ADCC-mediating non-neutralizing antibodies can exert immune pressure in early HIV-1 infection.

Dieter Mielke,Nigel Garrett,Valerie Bekker,Guido Ferrari,Carolyn Williamson,Gama Bandawe,Penny L Moore,Salim Abdool Karim,Christina Ochsenbauer,Lynn Morris,Jie Zheng,David Montefiori,Colin Anthony,Melissa-Rose Abrahams,Jennifer Jones,Guido Silvestri

doi:10.1371/journal.ppat.1010046

Abstract

Despite antibody-dependent cellular cytotoxicity (ADCC) responses being implicated in protection from HIV-1 infection, there is limited evidence that they control virus replication. The high mutability of HIV-1 enables the virus to rapidly adapt, and thus evidence of viral escape is a very sensitive approach to demonstrate the importance of this response. To enable us to deconvolute ADCC escape from neutralizing antibody (nAb) escape, we identified individuals soon after infection with detectable ADCC responses, but no nAb responses. We evaluated the kinetics of ADCC and nAb responses, and viral escape, in five recently HIV-1-infected individuals. In one individual we detected viruses that escaped from ADCC responses but were sensitive to nAbs. In the remaining four participants, we did not find evidence of viral evolution exclusively associated with ADCC-mediating non-neutralizing Abs (nnAbs). However, in all individuals escape from nAbs was rapid, occurred at very low titers, and in three of five cases we found evidence of viral escape before detectable nAb responses. These data show that ADCC-mediating nnAbs can drive immune escape in early infection, but that nAbs were far more effective. This suggests that if ADCC responses have a protective role, their impact is limited after systemic virus dissemination.

Highlights

Non-neutralizing antibodies have been correlated with protection for many licenced vaccines [1]
We assessed the impact of early antibody-dependent cellular cytotoxicity (ADCC)-mediating neutralizing antibodies (nnAbs) on HIV-1 envelope evolution in infected individuals where we had early samples, prior to the detection of neutralizing antibody (nAb)
We found evidence of escape from ADCC-mediating nnAbs, but in only one individual

Summary

Introduction

Non-neutralizing antibodies (nnAbs) have been correlated with protection for many licenced vaccines [1]. In the RV144 vaccine trial, protection against HIV-1 infection was associated with Envelope (Env) variable loop V2-directed nnAbs [2, 3]. A sieve effect which may have been due to ADCC-mediating nnAbs provided further evidence of their importance [4] In addition to their potential role in protection, numerous studies provide substantial evidence that ADCC-mediating antibodies play an important role in the context of HIV and SIV infection. Non-human primate and human studies have associated ADCC responses with lower viral loads [5,6,7,8,9,10,11,12,13], protection from infection [14, 15], improved clinical outcome in linked transmission [12], and reduced mother-to-child transmission [16]. We recently identified an instance where ADCC-mediating nnAbs were able to limit nAb escape in an HIV-infected individual [17]

Methods

Results

Discussion

Conclusion