The purpose of this proposal is to test the hypothesis that neonatal BCG vaccination leads to activation of immune response that may increase the susceptibility to HIV infection in breast-fed infants of HIV-positive mothers. This investigation stems from the candidate's research as a post-doctoral fellow in heterologous ^ immunity and will allow her to develop expertise in patient-based immunology research. Furthermore, it provides a long-sought opportunity to develop skills in international research and foster an academic collaboration with Latin America, the candidate's region of origin.
The specific aim of this proposal is to evaluate the effect of BCG on expression of co-receptors required for HIV entry (CCR5 and CXCR4) and on susceptibility of mononuclear cells to HIV infection. The initial phase of the study will be performed in vitro, using cord blood cells from healthy infants. Determination of co- receptors levels will be performed using FACS analysis and single-round HIV infection will be measured with a recombinant GFP-expressing HIV-1. The clinical phase of the study will proceed after optimization of all assays involved, and will involve healthy neonates. This phase is a longitudinal assessment of co-receptor expression and HIV susceptibility of mononuclear cells before and after BCG vaccination. Activation markers and HIV susceptibility will be measured in cord blood mononuclear cells (pre-BCG) and peripheral blood mononuclear cells obtained from the same infants 6 weeks'after BCG vaccination. A significant proportion of infants infected with HIV through maternal-to-child-transmission (MTCT) are infected in the post-partum period through exposure to breastmilk. Although exclusive replacement feeding eliminates the risk of HIV acquisition through lactation, this option is often not safe or feasible for women in lower income settings due to stigma, high cost of formula, or poor access to potable water. The results from this study will provide a conceptual immunologic basis for further exploring the clinical effect of BCG-induced immune activation on host susceptibility to HIV. The effect of BCG on co-receptors required for HIV entry may have implications regarding the timing of BCG vaccination in HIV-exposed breastfed neonates.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HD056957-05
Application #
8294777
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Mofenson, Lynne M
Project Start
2008-06-05
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$130,515
Indirect Cost
$9,668
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Thayil, Seema M; Ho, Ya-Chi; Bollinger, Robert C et al. (2012) Mycobacterium tuberculosis complex enhances susceptibility of CD4 T cells to HIV through a TLR2-mediated pathway. PLoS One 7:e41093
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Chen, Nadine E; Gallant, Joel E; Page, Kathleen R (2012) A systematic review of HIV/AIDS survival and delayed diagnosis among Hispanics in the United States. J Immigr Minor Health 14:65-81
Berry, Stephen A; Ghanem, Khalil G; Page, Kathleen R et al. (2011) Increased gonorrhoea and chlamydia testing did not increase case detection in an HIV clinical cohort 1999-2007. Sex Transm Infect 87:469-75
Page, Kathleen Raquel; Castillo-Page, Laura; Wright, Scott M (2011) Faculty diversity programs in U.S. medical schools and characteristics associated with higher faculty diversity. Acad Med 86:1221-8
Berry, Stephen A; Ghanem, Khalil G; Page, Kathleen R et al. (2010) Gonorrhoea and chlamydia testing rates of HIV-infected men: low despite guidelines. Sex Transm Infect 86:481-4

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