HIV-1 continues to spread at an alarming rate, with an estimated 4 million new infections occurring each of the last several years. There are currently no HIV-1 vaccine candidates that demonstrate efficacy against the diverse HIV-1 strains that are circulating globally. Neutralizing antibodies have been shown to block HIV-1 infection in experimental model systems. However, these results were obtained under ideal conditions, where passively administered antibodies that were known to readily neutralize the virus being tested were used;most HIV-1 strains would not be neutralized by these same antibodies. At present, it is unclear what types of antibodies would be most effective in blocking the strains of HIV-1 that are circulating in highly affected populations. Antibodies are passively acquired in the setting of mother-to-child HIV-1 transmission, and our recent studies suggest that these antibodies may select for transmission of escape variants to the infant. Thus, the exposure of infants to HIV-1 from their mother provides a setting in which to examine the role of neutralizing antibodies in HIV-1 transmission, and to characterize the specificity of antibody responses that may be protective. We hypothesize that there are neutralizing antibodies that contribute to protection of the infant from HIV-1 infection. Here, we propose to test this hypothesis using banked samples collected from a clinical trial of breastfeeding transmission of HIV-1 that included 425 mother-infant pairs from Nairobi, Kenya. In this cohort, infant infection status was monitored at regular intervals, so that the timing of infection is well defined;In addition a variety of clinical and virological data is available. Using samples from this cohort, maternal neutralizing antibody breadth and potency will be examined against a panel of HIV-1 variants isolated from early in infection. Passively transferred antibody profiles will be similarly evaluated in a subset of infants. The goal of these aims will be to identify the neutralizing antibody responses that correlate with a reduced risk of HIV-1 transmission, and specifically, whether potency, breadth or specificity for particular viral strains is the best predictor of transmission risk. In addition, we propose to examine the molecular basis for escape from neutralizing antibodies in cases where transmission has occurred. These studies will help define critical epitopes on the HIV-1 envelope protein that contribute to neutralization escape during HIV-1 transmission. Together, these studies will test the hypothesis that broad and/or potent neutralizing antibody responses can help protect against HIV-1 infection, and they may provide unique insights into the specificity of antibodies that are capable of blocking HIV-1 acquisition. Testing this hypothesis is of critical importance to future vaccine design, because it will provide data to support or refute the importance of eliciting neutralizing antibodies with a vaccine immunogen. PROJECT NARRATIVE A major goal of HIV vaccine research is to find a means to elicit broad and potent neutralizing antibodies. However, there is no direct evidence that such antibodies actually protect humans from HIV-1 infection. Here, we propose to test the hypothesis that broad and potent neutralizing antibodies protect infants of HIV- 1 positive mothers from infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI076105-05
Application #
8235071
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Zwerski, Sheryl L
Project Start
2008-03-01
Project End
2013-05-31
Budget Start
2012-03-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$483,694
Indirect Cost
$183,065
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Overbaugh, Julie (2014) Mother-infant HIV transmission: do maternal HIV-specific antibodies protect the infant? PLoS Pathog 10:e1004283
Goo, Leslie; Chohan, Vrasha; Nduati, Ruth et al. (2014) Early development of broadly neutralizing antibodies in HIV-1-infected infants. Nat Med 20:655-8
Roxby, Alison C; Atkinson, Claire; Asbjörnsdóttir, Kristjana et al. (2014) Maternal valacyclovir and infant cytomegalovirus acquisition: a randomized controlled trial among HIV-infected women. PLoS One 9:e87855
Roxby, Alison C; Liu, Amy Y; Drake, Alison L et al. (2013) Short communication: T cell activation in HIV-1/herpes simplex virus-2-coinfected Kenyan women receiving valacyclovir. AIDS Res Hum Retroviruses 29:94-8
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Omenda, Maxwel M; Milligan, Caitlin; Odem-Davis, Katherine et al. (2013) Evidence for efficient vertical transfer of maternal HIV-1 envelope-specific neutralizing antibodies but no association of such antibodies with reduced infant infection. J Acquir Immune Defic Syndr 64:163-6
Mabuka, Jennifer; Goo, Leslie; Omenda, Maxwel M et al. (2013) HIV-1 maternal and infant variants show similar sensitivity to broadly neutralizing antibodies, but sensitivity varies by subtype. AIDS 27:1535-44
Lehman, Dara A; Wamalwa, Dalton C; McCoy, Connor O et al. (2012) Low-frequency nevirapine resistance at multiple sites may predict treatment failure in infants on nevirapine-based treatment. J Acquir Immune Defic Syndr 60:225-33
Drake, Alison L; Roxby, Alison C; Ongecha-Owuor, Francisca et al. (2012) Valacyclovir suppressive therapy reduces plasma and breast milk HIV-1 RNA levels during pregnancy and postpartum: a randomized trial. J Infect Dis 205:366-75

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