The main objectives of Project 2 are to identify primary HIV-1 envelope protein (Env) that have high ability in eliciting antibodies against the CD4 binding site (CD4bs) and, if successful, to further select those Env antigens that can also elicit broad neutralizing activities through the induction of anti-CD4bs antibodies.
Aim 1 To Identify variation in the antigenicity of the CD4bs for primary Envs of HIV-1. CD4bs is a key target for eliciting broad neutralizing antibodies (NAbs) against HIV-1, as shown by previous studies that had used mAb b12, and more recently, using sera from HIV infected individuals. Our recent studies have shown that not every HIV primary Env antigen is equally effective in inducing NAb responses.
In Aim 1, we will test whether Envs from primary isolates of different backgrounds, phenotypes, and clades may have varying antigenicity for both neutralizing and non-neutralizing CD4bs antibodies.
Aim 2 To understand the consequences of CD4bs antigenic variation on the neutralization sensitivity of primary HIV-1 isolates. It is well known that heavy glycosylation and epitope masking play a key role in resistance to neutralization. Beyond these generalizations however, specific determinants of neutralization sensitivity or resistance are difficult to identify due to the complexity of the Env and the often unknown interactions and changes in conformation that occur as a result of trimerization of Env.
In Aim 2, we intend to determine if there is a link between CD4bs antigenicity and neutralization sensitivity.
Aim 3 To determine the immunogenicity of primary envelopes with varying levels of CD4bs antigencity and to select Env antigens that can elicit anti-CD4bs mediated neutralizing activities. The precise characteristics of a good HIV immunogen have yet to be identified. Previous studies have made a number of attempts to increase the immunogenicity of the HIV Env with limited success.
In Aim 3, we will test whether the CD4bs antigenicity may be one, as of yet unidentified, determinant of a good immunogen. Immunogenicity studies will be conducted with the DMA prime-protein boost approach to identify those primary Env antigens that can elicit strong anti-CD4bs antibodies, possibly with broad neutralizing activities as well.

Public Health Relevance

(Seeinstructions): We plan to study the unique structure of HIV outside coat to find a common pattern on the coat that will allow scientists to use them as part of the vaccine components to induce good protective immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI082274-05
Application #
8513892
Study Section
Special Emphasis Panel (ZAI1-EC-A)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$416,463
Indirect Cost
$87,035
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Li, Xiaoyan; Grant, Oliver C; Ito, Keigo et al. (2017) Structural Analysis of the Glycosylated Intact HIV-1 gp120-b12 Antibody Complex Using Hydroxyl Radical Protein Footprinting. Biochemistry 56:957-970
Marty-Roix, Robyn; Vladimer, Gregory I; Pouliot, Kimberly et al. (2016) Identification of QS-21 as an Inflammasome-activating Molecular Component of Saponin Adjuvants. J Biol Chem 291:1123-36
Costa, Matthew R; Pollara, Justin; Edwards, Regina Whitney et al. (2016) Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001. J Virol 90:10362-10378
Suschak, John J; Wang, Shixia; Fitzgerald, Katherine A et al. (2016) A cGAS-Independent STING/IRF7 Pathway Mediates the Immunogenicity of DNA Vaccines. J Immunol 196:310-6
Townsley, Samantha; Li, Yun; Kozyrev, Yury et al. (2016) Conserved Role of an N-Linked Glycan on the Surface Antigen of Human Immunodeficiency Virus Type 1 Modulating Virus Sensitivity to Broadly Neutralizing Antibodies against the Receptor and Coreceptor Binding Sites. J Virol 90:829-41
Liu, Shuying; Wang, Shixia; Lu, Shan (2016) DNA immunization as a technology platform for monoclonal antibody induction. Emerg Microbes Infect 5:e33
Townsley, Samantha; Mohamed, Zeinab; Guo, Wenjin et al. (2016) Induction of Heterologous Tier 2 HIV-1-Neutralizing and Cross-Reactive V1/V2-Specific Antibodies in Rabbits by Prime-Boost Immunization. J Virol 90:8644-60
Musich, Thomas; O'Connell, Olivia; Gonzalez-Perez, Maria Paz et al. (2015) HIV-1 non-macrophage-tropic R5 envelope glycoproteins are not more tropic for entry into primary CD4+ T-cells than envelopes highly adapted for macrophages. Retrovirology 12:25
Suschak, John J; Wang, Shixia; Fitzgerald, Katherine A et al. (2015) Identification of Aim2 as a sensor for DNA vaccines. J Immunol 194:630-6
Kumar, Rajnish; Pan, Ruimin; Upadhyay, Chitra et al. (2015) Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL. J Virol 89:9090-102

Showing the most recent 10 out of 43 publications