The Role of Tunneling Nanotubes and Mitochondrial programming in HIV-Associated Placental Dysfunction - PROJECT SUMMARY / ABSTRACT HIV is known to be transmissible from mother to the developing fetus during pregnancy, leading to adverse health outcomes for both. Although HIV is linked to placental pathologies, there is still a large gap in knowledge about the mechanisms underlying HIV-associated pregnancy complications, despite four decades of research in general on HIV topics. The objective of this project is to investigate the role of intercellular conduits composed of F-actin microtubules that connect plasma membranes of neighboring cells enabling cytoplasmic continuing and intercellular transfer of cargo. These conduits are known as tunneling nanotubes (TNTs). Recent investigations by the PI and others have demonstrated that other viruses such as Zika and SARS-CoV-2 induce the formation of TNTs in placental trophoblast cells, and there is evidence they serve as a means of mitochondrial transfer and possibly viral transfer that promotes infectious spread. There is evidence that HIV induces TNT formation in neurons, but it is not known whether the virus has this effect on placental cells. Building on prior studies and ongoing work by the PI, the central hypothesis of this project is that HIV uses TNTs to spread infection in trophoblasts, and that TNTs mediate placental dysfunction by transferring damaged mitochondria and adversely reprogramming trophoblast metabolism. This metabolic reprogramming may contribute to placental dysfunction and adverse pregnancy outcomes. Aim 1 of this project will elucidate the molecular mechanisms of TNT formation between HIV-infected immune cells and trophoblasts. Aim 2 will determine the impact of HIV on mitochondrial dynamics and transfer and resulting trophoblast function. These two aims will be pursued during the final postdoctoral training period of the K99 phase. Aim 3 seeks to identify how HIV-exposed mitochondria reprogram trophoblast biology, impairing placental function and affecting fetal development in vivo. This third aim will be pursued during the R00 phase of the project. Successful completion of these aims will provide new insights into the mechanisms underlying HIV infection, identifying potential therapeutic targets to mitigate vertical transmission and placental pathologies caused by HIV and other viruses. During the mentored phase, the PI will gain expertise in primary cell culture, metabolomics, trophoblast organoids, and mitochondrial epigenetics to examine how HIV infects the placenta and disrupts cellular metabolism—establishing a foundation for the R00 phase. With guidance from the advisory team, this training and research will contribute to the identification of therapeutic strategies to improve outcomes for infants and individuals with HIV, while positioning the investigator to establish an independent, competitive R01-funded laboratory at the intersection of HIV, TNTs, placental biology, and mitochondria.
