Robust innate immune responses at the placenta during early gestation may limit in utero HIV transmission

Abstract

In 2019, >90% of new HIV infections in infants globally occurred vertically. Studies suggest intrauterine transmission most often occurs in the third trimester; however, there are no mechanistic studies to support these observations. We therefore obtained early/mid-gestation and term placentae from 20 HIV/Hepatitis B/CMV negative women. Isolated primary placental macrophages (Hofbauer cells [HCs]) were exposed to HIV-1BaL and/or interferon (IFN)-α, IFN-β, IFN-λ1, and RIG-I-like receptor (RLR) agonists. qRT-PCR, FACS, ELISA, Luminex, and Western blot analyses determined expression of activation markers, co-receptors, viral antigen, cytokines, antiviral genes, and host proteins. Early gestation HCs express higher levels of CCR5 and exhibit a more activated phenotype. Despite downregulation of CCR5, term HCs were more susceptible to HIV replication. Early gestation HCs displayed a more activated phenotype than term HCs and HIV exposure lead to the further up-regulation of T-cell co-stimulatory and MHC molecules. Limited HIV replication in early/mid gestation HCs was associated with increased secretion of anti-inflammatory cytokines, chemokines, and a more robust antiviral immune response. In contrast, term HCs were more susceptible to HIV replication, associated with dampening of IFN-induced STAT1 and STAT2 protein activation. Treatment of early/mid gestation and term HCs, with type I IFNs or RLR agonists reduced HIV replication, underscoring the importance of IFN and RLR signaling in inducing an antiviral state. Viral recognition and antiviral immunity in early gestation HCs may prevent in utero HIV infection, whereas diminished antiviral responses at term can facilitate transmission. Defining mechanisms and specific timing of vertical transmission are critical for the development of specific vaccines and antiviral therapeutics to prevent new HIV infections in children globally.

Monocytes and macrophages in pregnancy: The good, the bad, and the ugly*

“…140 However, in vitro studies have found that HBCs limit HIV-1 replication by producing IL-10, sequestering HIV in acidic compartments, and reducing the triggering of pro-inflammatory responses that could be detrimental to pregnancy. 141 Zika virus (ZIKV) is a flavivirus that can be transmitted via blood transfusion, sexual contact, or mosquito bite. ZIKV is known for its ability to surmount intrinsic defense mechanisms of the placenta allowing it to reach 10% of developing fetuses 123 resulting in adverse birth defects such as microcephaly.…”

Preterm Birth in Women With HIV: The Role of the Placenta

“…HIV can cross the placenta and the virions can either be cellassociated, antibody-associated or free (32,33). The virions can interact directly with the tissue resident immune cells including Hofbauer cells and decidual macrophages which express the HIV receptor CD4 and co-receptors C-C chemokine receptor 5 (CCR5), C-X-C chemokine receptor 4 (CXCR4) and Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-Integrin (DC-SIGN) (32,33). In fact, there is evidence that viral replication may occur locally within the placenta based on phylogenetic studies demonstrating genetic divergence between placental and systemic maternal HIV quasi species (34,35).…”

“…HIV can cross the placenta and the virions can either be cell-associated, antibody-associated or free ( 32 , 33 ). The virions can interact directly with the tissue resident immune cells including Hofbauer cells and decidual macrophages which express the HIV receptor CD4 and co-receptors C-C chemokine receptor 5 (CCR5), C-X-C chemokine receptor 4 (CXCR4) and Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-Integrin (DC-SIGN) ( 32 , 33 ). In fact, there is evidence that viral replication may occur locally within the placenta based on phylogenetic studies demonstrating genetic divergence between placental and systemic maternal HIV quasi species ( 34 , 35 ).…”

“…In fact, there is evidence that viral replication may occur locally within the placenta based on phylogenetic studies demonstrating genetic divergence between placental and systemic maternal HIV quasi species ( 34 , 35 ). In this section we review evidence that from studies that demonstrate how the placenta “naturally” protects the fetus from viral infection in utero ( 33 , 36 , 37 ). This protection is mediated by key placental immunocytes including decidual NK (dNK) and Hofbauer cells which inhibit HIV infection at the maternal fetal interface.…”

“…The risk of vertical transmission seems to increase with an increase in gestational age; with lowest and highest transmission in the first trimester and third trimester respectively ( 33 , 43 , 44 ). A recent report by Johnson et al ( 33 ) provides mechanistic evidence in support of this observation. In their study, early gestation Hofbauer cells (HCs) displayed a more activated phenotype compared to term cell isolates.…”