NK cells are effectors of the innate immune system capable of innately identifying and eliminating virally contaminated cells via multiple ways. Epidemiological and genetic research have demonstrated that NK cell interactions with self-HLA molecules are essential in detecting HIV-infected cells and may decrease disease development, diminish viral setpoint, or moderate immune pressure.
The role of NK cell interactions with NK cell ligands in recognizing HIV-infected cells has been proven conclusively by in vitro research. Multiple organizations have used adoptively transferred NK cells to reduce HIV infection in humanized mice, in addition to in vitro trials. Due to a lack of humanized mouse models, in vivo studies of the biology of endogenous human NK cell immune responses during acute and chronic HIV infection have been limited.
As per Journal of Clinical Investigation, Sangur and colleagues developed MISTRG-6-15 mice by introducing human IL-6 and IL-15 into MISTRG mice. After transplantation of human cord blood-derived hematopoietic stem and progenitor cells (HSPCs), these animals demonstrated superior human NK cell repopulation compared to the commonly utilized humanized NSG mouse model.
Nonlymphoid organs displayed degranulation, cytotoxicity, and cytokine secretion in response to HIV infection in MISTRG-6-15 animals with rapidly expanding NK cells. In addition, NK cells in lymphoid organs had decreased CD16 expression and function, which may reflect tissue-specific variations observed in human circulating and tonsillar NK cells. The authors’ capacity to monitor HIV infection in MISTRG-6-15 mice for almost five months while longitudinally sampling NK cells and performing ex vivo functional assays was an essential strength of this investigation.
Ex vivo, the NK cells collected during the initial weeks of an acute infection were more activated, proliferative, and functional. NK cells collected several months after the original infection displayed immunological exhaustion, as evidenced by an increase in immune checkpoint–receptor surface expression and a decline in ex vivo activity. Antiretroviral therapy (ART) inhibited viral replication in vivo, which partially restored NK cell numbers and functionality compared to mice demonstrating rebound viremia after ART discontinuation.
Importantly, the scientists demonstrated conclusively that NK cell depletion caused by an NK-specific NKp46 antibody enhanced plasma and tissue cell–associated HIV-1 RNA levels. This implies that circulating and tissue-specific NK cells inhibit HIV-1 replication in vivo. This observation is also consistent with our recent findings that the injection of exogenous human NK cells inhibits viral rebound following discontinuation of antiretroviral therapy in a separate humanized mouse model.
The authors also used a broadly neutralizing antibody (bNab) — PGT121 with a mutation to disrupt Fc binding — to demonstrate that NK activation and functionality were enhanced in an Fc-dependent manner, which is consistent with a recent study demonstrating that NK cell ADCC function in SRG-15 mice can be utilized to control and reduce HIV infection.
Sangur and colleagues hypothesized that knocking in human IL-6 would generate a mouse model with greater physiological relevance than NSG mice humanized with cord blood CD34+ HSPCs. They hypothesized that the expression of human IL-6 enhances human HSPC and myeloid differentiation while partially inhibiting mouse hematopoiesis.
Moreover, scientists believe that human IL-15 knock-in boosted NK engraftment in their mice model. As direct comparisons were not undertaken, it is unknown whether humanized MISTRG-6-15 mice are superior than more current humanized MISTRG or SRG-15 mice.
In researching the innate immune response during HIV infection, the authors explore a fascinating field of research. Future research will require the MISTRG-6-15 mice to determine which NK receptor and ligand interactions are required for the recognition and clearance of HIV-infected cells in vivo. This model will also assist in the creation of strategies to utilize the innate immune response to combat HIV infection.