Four critical aspects of the proposed research include mouse models: testing Abs designed for improved potency, breadth and/or effector function in a novel in vivo mouse model to assess viral entry, evaluating designed immunogens in human VH germline knock-in mice, determining the basis for HIV resistance using HIV-infected humanized NOD/SCID yc-/- mice, and testing AAV models in humanized NOD/SCID yc-/- mice. First, Dr. Nussenzweig and Dr. Ravetch will develop an in vivo assay to assess the ability of broadly neutralizing antibodies to prevent viral entry in mice bearing human Fc receptors (Aim 1 of Project 1 and Aim 2 of Project 2). HIV neutralization is currently assayed in vitro using TZM-bl cells. This system is based on HIV gpl60 pseudotype viruses that carry a transcriptional activator that induces luciferase. Although the TZM-bl assay provides vital information on neutralizing activity in vitro, it fails to inform about innate effector mechanisms that are likely to be essential for neutralizing activity in vivo. The new proposed in vivo viral entry assay, using HIVr^(flox)Luc mice carrying the ROSA-stop-FloxLuciferase gene and the human CD4 and CCR5 genes, will be used by Dr. Nussenzweig, Dr. Ravetch, and Dr. Bjorkman to assess the impact of antibody specificity and effector function on neutralizing activity in vivo. In addition, we will work with our collaborator Dr. Alexander Ploss who is the head of the Rockefeller University, Memorial Sloan-Kettering Cancer and Weill Cornell Medical College humanized mouse user interest group (HuMIG), to produce humanized mice for experiments proposed in Aim 2 of Project 1 and Aim 3 of Project 2. This will require that we maintain a colony of NOD/SCID yc-/- mice to produce chimeric mice reconstituted with human CD34+ stem cells. The core will perform the human CD34+ stem cell transfers to produce humanized mice for testing bNAbs and defining the basis for HIV resistance (Nussenzweig) and for AAV experiments (Ravetch). Core C will maintain and breed the HIVr^(flox)Luc mice, FcR transgenic mice, and NOD/SCID yc-/- mice and will perform the breeding experiments required to produce hFcR/HIVr^(flox)Luc mice that carry human Fc receptors for the experiments proposed by Dr. Nussenzweig and Dr. Ravetch. Core C will also maintain the human VH germline knock-in mice that will be used in Project 1, Aim 3 to test potential immunogens designed by Dr. Bjorkman in Project 3, Aim 4. In addition Core C will distribute HIVr^(flox)Luc mice to other interested investigators in accordance with our Data Sharing plan and NIH policy.

Public Health Relevance

Core C is essential to the the overall application because it will breed, maintain, monitor, and distribute to researchers the mouse models generated in Projects 1 and 2 and used to evalute the antibodies and potential immunogens created in Projects 2, and 3. Core C will provide humanized mice and other mouse species to researchers for the studies proposed in Projects 1 and 2.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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California Institute of Technology
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Scheid, Johannes F; Horwitz, Joshua A; Bar-On, Yotam et al. (2016) HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 535:556-60
Lu, Ching-Lan; Murakowski, Dariusz K; Bournazos, Stylianos et al. (2016) Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science 352:1001-4
Escolano, Amelia; Steichen, Jon M; Dosenovic, Pia et al. (2016) Sequential Immunization Elicits Broadly Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice. Cell 166:1445-1458.e12
McGuire, Andrew T; Gray, Matthew D; Dosenovic, Pia et al. (2016) Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice. Nat Commun 7:10618
Gautam, Rajeev; Nishimura, Yoshiaki; Pegu, Amarendra et al. (2016) A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533:105-9
Zolla-Pazner, Susan; Cohen, Sandra Sharpe; Boyd, David et al. (2016) Structure/Function Studies Involving the V3 Region of the HIV-1 Envelope Delineate Multiple Factors That Affect Neutralization Sensitivity. J Virol 90:636-49
Halper-Stromberg, Ariel; Nussenzweig, Michel C (2016) Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest 126:415-23
Steichen, Jon M; Kulp, Daniel W; Tokatlian, Talar et al. (2016) HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies. Immunity 45:483-96
Gristick, Harry B; von Boehmer, Lotta; West Jr, Anthony P et al. (2016) Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site. Nat Struct Mol Biol 23:906-915
Scharf, Louise; West, Anthony P; Sievers, Stuart A et al. (2016) Structural basis for germline antibody recognition of HIV-1 immunogens. Elife 5:

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