Date Published: January 8, 2016
Publisher: Public Library of Science
Author(s): Margaret E. Ackerman, Anastassia Mikhailova, Eric P. Brown, Karen G. Dowell, Bruce D. Walker, Chris Bailey-Kellogg, Todd J. Suscovich, Galit Alter, Daniel C. Douek.
Elite controllers (ECs) represent a unique model of a functional cure for HIV-1 infection as these individuals develop HIV-specific immunity able to persistently suppress viremia. Because accumulating evidence suggests that HIV controllers generate antibodies with enhanced capacity to drive antibody-dependent cellular cytotoxicity (ADCC) that may contribute to viral containment, we profiled an array of extra-neutralizing antibody effector functions across HIV-infected populations with varying degrees of viral control to define the characteristics of antibodies associated with spontaneous control. While neither the overall magnitude of antibody titer nor individual effector functions were increased in ECs, a more functionally coordinated innate immune–recruiting response was observed. Specifically, ECs demonstrated polyfunctional humoral immune responses able to coordinately recruit ADCC, other NK functions, monocyte and neutrophil phagocytosis, and complement. This functionally coordinated response was associated with qualitatively superior IgG3/IgG1 responses, whereas HIV-specific IgG2/IgG4 responses, prevalent among viremic subjects, were associated with poorer overall antibody activity. Rather than linking viral control to any single activity, this study highlights the critical nature of functionally coordinated antibodies in HIV control and associates this polyfunctionality with preferential induction of potent antibody subclasses, supporting coordinated antibody activity as a goal in strategies directed at an HIV-1 functional cure.
Vaccine-mediated protection from HIV-1 infection has been observed in humans in association with extra-neutralizing antibody functions, including the ability to induce effector functions such as antibody-dependent cellular cytotoxicity (ADCC) . Similarly, HIV-infected patients who are able to spontaneously suppress infection in the absence of antiretroviral therapy (i.e., HIV-1 controllers) have been found to exhibit potentiated ADCC activity [2–10]. Importantly, as HIV-1 controllers represent an alternative vaccine goal—the induction of immunity able to contain viral replication subsequent to infection—these data suggest that beyond cellular correlates associated with control [11,12], antibodies with enhanced ability to direct the potent anti-viral activities of innate effector cells may also contribute to a functional cure.
While the development of an HIV vaccine able to induce neutralizing antibodies that block HIV acquisition represents the ultimate goal in HIV vaccine design, vaccines to date have had limited success in inducing these types of immune responses. Conversely, protection from infection has been observed in both humans  and non-human primates  in the absence of potent neutralization. Instead, non-neutralizing antibody mechanisms, including the ability of antibodies to induce antibody effector functions, have been implicated in protective activity.