Modeling HIV-1 pathogenesis and therapy in humanized mice

Abstract

Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS) and currently, there are no complete cure or effective vaccines available. Animal models that highly resembles human systems may enhance the delineation of mechanisms underlying HIV-1/AIDS. Among them, humanized mice have been extensively used and have greatly facilitated HIV/AIDS research. However, absence or low levels of cross-reactivities between human and mouse cytokines substantially impairs the establishment of human immune system in immunodeficient mice. As compared to gene knock-in technology, adeno-associated virus (AAV)-mediated gene delivery is an easier method to achieve long-term protein expression. Therefore, I evaluated the effects of AAV-delivered human GM-CSF and Fms-like tyrosine kinase 3 ligand (Flt3L) on repopulating human immune cells in NOD.Cg-PrkdcscidIl2rgtm1Wjl (NSG) mice. I found that GM-CSF substantially expanded while Flt3L significantly inhibited the engraftment of human immune cells by inducing myeloid-derived suppressor cells (MDSCs).

On the other hand, intrarectal infection represents a major route of HIV-1 transmission among men who have sex with men (MSM). However, the susceptibility of huCD34 (immunodeficient mice transplanted with human stem cells) mice to mucosal HIV-1 transmission remains controversial. Therefore, the vulnerability of NSG-huCD34 to rectal HIV-1 exposure was evaluated in the current study. Systemic HIV-1 infection was confirmed in NSG-huCD34 mice since HIV-1-infected cells with dramatic depletion of human CD4+ T cells were observed in multiple tissues. Next, the protective effects of a tandem bispecific antibody (BiIA-SG-IgG1) on rectal HIV-1 transmission in NSG-huCD34 mice were evaluated. NSG-huCD34 mice were partially protected from rectal HIV-1 acquisition but led to serious loss of CD4 T cells by BiIA-SG-IgG1. To avoid CD4 T cell depletion, BiIA-SG-IgG1 was redesigned with IgG4 Fc. Results showed that BiIA-SG-IgG4 conferred partial protection to humanized mice against rectal HIV-1 acquisition without inducing CD4 T loss.

The combined combination antiretroviral therapy (cART) and anti-α4β7 antibody therapy allows macaques to durably control SIV rebound after withdrawal of the interventions. We sought to determine whether similar effects would also happen on HIV-1. Thus, the anti-HIV-1 efficacies of humanized anti-α4β7 antibody vedolizumab (VDZ) were determined in vitro and in humanized mice. Pre-treating the mice with VDZ enhanced the infectivity of pseudotyped HIV-1SF162 on (retinoic acid) RA-induced α4β7+ MEMT cells. Moreover, VDZ failed to prevent live HIV-1SF162 infection when administrated prior HIV-1 challenge in humanized mice. Lastly, withdrawal of combined cART with VDZ or rhesus recombinant anti-α4β7 antibody (RM-α4β7) resulted in an uncontrolled HIV-1SF162 rebound in humanized mice.

In summary, persistent expression of human GM-CSF mediated by AAV enhanced, while hFlt3L substantially inhibited the repopulation of human cells in humanized mice. Furthermore, NSG-huCD34 model was a useful model for recapitulating rectal HIV-1 pathogenesis and prevention. Finally, VDZ was found to neither prevent nor control HIV-1SF162 infection both in vitro and in humanized mice. Overall, findings of the current study highlighted the potential of huCD34 mice as an important research tool in modeling HIV-1 pathogenesis and therapy.