Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission

Xiao Lan Chang ,Timothy R Brown,Shaheed Abdulhaqq,Katherine B Bateman,Helen L Wu,Nader Pourhassan,Lishomwa C Ndhlovu,Whitney C Weber,Miranda Fischer,Cleiton Pessoa,Rebecca Agnor,Justin M Greene,Nicole D Burnett ,Jeremy Smedley,Nancy L Haigwood,Diogo M Magnani,Oriene Shiel,Scott A Kelly ,Cassandra Rae Moats ,Kush Dhody,Scott G Hansen,Jason S Reed,Roxanne M Gilbride,Jeffrey Torgerson,Glen M Chew,Nicholas Maier,Benjamin N Bimber,Lina Gao,Travis Giobbi,Don C Siess ,Bruce K Patterson ,Gabriela M Webb,Jonah B Sacha

doi:10.1038/s41467-021-23697-6

Abstract

In the absence of a prophylactic vaccine, the use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition by uninfected individuals is a promising approach to slowing the epidemic, but its efficacy is hampered by incomplete patient adherence and ART-resistant variants. Here, we report that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of CCR5-tropic SHIVSF162P3. Injection of Leronlimab weekly at 10 mg/kg provides significant but partial protection, while biweekly 50 mg/kg provides complete protection from SHIV acquisition. Tissue biopsies from protected macaques post challenge show complete CCR5 receptor occupancy and an absence of viral nucleic acids. After Leronlimab washout, protected macaques remain aviremic, and adoptive transfer of hematologic cells into naïve macaques does not transmit viral infection. These data identify CCR5 blockade with Leronlimab as a promising approach to HIV prophylaxis and support initiation of clinical trials.

Highlights

In the absence of a prophylactic vaccine, the use of antiretroviral therapy (ART) as preexposure prophylaxis (PrEP) to prevent HIV acquisition by uninfected individuals is a promising approach to slowing the epidemic, but its efficacy is hampered by incomplete patient adherence and ART-resistant variants
Because cell-associated virus plays an important role in mucosal transmission[26], we first assessed the ability of Leronlimab to inhibit HIV cell-to-cell transmission in an in vitro spreading assay
Leronlimab inhibits diverse HIV isolates with an IC50 value comparable to HIV broadly neutralizing antibodies (bNAbs) such as 10E8, PGT128, and 3BNC117

Summary

Introduction

In the absence of a prophylactic vaccine, the use of antiretroviral therapy (ART) as preexposure prophylaxis (PrEP) to prevent HIV acquisition by uninfected individuals is a promising approach to slowing the epidemic, but its efficacy is hampered by incomplete patient adherence and ART-resistant variants. After Leronlimab washout, protected macaques remain aviremic, and adoptive transfer of hematologic cells into naïve macaques does not transmit viral infection These data identify CCR5 blockade with Leronlimab as a promising approach to HIV prophylaxis and support initiation of clinical trials. The ability to self-administer Leronlimab at home as a subcutaneous injection augurs well for its adherence profile as a PrEP agent In both single dose and multiyear monotherapy studies, no viral co-receptor switching occurred, underscoring the high genetic barrier to developing Leronlimab resistance. Based on these antiviral, safety, and user-friendly characteristics, we hypothesized that Leronlimab could be utilized as an effective PrEP strategy with the potential for high patient usage and set out to establish the efficacy of Leronlimab-based PrEP in the macaque model of HIV

Methods

Results

Conclusion