Human Breast Milk and Antiretrovirals Dramatically Reduce Oral HIV-1 Transmission in BLT Humanized Mice

Angela Wahl,Michael D Swanson,Tomonori Nochi,Rikke Olesen,J Victor Garcia,Paul W Denton,Morgan Chateau,Guido Silvestri

doi:10.1371/journal.ppat.1002732

Angela Wahl, Michael D Swanson + Show 6 more

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https://doi.org/10.1371/journal.ppat.1002732

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Abstract

Currently, over 15% of new HIV infections occur in children. Breastfeeding is a major contributor to HIV infections in infants. This represents a major paradox in the field because in vitro, breast milk has been shown to have a strong inhibitory effect on HIV infectivity. However, this inhibitory effect has never been demonstrated in vivo. Here, we address this important paradox using the first humanized mouse model of oral HIV transmission. We established that reconstitution of the oral cavity and upper gastrointestinal (GI) tract of humanized bone marrow/liver/thymus (BLT) mice with human leukocytes, including the human cell types important for mucosal HIV transmission (i.e. dendritic cells, macrophages and CD4+ T cells), renders them susceptible to oral transmission of cell-free and cell-associated HIV. Oral transmission of HIV resulted in systemic infection of lymphoid and non-lymphoid tissues that is characterized by the presence of HIV RNA in plasma and a gradual decline of CD4+ T cells in peripheral blood. Consistent with infection of the oral cavity, we observed virus shedding into saliva. We then evaluated the role of human breast milk on oral HIV transmission. Our in vivo results demonstrate that breast milk has a strong inhibitory effect on oral transmission of both cell-free and cell-associated HIV. Finally, we evaluated the effect of antiretrovirals on oral transmission of HIV. Our results show that systemic antiretrovirals administered prior to exposure can efficiently prevent oral HIV transmission in BLT mice.

Highlights

Pediatric HIV infection is associated with an accelerated course of disease and high mortality rate
This limited transmission has led to two apparently contradictory roles for milk in HIV infection: vector of transmission or vehicle of protection? Milk has a strong inhibitory effect on HIV infection in vitro. This has never been demonstrated in an in vivo system. We address this paradox in a bone marrow/liver/thymus humanized mouse model of oral transmission of cellfree and cell-associated HIV
Reconstitution of the oral cavity of bone marrow/liver/thymus (BLT) mice with human hematopoietic cells Highlighting the importance of the oral cavity as the first site of exposure for HIV that is transmitted during breastfeeding, our initial aim for this study was to examine if the oral mucosa of BLT mice is repopulated with human hematopoietic cells

Summary

Introduction

Pediatric HIV infection is associated with an accelerated course of disease and high mortality rate. In the absence of antiretroviral therapy, only 65% of HIV-infected children survive until their first birthday and less than half will reach two years of age [1]. In developed countries the incidence of mother-to-child transmission of HIV is extremely low; HIV-infected women receive antiretroviral therapy during pregnancy and delivery and abstain from breastfeeding. Their children receive antiretroviral prophylaxis at birth and for several weeks thereafter. The majority of HIV-infected children live in sub-Saharan Africa where HIV-positive women have limited access to antiretroviral drugs and the health benefits of breastfeeding outweigh the risk of HIV transmission [3]

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