eliminate HIV-1-infected cells in vitro.…”

Plasmodium berghei sporozoite challenge of vaccinated BALB/c mice leads to the induction of humoral immunity and improved function of CD8+ memory T cells

“…In addition there is evidence that antibodies and T cells can act synergistically leading to improved induction and maintenance of antiviral T-cell responses and to enhanced levels of protection against different viral infections [34][35][36]. With regard to our results one explanation could be that anti-sporozoite antibodies support the maintenance of CSP-specific memory T cells but also facilitate the activation of these memory T cells in case of reinfection with Plasmodium sporozoites.…”

Virus-specific antibodies allow viral replication in the marginal zone, thereby promoting CD8+ T-cell priming and viral control

“…Some reports suggest that, after secondary infection or vaccination, contact with the virus will further activate the immune system, which then induces protective T-cell immunity [22][23][24] . Indeed, in the Friend virus model, antibodies can enhance the virus-specific CD8 + T-cell response 25 . The results of our study show that specific antibodies block viral replication within peripheral organs within the first days after infection but still allow enforced viral replication in lymphoid organs.…”