Maternal HIV-1 infection during pregnancy is associated with mother-to-child transmission. In the absence of clinical interventions, the risk of intrauterine transmission is estimated at 5% to 10%, suggesting that mechanisms have evolved at the maternal-fetal interface over millennia to restrict retroviral infection. These mechanisms have been characterized over the last decade by our group.
Major findings include: [1-6]
- Placental macrophages exhibit reduced ability to replicate HIV-1 in vitro.
- These cells sequester virus and may serve as protective reservoirs to permit intracellular neutralization in virus-containing compartments and permit antiretroviral (ARV) drug entry.
- Limited availability of CD4+CCR5+ target cells in cord blood may restrict establishment of viral infection.
- Maternal CMV co-infection during pregnancy may facilitate fetal HIV-1 acquisition.
- Recently, we showed that placental macrophages early in gestation express higher levels of CCR5, exhibiting a more activated phenotype than term cells
Our current focus is on ex vivo characterization of the placenta during maternal HIV-1 infection using novel imaging, transcriptomic and proteomic approaches. Identified correlates of protection may contribute toward vaccine development.
Our collaborators include Dr. Erica Johnson at Morehouse School of Medicine, professor Clive Gray at the University of Cape Town, and professor Sarah Rowland-Jones at the University of Oxford.
Globally, many individuals are infected with CMV, reflecting the ubiquity of this virus and its ability to spread by horizontal and vertical transmission. Seroprevalence of 100% is estimated in many parts of Africa and Asia, with numbers up to 86 % in women of childbearing age. CMV infection in pregnant women infected with HIV-1 may alter fetal immune responses even in the absence of mother-to-child transmission of HIV-1. Maternal primary infection during early gestation (first or early second trimester) is associated with an increased incidence of fetal CMV infection. Congenital CMV infection can be asymptomatic, but severe manifestations include sensorineural hearing loss, cognitive delay, and impairment of neurodevelopment, chorioretinitis and hepatosplenomegaly.
Several studies, including from our group, have identified placental cytotrophoblasts and macrophages as mediators of CMV transmission [7, 8]. We have shown that infection of fetal lymphocytes and placental macrophages upregulates CCR5 expression, induces cellular activation and secretion of inflammatory mediators, and inhibits signal transducer and activator of transcription 2 (STAT2) [5, 6].
Current research includes defining immune-mediated placental responses in infants diagnosed with congenital CMV, specifically phenotyping of infiltrating immune cells. We are also characterizing the dynamics of maternal-fetal cross-talk following CMV exposure using transcriptomic and proteomic approaches.
Zika is an arthropod-born virus transmitted by Aedes aegypti and Aedes Albopictus mosquitoes, which are also vectors for dengue and chikungunya viruses. Zika can pass through the placental barrier and replicate in placental macrophages, leading to viral dissemination in the fetus with signs of congenital Zika syndrome.
Our group has shown that the Zika virus can infect placental macrophages. Infected cells may disseminate the Zika virus to the fetus. Zika virus replication coincides with induction of type 1 interferons, pro-inflammatory cytokines and antiviral gene expression, but with minimal cell death. These results suggest a mechanism for intrauterine transmission in which the Zika virus gains access to the fetal compartment by directly infecting placental cells. 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is a global pandemic with significant mortality. The number of pregnant women with COVID-19 is increasing. However, the impact of maternal infection on vertical transmission and pregnancy outcomes remains unclear. While some reports document no transmission from mother to newborn, others have identified infants infected with SARS-CoV-2. Additionally, pregnant women with COVID-19 had increased fetal complications, including miscarriage (2%), intrauterine growth restriction (10%) and preterm birth (39%), and complications postpartum.
While we are quickly gaining knowledge regarding mechanisms and risk factors for COVID-19 in adults, most studies have not included pregnant women. Transmission of SARS-CoV-2 to the fetus may be promoted or protected by immune mechanisms in the placenta; furthermore, placental dysfunction may occur in the absence of intrauterine transmission. Our group is characterizing placental immune responses to SARS-CoV-2 to identify host genetic and immune correlates. Our studies will identify whether SARS-CoV-2 can be transmitted transplacentally, and genes that are affected during maternal infection in pregnancy. We are also examining the effects of COVID-19 vaccination on the placenta.
- Johnson EL, Chakraborty R. Placental Hofbauer cells limit HIV-1 replication and potentially offset mother to child transmission (MTCT) by induction of immunoregulatory cytokines. Retrovirology. 2012; doi:10.1186/1742-4690-9-101.
- Rimawi BH, Johnson E, Rajakumar A, Tao S, Jiang Y, Gillespie S, Schinazi RF, Mirochnick M, Badell ML, Chakraborty R. Pharmacokinetics and placental transfer of elvitegravir, dolutegravir, and other antiretrovirals during pregnancy. Antimicrobial Agents and Chemotherapy. 2017; doi:10.1128/AAC.02213-16.
- Johnson EL, Chu H, Byrareddy SN, Spearman P, Chakraborty R. Placental Hofbauer cells assemble and sequester HIV-1 in tetraspanin-positive compartments that are accessible to broadly neutralizing antibodies. Journal of the International AIDS Society. 2015; doi:10.7448/IAS.18.1.19385.
- Johnson EL, Howard CL, Thurman J, Pontiff K, Johnson ES, Chakraborty R. Cytomegalovirus upregulates expression of CCR5 in central memory cord blood mononuclear cells, which may facilitate in utero HIV type 1 transmission. The Journal of Infectious Diseases. 2015; doi:10.1093/infdis/jiu424.
- Johnson EL, Boggavarapu S, Johnson ES, Lal AA, Agrawal P, Bhaumik SK, Murali-Krishna K, Chakraborty R. Human cytomegalovirus enhances placental susceptibility and replication of human immunodeficiency virus type 1 (HIV-1), which may facilitate in utero HIV-1 transmission. The Journal of Infectious Diseases. 2018; doi:10.1093/infdis/jiy327.
- Johnson EL, Swieboda D, Olivier A, Enninga EAL, Chakraborty R. Robust innate immune responses at the placenta during early gestation may limit in utero HIV transmission. PLOS Pathogens. 2021; doi:10.1371/journal.pat.1009860.
- Wussow F, Chiuppesi F, Martinez J, Campo J, Johnson E, Flechsig C, Newell M, Tran E, Ortiz J, La Rosa C, Herrmann A, Longmate J, Chakraborty R, Barry PA, Diamond DJ. Human cytomegalovirus vaccine based on the envelope gH/gL pentamer complex. PLOS Pathogens. 2014; doi:10.1371/journal.ppat.1004524.
- Chiuppesi F, Wussow F, Johnson E, Bian C, Zhuo M, Rajakumar A, Barry PA, Britt WJ, Chakraborty R, Diamond DJ. Vaccine-derived neutralizing antibodies to the human cytomegalovirus gH/gL pentamer potently block primary cytotrophoblast infection. Journal of Virology. 2015; doi:10.1128/JVI.01701-15.
- Quicke KM, Bowen JR, Johnson EL, McDonald CE, Ma H, O'Neal JT, Rajakumar A, Wrammert J, Rimawi BH, Pulendran B, Schinazi RF, Chakraborty R, Suthar MS. Zika virus infects human placental macrophages. Cell Host and Microbe. 2016; doi:10.1016/j.chom.2016.05.015.