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.

Public Health Relevance

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.

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 #
5R37AI055332-08
Application #
8013941
Study Section
Special Emphasis Panel (ZRG1-AARR-H (02))
Program Officer
Shapiro, Stuart Z
Project Start
2003-05-15
Project End
2014-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
8
Fiscal Year
2011
Total Cost
$1,087,698
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Moldt, Brian; Le, Khoa; Carnathan, Diane G et al. (2016) Neutralizing antibody affords comparable protection against vaginal and rectal SHIV challenge in macaques. AIDS :
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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
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