Placenta analysis of Hofbauer cell profile according to the class of antiretroviral therapy used during pregnancy in people living with HIV

Introduction: The use of antiretroviral therapy drastically reduces vertical transmission of Human Immunodeficiency Virus. However, recent studies demonstrate associations between ART use during pregnancy and placental inflammation, particularly within protease inhibitor (PI)-based regimens. We sought to characterize placental macrophages, namely Hofbauer cells, according to the class of ART used during pregnancy. Methods: Using immunofluorescence and immunohistochemistry, placentas from 79 pregnant people living with HIV (PPLWH) and 29 HIV-uninfected people were analyzed to quantify the numbers and frequencies of leukocytes (CD45⁺) and Hofbauer cells (CD68⁺ and/or CD163⁺). PPLWH were stratified into three groups based on class of ART: non-nucleoside reverse transcriptase inhibitor (NNRTI)-based, integrase strand-transfer inhibitor (INSTI)-based, and PI-based regimens. Results: Placentas of PPLWH contained significantly more leukocytes and Hofbauer cells than controls. Multivariable analyses revealed that this increase in immune cells was associated with a predominantly CD163⁺ profile in all ART subgroups compared to the HIV-negative group. This was characterized by an increase in total CD163⁺ cells in the PI and INSTI subgroups, and a higher frequency of CD163⁺ cells and CD163⁺/CD68⁺ ratio in the NNRTI and PI subgroups. Discussion: Placentas of PPLWH treated with any ART regimen during their entire pregnancy displayed a selection for CD163⁺ cells compared to the HIV-negative group, regardless of class of ART, suggesting that class of ART does not intrinsically affect selection of CD163+ and CD68⁺ Hofbauer cells. Further investigations into the role of Hofbauer cells in ART-associated placental inflammation are warranted to identify the mechanisms behind their potential involvement in maternal-fetal tolerance maintenance.