Complementing broadly neutralizing antibodies and autologous responses to restrict virus escape and durably suppress HIV-1

Modified Project Summary/Abstract Section:
Advances in B cell biology and molecular virology have enabled the discovery,
characterization, and commercial development of several classes of broadly neutralizing antibodies (bnAbs),
with applications for prevention, treatment, and cure of HIV disease are under study. Yet, virus resistance
remains the central vulnerability of effective bnAb use. This application proposes to address the problem of
bNAb escape by rationally selecting combination bNAb therapy that limits virus escape. We propose to apply
lessons from the successful development of combination antiretrovial therapy (cART), whereby bidirectional
phenotypic antagonism was exploited. Our multidisciplinary team has secured plasma virus or virus sequences
from recent or ongoing prevention and treatment studies of VRC01-class CD4 binding site (CD4bs)-targeting
monotherapy, as well as combination therapy with V3 glycan-targeting (Table 1). We will leverage these
unique samples to map the in vivo escape pathways of virus replicating in the presence of sub-suppressive
levels of these clinically relevant bNAbs (Aim 1). Using the evolving escape variants, we will identify putative
complementary bNAbs with maintained or inverse antibody sensitivities from rationally designed panels of
candidate bNAbs (Aim 1). We will then characterize the autologous neutralizing antibody (anAb) response in
the treatment cohorts, to determine the capacity of anAbs to impede virus escape from administered bNAbs
(Aim 2). Finally, we will test the most promising complementary bNAbs to restrict virus escape in cell culture, in
vivo in humanized mice and a validated barcoded TF SHIV/NHP model (Aim 3). Our scientific premise is that in
vivo mapping of virus escape from bNAbs, identification of complementary bNAbs, defining the role of
autologous antibodies, and rigorous in vivo testing in an authentic NHP model will elucidate basic mechanisms
of virus resistance to bNAbs and inform more effective use of bNAbs across the HIV prevention, treatment and
cure fields. If accomplished we will (i) have defined the sensitivities of escaped viruses from clinical trials to
alternate bNAbs, (ii) identified bNAbs that cannot mutually escape using the same pathway, (iii) defined the
role of anAbs in bnAb escape and (iv) tested the ability of complementary bnAbs to improve therapy in an
authentic NHP model.

Grant Number: 5U01AI169767-04
NIH Institute/Center: NIH
Principal Investigator: Katharine Bar