Biology and biological impact of HIV-1-specific antibody-dependent cellular cytotoxicity

© 2015 Dr. Vijaya MadhaviBackground A safe and effective vaccine has eluded the scientific community for over three decades. With the failure of vaccines based primarily on neutralizing antibody (NAb) and cytotoxic T lymphocytes (CTL), attention has been directed towards novel approaches. The partially successful RV144 vaccine trial focused scientific interest on binding Abs, particularly those that mediate Ab-dependent cellular cytotoxicity (ADCC). Anti-HIV-1 ADCC responses have been associated with slower HIV-1 disease progression in most human studies. Whether such ADCC responses can target HIV-1 envelope protein (Env) from diverse subtypes, however, is largely unknown. It is important to define the breadth of ADCC immunity associated with control of HIV-1. Another unexplored aspect of HIV-1-specific ADCC is the effect of combination antiretroviral therapy (cART) on ADCC Abs. Latent HIV-1 remains unaffected by cART and there is considerable research aimed at achieving a cure for HIV-1 by eliminating the latent reservoir. HIV-1-specific ADCC may assist in eliminating reactivated latently infected cells. An understanding of the effect of cART on ADCC will assist in efforts to enhance immune control of HIV-1 under cART. Furthermore, the biological importance of HIV-1-specific ADCC is strongly suggested by the generation of ADCC-escape HIV-1 variants to linear peptide epitopes. HIV-1 peptide-specific ADCC responses associated with escape from immune recognition represent interesting HIV-1 vaccine antigens. It is therefore important to elucidate the mechanism by which these HIV-1 peptide epitopes are expressed and whether or not they induce ADCC-mediated killing of target cells expressing such peptide-antigens. Methods The breadth of ADCC recognition to 10 HIV-1 gp120 and 8 gp140 proteins from the four major HIV-1 subtypes (A, B, C and E) were analysed in plasma from 11 HIV-1 controllers and 11 HIV-1 progressors, primarily infected with subtype B. Studies were carried out using both an assay that assessed ADCC activity based on the activation of natural killer (NK) cells and the rapid flourometric ADCC (RFADCC) assay that measures ADCC-mediated killing of HIV-1 Env-pulsed target cells. The effect of cART on ADCC responses was analysed in a cohort of 49 cART-naive HIV-1-infected subjects from Thailand (mean baseline CD4 count, 188 cells/μL; mean viral load, 5.4 log10 copies/mL). The subjects were followed for 96 weeks after initiating cART. NK cell activation ADCC, RFADCC and Ab-dependent phagocytosis (ADP) assays were performed using serum samples obtained at baseline and after 96 weeks of cART. To elucidate the mechanism of HIV-1 peptide epitope expression in the whole blood NK activation ADCC assay, we fluorescently tagged ADCC peptide epitopes to identify its target cells. We then assessed ADCC-mediated killing of target cells by the measuring the expression of apoptosis marker Annexin V as well as cell numbers. Results ADCC-mediated NK cell activation was significantly broader (p=0.02) and of higher magnitude (p<0.001) in HIV-1 controllers than in HIV-1 progressors. HIV-1 controllers also showed significantly higher magnitude of ADCC-mediated killing of Env-coated target cells than HIV-1 progressors to both HIV-1 subtype B and the heterologous subtype E gp140 (p=0.001). We found good ADCC reactivity to subtype B and E Envs, less cross-reactivity to subtype A and minimal cross-reactivity to subtype C Envs. We observed 35% reduction in HIV-1 Env-specific ADCC-mediated killing of target cells (p<0.001) after 96 weeks of cART. This was corroborated by a significant reduction in the ability of Env-specific ADCC Abs to activate NK cells (p