The potential role of antibody dependent cellular cytotoxicity in protection from HIV-1

© 2013 Dr. Leia Helen WrenPublications included in thesis:Wren, L. H., Chung, A. W., Isitman, G., Kelleher, A. D., Parsons, M. S., Amin, J., et al. (2012). Specific antibody-dependent cellular cytotoxicity responses associated with slow progression of HIV infection. Immunology, 138(2), 116-123. DOI: 10.1111/imm.12016Madhavi, V., Navis, M., Chung, A., Isitman, G., Wren, L., De Rose, R., et al. (2013). Activation of NK cells by HIV-specific ADCC antibodies: role for granulocytes in expressing HIV-1 peptide epitopes. Human Vaccines & Immunotherapeutics, 9( 5). DOI: 10.4161/hv.23446Wren, L., Parsons, M. S., Isitman, G., Center, R. J., Kelleher, A. D., Stratov, I., et al. (2012). Influence of cytokines on HIV-specific antibody-dependent cellular cytotoxicity activation profile of natural killer cells. PLoS ONE, 7(6), e38580. DOI: 10.1371/journal.pone.0038580Parsons, M. S., Wren, L., Isitman, G., Navis, M., Stratov, I., Bernard, N. F., et al. (2012). HIV infection abrogates the functional advantage of natural killer cells educated through KIR3DL1/HLA-Bw4 interactions to mediate anti-HIV antibody-dependent cellular cytotoxicity. Journal of Virology, 86(8), 4488-4495. DOI: 10.1128/JVI.06112-11Kramski, M., Lichtfuss, G. F., Navis, M., Isitman, G., Wren, L., Rawlin, G., et al. (2012). Anti-HIV-1 antibody-dependent cellular cytotoxicity mediated by hyperimmune bovine colostrum IgG. European Journal of Immunology, 42.2771-2781. DOI: 10.1002/eji.201242469Chung, A. W., Navis, M,, Isitman, G., Wren, L., Silvers, J., Amin, J., et al. (2011). Activation of KN cells by ADCC antibodies and HIV disease progression. Journal of Acquired Immune Deficiency Syndrome, 58(2),127-131. DOI: 10.1097/QAI.0b013e31822c62b9Wren, L., & Kent, S. J. (2011). HIV vaccine efficacy trials: glimmers of hope and the potential role of antibody-dependent cellular cytotoxicity. Human Vaccines, 7(4), 466-473. DOI: 10.4161/hv.7.4.14123Background: Antibodies (Ab) mediating cellular cytotoxicity (ADCC) could potentially provide protection from HIV-1 acquisition in a vaccine setting. ADCC Abs mediate the cytolysis of HIV-1 infected target cells through the cross-linking of the Fc portion of the Abs by effector cell populations bearing Fc receptors (FcRs) such as NK cells. ADCC activated effector cells also secrete pro-inflammatory cytokines, which helps to recruit other immune cells to aid in the clearance of infected cells. ADCC responses occur naturally in HIV-1 positive people and have often, but not always, been associated with slower progression of HIV-1 to AIDS. In addition, ADCC responses were elicited by the recent RV144 HIV-1 vaccine trial carried out in Thailand. This trial provided a modest 31.2% reduction in HIV-1 acquisition in the vaccinated cohort. By studying ADCC responses elicited naturally and by vaccination, the potential of ADCC responses to protect from HIV-1 acquisition can be explored. Furthermore a better understanding of ADCC targets and methods for manipulating or enhancing this potentially beneficial immune response will enable the development of more effective HIV-1 vaccines. Methods: ADCC responses against whole Env glycoprotein (gp) 140 and multiple linear HIV-1 overlapping peptide pools were analysed in 65 Long term slow progressors (LTSP) and 74 subjects with progressive HIV-1 disease. Studies were carried out using an assay that assessed ADCC activity based on the activation of NK cells. We evaluated the effect of Ab purification from the plasma of HIV+ subjects and the effect of a number of HIV-relevant soluble factors on the activation profile of healthy donor NK cells using the NK cell activation ADCC assay. This assay was used in conjunction with a rapid fluorescent ADCC (RFADCC) assay, which measures ADCC based on target cell cytolysis, to assess ADCC responses elicited by the phase II RV135 and phase III RV144 HIV-1 vaccine trials. Results: We found that the breadth but not the magnitude of ADCC responses was correlated with slow progression of HIV-1. In addition regulatory/accessory HIV-1 proteins were targeted more frequently in LTSPs. ADCC responses targeting HIV-1 Vpu were over represented in LTSPs and Vpu-specific ADCC Abs were mapped to 3 distinct epitopes within the protein. The cytokines interleukin (IL)-15 and IL-10 were found to consistently enhance both the cytokine production and degranulation of ADCC activated NK cells. Envspecific ADCC responses were detected in plasma samples from the RV135 and RV144 trials, consistent with recent reports in the literature, although improved methods will be needed to map epitope-specific responses. Conclusions: Broader ADCC responses may play a role in long-term control of HIV-1 progression in a subset of LTSPs. Conserved ADCC epitopes within HIV-1 Vpu may represent potentially beneficial vaccine targets. The cytokine milieu influences the ADCC effector cell response and those involved with enhancing the magnitude of ADCC responses may be useful vaccine adjuvants. Improvements to the breadth, specificity and durability of the HIV-1-specific ADCC responses elicited by the RV144 trial could improve vaccine efficacy to the point where it would be a viable vaccine to administer to large human populations