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Potent Simian Immunodeficiency Virus-Specific Cellular Immune Responses in the Breast Milk of Simian Immunodeficiency Virus-Infected, Lactating Rhesus Monkeys¹

Sallie R. Permar^2,*,, Helen H. Kang^*, Angela Carville, Keith G. Mansfield, Rebecca S. Gelman, Srinivas S. Rao^¶, James B. Whitney^* and Norman L. Letvin^*

^* Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; Division of Infectious Disease, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115; New England Regional Primate Research Center, Harvard Medical School, Southboro, MA 01772; Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; and ^¶ Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892

Breast milk transmission of HIV is a leading cause of infant HIV/AIDS in the developing world. Remarkably, only a small minority of breastfeeding infants born to HIV-infected mothers contract HIV via breast milk exposure, raising the possibility that immune factors in the breast milk confer protection to the infants who remain uninfected. To model HIV-specific immunity in breast milk, lactation was pharmacologically induced in Mamu-A*01⁺ female rhesus monkeys. The composition of lymphocyte subsets in hormone-induced lactation breast milk was found to be similar to that in natural lactation breast milk. Hormone-induced lactating monkeys were inoculated i.v. with SIVmac251 and CD8⁺ T lymphocytes specific for two immunodominant SIV epitopes, Gag p11C and Tat TL8, and SIV viral load were monitored in peripheral blood and breast milk during acute infection. The breast milk viral load was 1–2 logs lower than plasma viral load through peak and set point of viremia. Surprisingly, whereas the kinetics of the SIV-specific cellular immunity in breast milk mirrored that of the blood, the peak magnitude of the SIV-specific CD8⁺ T lymphocyte response in breast milk was more than twice as high as the cellular immune response in the blood. Furthermore, the appearance of the SIV-specific CD8⁺ T lymphocyte response in breast milk was associated with a reduction in breast milk viral load, and this response remained higher than that in the blood after viral set point. This robust viral-specific cellular immune response in breast milk may contribute to control of breast milk virus replication.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Center for HIV/AIDS Vaccine Immunology (to S.R.P. and N.L.L.; R01AI067854), the Fred Lovejoy Research and Education Fund (to S.R.P.), the Children’s Hospital House Officer Research Award (to S.R.P.), the Pediatric Infectious Disease Society/St. Jude Children’s Hospital Basic Science Research Award (to S.R.P.), and the Harvard Center for AIDS Research (to R.S.G.; P30AI060354).

² Address correspondence and reprint requests to Dr. Sallie R. Permar, 330 Brookline Avenue, Research East, Beth Israel Deaconess Medical Center, Boston, MA 02115. E-mail address: sallie.permar{at}childrens.harvard.edu

³ Abbreviations used in this paper: EM, effector memory; CM, central memory; HIL, hormone-induced lactation; NL, natural lactation; sIgA, secretory IgA.