PLoS Pathogens: Human Breast Milk and Antiretrovirals Dramatically Reduce Oral HIV-1 Transmission in BLT Humanized Mice
Human Breast Milk and Antiretrovirals Dramatically Reduce Oral HIV-1 Transmission in BLT Humanized Mice
1 Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America, 2 Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark
Abstract Top
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.Author Summary Top
Infected children acquire HIV from their mother in utero, intrapartum or by ingesting their mother's breast milk which can contain both HIV particles (cell-free) and HIV-infected cells (cell-associated). Although breastfeeding is attributed to a significant number of HIV infections in children, most breastfed infants remain uninfected despite prolonged and repeated exposure to HIV. 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. However, this has never been demonstrated in an in vivo system. In the present study, we address this paradox in a bone marrow/liver/thymus (or BLT) humanized mouse model of oral transmission of cell-free and cell-associated HIV. We demonstrate that human breast milk has potent HIV inhibitory activity that can prevent oral transmission of cell-free and cell-associated HIV in vivo. Our results provide key insight into oral HIV transmission and the protective role of milk. However, since transmission can and does occur in some instances after continued exposure to HIV in milk, we demonstrate that oral HIV transmission can be efficiently prevented in BLT humanized mice by the systemic administration of antiretrovirals.Citation: Wahl A, Swanson MD, Nochi T, Olesen R, Denton PW, et al. (2012) Human Breast Milk and Antiretrovirals Dramatically Reduce Oral HIV-1 Transmission in BLT Humanized Mice. PLoS Pathog 8(6): e1002732. doi:10.1371/journal.ppat.1002732
Editor: Guido Silvestri, Emory University, United States of America
Received: February 28, 2012; Accepted: April 20, 2012; Published: June 14, 2012
Copyright: © 2012 Wahl et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by grants from the NIH NIAID AI071940, AI073146 and The University of North Carolina Center for AIDS Research P30 AI50410. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: victor_garcia@med.unc.edu
Editor: Guido Silvestri, Emory University, United States of America
Received: February 28, 2012; Accepted: April 20, 2012; Published: June 14, 2012
Copyright: © 2012 Wahl et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by grants from the NIH NIAID AI071940, AI073146 and The University of North Carolina Center for AIDS Research P30 AI50410. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: victor_garcia@med.unc.edu
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