Long-Term Persistence of Anti-HIV Broadly Neutralizing Antibody-Secreting Hematopoietic Cells in Humanized Mice

Abstract

Broadly neutralizing antibodies (bNAbs) are among the most promising strategies to achieve long-term control of HIV-1 in the absence of combination antiretroviral therapy. Passive administration of such antibodies in patients efficiently decreases HIV-1 viremia, but is limited by the serum half-life of the protein. Here, we investigated whether antibodysecreting hematopoietic cells could overcome this problem. We genetically modified human CD34 + hematopoietic stem and progenitor cells (HSPCs) to secrete bNAbs and transplanted them into immunodeficient mice. We found that the gene-modified cells engraft and stably secrete antibodies in the peripheral blood of the animals for the 9 months of the study. Antibodies were predominantly expressed by human HSPC-derived T-and B cells. Importantly, we found that secreted PGT128 was able to delay HIV-1 viremia in vivo and also prevent a decline in CD4 + cells. Gene-modified cells were maintained in bone marrow and were also detected in spleen, thymus, lymph nodes, and gut-associated lymphoid tissue. These data indicate that the bNAb secretion from HSPC-derived cells in mice is functional and can affect viral infection and CD4 + cell maintenance. This study paves the way for potential applications to other diseases requiring long-lasting protein or antibody delivery.

Engineered Antigen-Specific T Cells Secreting Broadly Neutralizing Antibodies: Combining Innate and Adaptive Immune Response against HIV

“…Our results echo related findings from groups that modified hematopoietic stem cells to secrete broadly neutralizing antibodies. 33 , 34 , 35 In these prior publications, the antibodies were secreted by antibody-producing B cells after transduced hematopoietic stem cells differentiated. These modified B cells produced neutralizing antibodies that provided continuous amounts of HIV neutralization in vivo .…”

“…These modified B cells produced neutralizing antibodies that provided continuous amounts of HIV neutralization in vivo . 33 , 34 These antibodies were able to delay HIV viremia and persisted in circulation—detectable in the spleen, thymus, lymph node, and gut-associated lymphoid tissue in humanized mice. 34 While the modification of B cells to express antibodies is the most straightforward approach, we hypothesized that modifying T cells to secrete these antibodies could allow for spatio-temporal coordination of innate and adaptive responses to sites of HIV infection.…”

“… 33 , 34 These antibodies were able to delay HIV viremia and persisted in circulation—detectable in the spleen, thymus, lymph node, and gut-associated lymphoid tissue in humanized mice. 34 While the modification of B cells to express antibodies is the most straightforward approach, we hypothesized that modifying T cells to secrete these antibodies could allow for spatio-temporal coordination of innate and adaptive responses to sites of HIV infection. Our group is currently pursuing T cell therapy with HIV-specific T cells, and modification to include broadly neutralizing antibodies is a natural extension of this clinical trial (NCT03485963).…”

B cells engineered to express pathogen-specific antibodies using CRISPR/Cas9 protect against infection

“…One approach involves viral transduction of muscle cells with an adenoviral vector encoding a protective antibody 10,11 . Another approach is transduction of hematopoietic stem cells with a lentivirus-encoded secreted antibody, which are differentiated into antibody-secreting plasma cells in vitro prior to infusion, or allowed to differentiate in vivo after infusion 12,13 . A shared limitation to both the adenoviral/muscle and lentiviral/stem cell approaches is that the level of antibody produced is fixed and unresponsive to infection.…”

Ingénierie de lymphocytes B humains produisant des anticorps neutralisant le virus VIH-1 par édition génique CRISPR-Cas9

“…Anticorps monoclonaux : quand les cellules de l'immunité s'en mêlent musculaires avec des vecteurs viraux, lentivirus et virus adéno-associé, codant un anticorps neutralisant le VIH-1[5]. Une approche ex vivo consisterait, quant à elle, à isoler des cellules souches hématopoïétiques et à les transduire avec un vecteur lentiviral codant le bNAb avant de les réimplanter in vivo[6]. Plusieurs limitations peuvent être néanmoins associées à l'utilisation de ces vecteurs, telles qu'une expression faible et non durable du transgène, ainsi que le développement d'une immunité anti-vecteur délétère.…”