Recent information has shed new light on the importance of the V1/V2 domain of HIV-1 in viral infection and as a potential target for protective vaccines. The V1/V2 domain has been shown to be a critical determinant of an increasing number of monoclonal antibodies (mAbs) isolated from HIV-infected subjects that that target quaternary neutralization epitopes and possess broad and potently neutralizing activities. In addition to the role of the V1/V2 region as a classical neutralization target other evidence has accumulated showing that the interaction between a conserved V2 sequence and the ?4?7-integrin receptor stimulates infection of a fraction of activated T cells in the gut that may be important for infection in vivo, and that this interaction is inhibited by anti-V2 mAbs. Finally, a analysis of immune parameters in the RV144 vaccine trial recently carried out in Thailand showed that antibodies that bind to a V1/V2 fusion protein that we developed uniquely correlated with protection. Studies from our lab and others have shown that potent V1/V2 neutralization targets are both highly conformational and glycan-dependent, and developing V1/V2-based vaccines is complicated by the structural heterogeneity of this region, due to variation in both protein folding and glycosylation.
The aims of this project are to fully characterize the structural, functional and immunological properties of the V1/V2 domain, to identify and characterize protective epitopes in this region and to develop immunogens and vaccine strategies specific for conserved V1/V2 epitopes that efficiently elicit antibodies that contribute to protection against infection. The efficacy of novel V1/V2 immunogens developed by this program will be evaluated initially in a rabbit model by Dr. Shan Lu at UMass and towards the end of this study in a non-human primate challenge model by Dr. Shiu-Lok Hu at the WNPRC. The optimization of targets in the V1/V2 domain arising from these studies should be an important contribution towards the design of more effective HIV vaccines.

Public Health Relevance

Some progress towards developing a protective vaccine for HIV was made by the finding that the RV144 vaccine trial recently concluded in Thailand provided partial protection (31%). An analysis of immune parameters in the RV144 participants made the unexpected discovery that the only positive correlate of protection was the presence of antibodies against the native V1/V2 domain, expressed as a fusion protein that we provided, suggesting that the V1/V2 domain is a critical vaccine target. The goals of our proposal are to build on our past studies to fully characterize the structure and immunological properties of the V1/V2 domain, in order to optimize this region as a target for a protective vaccine.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-DR-A (M1))
Program Officer
Miller, Nancy R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rutgers University
Public Health & Prev Medicine
Schools of Medicine
United States
Zip Code
Qualls, Zakiya M; Choudhary, Alok; Honnen, William et al. (2018) Identification of Novel Structural Determinants in MW965 Env That Regulate the Neutralization Phenotype and Conformational Masking Potential of Primary HIV-1 Isolates. J Virol 92:
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
Tian, Jianhui; López, Cesar A; Derdeyn, Cynthia A et al. (2016) Effect of Glycosylation on an Immunodominant Region in the V1V2 Variable Domain of the HIV-1 Envelope gp120 Protein. PLoS Comput Biol 12:e1005094
Diaz, Francisco J; McDonald, Peter R; Pinter, Abraham et al. (2015) Measuring and Statistically Testing the Size of the Effect of a Chemical Compound on a Continuous In-Vitro Pharmacological Response Through a New Statistical Model of Response Detection Limit. J Biopharm Stat 25:757-80
Jalah, Rashmi; Kulkarni, Viraj; Patel, Vainav et al. (2014) DNA and protein co-immunization improves the magnitude and longevity of humoral immune responses in macaques. PLoS One 9:e91550
Shmelkov, Evgeny; Krachmarov, Chavdar; Grigoryan, Arsen V et al. (2014) Computational prediction of neutralization epitopes targeted by human anti-V3 HIV monoclonal antibodies. PLoS One 9:e89987
Zolla-Pazner, Susan; deCamp, Allan; Gilbert, Peter B et al. (2014) Vaccine-induced IgG antibodies to V1V2 regions of multiple HIV-1 subtypes correlate with decreased risk of HIV-1 infection. PLoS One 9:e87572
Salomon, Aidy; Krachmarov, Chavdar; Lai, Zhong et al. (2014) Specific sequences commonly found in the V3 domain of HIV-1 subtype C isolates affect the overall conformation of native Env and induce a neutralization-resistant phenotype independent of V1/V2 masking. Virology 448:363-74
Li, Shuying S; Gilbert, Peter B; Tomaras, Georgia D et al. (2014) FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial. J Clin Invest 124:3879-90
Yates, Nicole L; Liao, Hua-Xin; Fong, Youyi et al. (2014) Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection risk and declines soon after vaccination. Sci Transl Med 6:228ra39