Neisseria gonorrhoeae co-infection exacerbates vaginal HIV shedding without affecting systemic viral loads in human CD34+ engrafted mice

HIV synergy with sexually transmitted co-infections is well-documented in the clinic. Co-infection with Neisseria gonorrhoeae in particular, increases genital HIV shedding and mucosal transmission. However, no animal model of co-infection currently exists to directly explore this relationship or to bridge the gap in understanding between clinical and in vitro studies of this interaction. This study aims to test the feasibility of using a humanized mouse model to overcome this barrier. Combining recent in vivo modelling advancements in both HIV and gonococcal research, we developed a co-infection model by engrafting immunodeficient NSG mice with human CD34+ hematopoietic stem cells to generate humanized mice that permit both systemic HIV infection and genital N. gonorrhoeae infection. Systemic plasma and vaginal lavage titres of HIV were measured in order to assess the impact of gonococcal challenge on viral plasma titres and genital shedding. Engrafted mice showed human CD45+ leukocyte repopulation in blood and mucosal tissues. Systemic HIV challenge resulted in 104−105 copies/mL of viral RNA in blood by week 4 post-infection, as well as vaginal shedding of virus. Subsequent gonococcal challenge resulted in unchanged plasma HIV levels but higher viral shedding in the genital tract, which reflects published clinical observations. Thus, human CD34+ stem cell-transplanted NSG mice represent an experimentally tractable animal model in which to study HIV shedding during gonococcal co-infection, allowing dissection of molecular and immunological interactions between these pathogens, and providing a platform to assess future therapeutics aimed at reducing HIV transmission.

人类免疫缺陷病毒（Human Immunodeficiency Virus, HIV）与性传播合并感染的协同效应在临床中已有充分文献记载。其中，合并感染淋病奈瑟菌（Neisseria gonorrhoeae）会加剧生殖道HIV脱落及黏膜传播风险。然而，目前尚无可用的合并感染动物模型，可直接探究二者的相互作用关系，填补该交互作用的临床研究与体外研究之间的认知空白。本研究旨在验证使用人源化小鼠模型突破这一研究瓶颈的可行性。结合HIV与淋球菌研究领域近期的体内建模进展，我们通过向免疫缺陷NSG小鼠移植人源CD34+造血干细胞（CD34+ hematopoietic stem cells），构建了可同时支持系统性HIV感染与生殖道淋病奈瑟菌感染的人源化小鼠合并感染模型。通过检测系统性血浆与阴道灌洗液中的HIV病毒滴度，我们评估了淋球菌攻毒对血浆HIV滴度及生殖道病毒脱落的影响。经干细胞移植的小鼠，其血液与黏膜组织中呈现人源CD45+白细胞（CD45+ leukocyte）的定植重建。系统性HIV攻毒后第4周，小鼠血液中可检测到10^4~10^5 copies/mL的病毒RNA，同时伴随生殖道病毒脱落。后续淋球菌攻毒后，血浆HIV水平未发生显著变化，但生殖道病毒脱落量显著升高，这与已发表的临床研究结果一致。综上，经人CD34+造血干细胞移植的NSG小鼠是一种实验可操作性强的动物模型，可用于研究淋球菌合并感染期间的HIV脱落现象，从而解析这两种病原体之间的分子与免疫相互作用，并为评估旨在降低HIV传播的新型治疗手段提供研究平台。