Determining the effects of broadly neutralizing antibodies at antiretroviral therapy initiation

Project Summary
ART initiation (ARTi) is a unique clinical juncture in which virus replication and host immune responses are in
flux and treatment of a substantial component of people living with HIV (PLWH) is possible. In both preclinical
studies and recent clinical trials, infusion of broadly neutralizing antibodies (bnAbs) at ARTi has shown exciting
preliminary results, but key questions about the mechanisms of action, the requisite bnAb properties, and
the extent of clinical impact remain. Further, it is unclear if these benefits can be extended to the >35 million
PLWH currently on suppressive ART, by using bnAbs after treatment interruption and ART re-initiation. Several
clinical trials are planned or ongoing, but the complexity of human research limit the ability to definitively elucidate
key mechanisms. Our scientific premise is that our molecularly defined, mixed bnAb-sensitive and resistant,
barcoded transmitted/founder (TF) SHIV/NHP model system is uniquely poised to determine the extent and
durability of bnAb activity at ARTi/re-initiation and decipher the mechanistic role of neutralization potency and
effector function on reservoir dynamics, durable immune responses, and virus control. Our group has
generated a body of work demonstrating that TF SHIVs reproduce key features of HIV-1 immunopathogenesis.
We have expanded the model to incorporate genetic barcoding and virus inocula containing defined mixtures of
bnAb-sensitive and resistant viruses. In this system, each animal is infected with a precise ratio of TF SHIVs
encoding wildtype (WT; bnAb-sensitive) and escape mutant (EM; bnAb resistant) viruses, which have similar
replication kinetics but markedly different sensitivities to V3-glycan bnAbs. Because WT and EM viruses have
unique barcodes, we can track bnAb-sensitive vs. resistant virus clonotypes over time and across tissues through
high-throughput sequencing, allowing for statistically powerful within-animal comparisons, as well as
comparisons across treatment arms. Here, we will leverage this novel NHP system to determine the effects of
bnAbs at ARTi and re-initiation and dissect the roles of bnAbs’ neutralizing and effector functions through a
coordinated NHP experiment comparing 4 treatment groups: (i) ART alone, (ii) ART + bnAb, (iii) ART + bnAb
with disabled effector function, and (iv) ART + bnAb with enhanced effector function. We will then determine if
similar effects can be seen with use of bnAbs at ART re-initiation in animals already on suppressive ART who
underwent ATI. This strategy allows us to define bnAb’s clinical impact and test our overall hypothesis that
both the neutralizing potency and effector function of bnAbs at ARTi are essential to activity on the reservoir,
host immunity, and induction of virus control. Successful completion of this project would have substantial
significance to the HIV cure field, as it rigorously tests promising roles for bnAbs in HIV cure strategies that
could guide the clinical development of bnAbs in cure strategies.

Grant Number: 5R01AI179666-03
NIH Institute/Center: NIH
Principal Investigator: Katharine Bar