While the development of an HIV vaccine that can induce neutralizing antibodies (nAbs) remains a top priority, nearly 3 decades of research in this arena has proven that this is a daunting task. However, recent results from the modestly protective RV144 vaccine trial argue that protection from infection can be achieved in the absence of nAbs and cytotoxic T cell responses, and this protection and may be linked to the induction of functional antibodies (Abs) that target specific epitopes on the viral V2 loop. Likewise, more than 3 decades of research have pointed to a role for non-neutralizing, innate immune-recruiting Abs in antiviral control and slower disease progression. Interestingly, over the last R01 funding period, it has become clear that in both the setting of vaccine-induced immunity and natural infection, the most functional antibody (Ab) responses are driven by HIV-specific IgG3 Abs. However, what these IgG3 antibodies target, how these IgG3 responses are induced, and most critically how they persist in some patients has yet to be defined. Here, we hypothesize that the rules of long-lived IgG3 selection can be learned from both vaccination and natural infection, with the hope that the induction of these potent humoral effector molecules prior to exposure to HIV may lead to durable protection from infection. Therefore, in this application, we propose to specifically dissect the specificity and functional profile of the HIV-specific IgG3 responses in both infection and vaccination. Based on these results, we will isolate antigen-specific IgG3 B cells to begin to learn the rules by which these B cells select a particular antibody subclass as well as how these responses may be artificially skewed towards IgG3 with adjuvants, T cell help, and/or cytokines. Together, these studies, linking antibody function to B cell programming will provide a first-in-class composite picture of the evolution of protective functional Abs and define the mechanisms by which protective immunity may be elicited through vaccination to gain enhanced control over the virus.

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 #
5R37AI080289-07
Application #
8975593
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Boggiano, Cesar Augusto
Project Start
2008-07-01
Project End
2019-11-30
Budget Start
2015-12-01
Budget End
2016-11-30
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Miller-Novak, Leia K; Das, Jishnu; Musich, Thomas A et al. (2018) Analysis of Complement-Mediated Lysis of Simian Immunodeficiency Virus (SIV) and SIV-Infected Cells Reveals Sex Differences in Vaccine-Induced Immune Responses in Rhesus Macaques. J Virol 92:
Alter, Galit; Barouch, Dan (2018) Immune Correlate-Guided HIV Vaccine Design. Cell Host Microbe 24:25-33
Lofano, Giuseppe; Gorman, Matthew J; Yousif, Ashraf S et al. (2018) Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement. Sci Immunol 3:
Ogunshola, Funsho; Anmole, Gursev; Miller, Rachel L et al. (2018) Dual HLA B*42 and B*81-reactive T cell receptors recognize more diverse HIV-1 Gag escape variants. Nat Commun 9:5023
Mabuka, Jenniffer M; Dugast, Anne-Sophie; Muema, Daniel M et al. (2017) Plasma CXCL13 but Not B Cell Frequencies in Acute HIV Infection Predicts Emergence of Cross-Neutralizing Antibodies. Front Immunol 8:1104
Ackerman, Margaret E; Barouch, Dan H; Alter, Galit (2017) Systems serology for evaluation of HIV vaccine trials. Immunol Rev 275:262-270
Huang, Yunda; Ferrari, Guido; Alter, Galit et al. (2016) Diversity of Antiviral IgG Effector Activities Observed in HIV-Infected and Vaccinated Subjects. J Immunol 197:4603-4612
Gunn, Bronwyn; Schneider, Jeffrey; Shansab, Maryam et al. (2016) Enhanced binding of antibodies generated during chronic HIV infection to mucus component MUC16. Mucosal Immunol 9:1549-1558
Gunn, Bronwyn M; Alter, Galit (2016) Modulating Antibody Functionality in Infectious Disease and Vaccination. Trends Mol Med 22:969-982
Barouch, Dan H; Alter, Galit; Broge, Thomas et al. (2015) Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys. Science 349:320-4

Showing the most recent 10 out of 13 publications