There is a wide consensus that an HIV vaccine should elicit protective antibodies. To ensure that optimal responses are elicited, it is important to understand how antibodies exert their protective activity in vivo. For instance, is it only necessary to elicit antibodies that can neutralize in vitro, as is the current focus of immunogen development? Or are other antibody functions, present in vivo but not present in in vitro neutralization assays, important? If so, which functions? We are approaching the mechanism(s) of antibody protection in vivo using the SHIV/macaque model and a broadly neutralizing human anti-HIV antibody (b12) that we have studied intensively in the laboratory. In particular, we are attempting to probe mechanism by investigation of the protective effects of engineered variants of b12 whose ability to interact with other compartments of the immune system has been altered. We have provided evidence to suggest that the interaction of antibody and host cell Fc receptors is important in protection and now propose to explore this involvement more deeply to determine the features of antibody responses, in addition to neutralization, that will provide benefit in the context of a vaccine.
The specific aims are: (1) To determine the roles of the key Fc receptors FcRIIa and FcRIIIa in antibody protection against mucosal HIV challenge (2) To determine the effects of greatly enhancing the major FcR functions, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, on antibody protection against mucosal HIV challenge and (3) To investigate in vitro how monoclonal and polyclonal anti-HIV antibodies mediate the extra-neutralizing activities shown in Aims 1 and 2 to be crucial in antibody protection. These studies will help define the antibody specificities, and particularly combinations of specificities, most likely to offer optimal protection against HIV exposure.
This proposal seeks to understand how antibodies prevent HIV infection with HIV in a monkey model that is believed to mirror human infection. This understanding will help us greatly in designing vaccines that protect humans against HIV infection.
|Moldt, Brian; Le, Khoa M; Carnathan, Diane G et al. (2016) Neutralizing antibody affords comparable protection against vaginal and rectal simian/human immunodeficiency virus challenge in macaques. AIDS 30:1543-51|
|Moldt, Brian; Le, Khoa; Carnathan, Diane G et al. (2016) Neutralizing antibody affords comparable protection against vaginal and rectal SHIV challenge in macaques. AIDS :|
|von Bredow, Benjamin; Arias, Juan F; Heyer, Lisa N et al. (2016) Comparison of Antibody-Dependent Cell-Mediated Cytotoxicity and Virus Neutralization by HIV-1 Env-Specific Monoclonal Antibodies. J Virol 90:6127-39|
|Sok, Devin; Doores, Katie J; Briney, Bryan et al. (2014) Promiscuous glycan site recognition by antibodies to the high-mannose patch of gp120 broadens neutralization of HIV. Sci Transl Med 6:236ra63|
|Diebolder, Christoph A; Beurskens, Frank J; de Jong, Rob N et al. (2014) Complement is activated by IgG hexamers assembled at the cell surface. Science 343:1260-3|
|Li, Qingsheng; Zeng, Ming; Duan, Lijie et al. (2014) Live simian immunodeficiency virus vaccine correlate of protection: local antibody production and concentration on the path of virus entry. J Immunol 193:3113-25|
|Trist, Halina M; Tan, Peck Szee; Wines, Bruce D et al. (2014) Polymorphisms and interspecies differences of the activating and inhibitory Fc?RII of Macaca nemestrina influence the binding of human IgG subclasses. J Immunol 192:792-803|
|Barouch, Dan H; Whitney, James B; Moldt, Brian et al. (2013) Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503:224-8|
|Jaworski, J Pablo; Kobie, James; Brower, Zachary et al. (2013) Neutralizing polyclonal IgG present during acute infection prevents rapid disease onset in simian-human immunodeficiency virus SHIVSF162P3-infected infant rhesus macaques. J Virol 87:10447-59|
|Poignard, Pascal; Moldt, Brian; Maloveste, Karla et al. (2012) Protection against high-dose highly pathogenic mucosal SIV challenge at very low serum neutralizing titers of the antibody-like molecule CD4-IgG2. PLoS One 7:e42209|
Showing the most recent 10 out of 19 publications