HIV is adept in evading humoral immunity, a feature that likely contributes to its ability to replicate in the face of ongoing host immune responses. Although neutralizing antibodies are produced to viral envelope glycoproteins (Env), they are characteristically directed to hypervariable loops on gpl20 (V1/V2 and V3). These antibodies are in general """"""""type specific"""""""" and easily circumvented by mutations. These variable loops also serve to protect domains on the gpl20 core, which include the highly conserved binding sites for CD4 and chemokine receptors required for cell entry. In order for broadly neutralizing antibodies to be produced, it is likely that these and other conserved domains will need to be targeted. A priority for HIV vaccine research is to develop Env-based immunogens that can elicit these antibodies. Our laboratory has developed a novel strategy for producing replication-competent variants of HIV-2 that lack the V1/V2 and V3 hpervariable loops. Although other groups have produced functional HIV-1 and SIV Envs without V1/V2, viruses lacking V3 have not been described. Given the importance of V3 in binding to and determining specificity for chemokine receptors, and of VI/V2 and V3 in protecting critical domains on the gpl20 core from humoral immune responses, we hypothesize that these """"""""minimized"""""""" Envs will have novel structure/function properties, and that, while presenting exposed core domains in this physiological context, will elicit qualitatively different immune responses focused to biologically relevant and/or cryptic epitopes on the Env trimer. We propose 5 Specific Aims to further explore this HIV-2 model and to extend these findings to HIV-1 and SIV: 1) In our HIV-2 model, selection strategies will be used to derive and characterize viruses lacking V1/V2 and V3 in combination, with a goal of generating replication competent Env cores;2) These HIV-2 Envs will be characterized in functional, biochemical, morphologic, and immunologic assays that dissect underlying mechanisms for their novel biological activities;3) Compensatory mutations in gpl20 and gp41 that permit Env cores lacking hypervariable loops to be functional will be determined;4) Information Aims 2 and 3 will be extended to similar studies of HIV-1 and SIV;and 5) The immunogenicity of virions derived in Aims 1 and 4 will be assessed in a small animal model and sera evaluated to determine if functionally critical but exposed epitopes can be rendered immunogenic by this approach. These novel HIV and SIV Env variants will )rovide new opportunities for studies of Env structure, function, immunogenicity and pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI045378-14
Application #
8308550
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sharma, Opendra K
Project Start
1999-03-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
14
Fiscal Year
2012
Total Cost
$570,117
Indirect Cost
$213,794
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Parker, Zahra F; Iyer, Shilpa S; Wilen, Craig B et al. (2013) Transmitted/founder and chronic HIV-1 envelope proteins are distinguished by differential utilization of CCR5. J Virol 87:2401-11
Parrish, Nicholas F; Gao, Feng; Li, Hui et al. (2013) Phenotypic properties of transmitted founder HIV-1. Proc Natl Acad Sci U S A 110:6626-33
Parrish, Nicholas F; Wilen, Craig B; Banks, Lauren B et al. (2012) Transmitted/founder and chronic subtype C HIV-1 use CD4 and CCR5 receptors with equal efficiency and are not inhibited by blocking the integrin α4β7. PLoS Pathog 8:e1002686
White, Tommi A; Bartesaghi, Alberto; Borgnia, Mario J et al. (2011) Three-dimensional structures of soluble CD4-bound states of trimeric simian immunodeficiency virus envelope glycoproteins determined by using cryo-electron tomography. J Virol 85:12114-23
Acharya, Priyamvada; Dogo-Isonagie, Cajetan; LaLonde, Judith M et al. (2011) Structure-based identification and neutralization mechanism of tyrosine sulfate mimetics that inhibit HIV-1 entry. ACS Chem Biol 6:1069-77
Del Prete, Gregory Q; Leslie, George J; Haggarty, Beth et al. (2010) Distinct molecular pathways to X4 tropism for a V3-truncated human immunodeficiency virus type 1 lead to differential coreceptor interactions and sensitivity to a CXCR4 antagonist. J Virol 84:8777-89
Hoxie, James A (2010) Toward an antibody-based HIV-1 vaccine. Annu Rev Med 61:135-52
White, Tommi A; Bartesaghi, Alberto; Borgnia, Mario J et al. (2010) Molecular architectures of trimeric SIV and HIV-1 envelope glycoproteins on intact viruses: strain-dependent variation in quaternary structure. PLoS Pathog 6:e1001249
Nolan, Katrina M; Del Prete, Gregory Q; Jordan, Andrea P O et al. (2009) Characterization of a human immunodeficiency virus type 1 V3 deletion mutation that confers resistance to CCR5 inhibitors and the ability to use aplaviroc-bound receptor. J Virol 83:3798-809
Nolan, Katrina M; Jordan, Andrea P O; Hoxie, James A (2008) Effects of partial deletions within the human immunodeficiency virus type 1 V3 loop on coreceptor tropism and sensitivity to entry inhibitors. J Virol 82:664-73

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