Cabotegravir (CAB), an extended-release integrase inhibitor, is the first FDA approved long-acting, injectable option for HIV pre-exposure prophylaxis (PrEP) and is gaining preferences in pregnant women. To date, there is limited safety and outcome data in pregnancy after CAB exposure. However, a handful of studies indicated that CAB has adverse effects on the outcomes of pregnancy, such as early pregnancy loss, ectopic pregnancy, and preeclampsia. A few animal studies suggested that CAB interferes with embryonic stem cell differentiation. The placenta plays a central role in establishing and maintaining pregnancy, by forming multiple trophoblast sublineages. The placenta with extensive trophoblast differentiation during early pregnancy is vulnerable to nutritional, hormonal, and oxidative stresses.
Mitochondria play a critical role in maintaining cellular homeostasis, and, more specifically in the trophoblast cells, for steroidogenesis. Mitochondrial homeostasis is regulated by mitochondrial biogenesis and mitophagy, a specific procedure to remove dysfunctional mitochondria. Impaired mitophagy occurs in major pregnancy related disorders and is associated with reduced mitochondrial ATP production and enhanced reactive oxygen species (ROS) production in trophoblast cells. Currently, Dr. Gao's working hypothesis is that cabotegravir exposure impairs mitochondrial mitophagy and ATP production in the placental tissue and trophoblast cells. This hypothesis is tested by two specific aims:
- Specific Aim 1 is to determine whether CAB impairs mitochondrial functions and mitophagy in the process of differentiation of human trophoblast stem cell line, a recently developed cell model for the study of trophoblast differentiation in early pregnancy.
- Specific Aim 2 is to investigate whether CAB impairs mitochondrial functions and mitophagy in human primary trophoblast cells and tissues in late pregnancy when fetal growth is rapid.
Taken together, the novel proposed research is to investigate the effects of CAB on placental trophoblast cells, specifically mitochondrial function and mitophagy. The proposed link between CAB exposure and placental mitochondria will open a new window in mechanistic studies on adverse effects of CAB, which will be investigated in the following NIH grant applications, aiming at promoting the pregnancy outcome in women with PrEP. Considering that CAB is increasingly popular in PrEP in women with HIV in reproductive age, this proposal and following mechanistic studies are of great clinical significance.
Project Summary provided by investigator