1  

Breadth of HIV-1 Env-specific antibody-dependent cellular cytotoxicity - Relevance to global HIV vaccine design

Short title: Breadth of HIV-1 Env-specific ADCC

Vijaya MADHAVI1, Leia H WREN1, Rob J CENTER1, Christopher GONELLI1, Wendy R WINNALL1, Mathew S PARSONS1, Marit KRAMSKI1, Stephen J KENT1,2,3* and Ivan STRATOV1,2,3

1

Department of Microbiology and Immunology, University of Melbourne, 2Melbourne Sexual

Health Clinic, Carlton, 3Infectious Diseases Unit, Alfred Hospital, Prahran, Victoria, Australia

*Correspondence to Stephen J Kent, Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia Tel: +61 3 8344 9939; fax: +61 3 8344 3846; e-mail: [email protected]

Conflict of interest: We declare that we have no conflicts of interest Total number of words used: 3427 words Grant: National Health and Medical Research Council (NHMRC), Australia GNT1034770

 

2  

Abstract Objective: To determine the breadth of HIV-1 Env-specific antibody-dependent cellular cytotoxicity (ADCC) in HIV controllers and HIV progressors with a view to design globally relevant HIV vaccines. Design: The breadth of ADCC towards four major HIV-1 Env subtypes was measured in vitro for 12 HIV controllers and 12 HIV progressors. Methods: Plasma from 12 HIV controllers (including long-term slow progressors, viremic controllers, elite controller and post-treatment controller) and 12 HIV progressors, mostly infected with HIV-1 subtype B was analysed for ADCC responses. ADCC assays were performed against 10 HIV-1 gp120 and eight gp140 proteins from four major HIV-1 subtypes (A, B, C and E) and three glycosylation-mutant gp140 proteins. Results: ADCC-mediated natural killer cell activation was significantly broader (p=0.02) and of higher magnitude (p400 cells/mm3 more than seven years after acquisition of HIV), viremic controllers (VC; who maintain plasma viral loads 2% Env-specific ADCC responses to gp120 compared to 6 of 12 HIV progressors (Fisher exact two-tailed p=0.01). The magnitude of HIV-1 gp120specific ADCC responses of HIV controllers (median 4.1% NK cell activation, IQR=5.7%) was significantly higher than HIV progressors (median 0.6% NK cell activation, IQR=2.8%; Mann-Whitney U-test p2% NK cell activation) to more than two subtypes of the gp120 subtypes was detected in 9 of 12 HIV controllers compared with 3 of 12 HIV progressors (Fisher exact two-tailed p=0.03). A similar pattern of ADCC responses between subject groups was noted to HIV-1 gp140 Envs (Mann-Whitney U-test p