Current HIV Research - Volume 11, Issue 5, 2013

Antibody-mediated resistance to viral disease is often attributed solely to neutralizing antibodies (NAbs) despite a body of evidence -- more than 30 years in the making -- to show that other populations of antibodies (protective non-neutralizing antibodies, PnNAbs) can also contribute and are sometimes pivotal in host resistance to viruses. Recently, interest in varieties of PnNAbs has been restored and elevated by an HIV vaccine trial in which virus-specific nNAbs have been highlighted as a positive correlate of immunity. Here, I briefly review some of the historical precedents with many viruses other than HIV, along with the emergence of data over the course of some four decades, pointing emphatically to the importance of subsets of antiviral antibodies that operate by mechanisms other than classical virus neutralization. Foremost among suspected mechanisms of protection by PnNAbs is antibody-dependent cellular cytotoxicty (ADCC), but additional mechanisms have sometimes been incriminated or not experimentally excluded. Examples are given for the diversity of proteins and cognate epitopes bound by PnNAbs. Some such epitopes are restricted to virus-infected cell surfaces or found on secreted proteins; others may be associated with virions but unavailable to antibodies during much of the viral cycle; these are epitopes variously described as cryptic, transitional, dynamic, or reversibly masked.

Passive immunization studies in non-human primates have established unequivocally that virus neutralization can prevent infection, providing the impetus for current intense efforts to identify immunogens that elicit broadly neutralizing antibodies in humans. Although Fc-mediated effector function may also contribute to protection by neutralizing antibodies, its role in protection by non-neutralizing antibodies is controversial. Here, I review the literature suggesting a role for Fc-mediated effector by non-neutralizing antibodies in protective immunity against HIV-1 with a primary focus on antibody mediated cellular cytotoxicity (ADCC) and related responses such as antibody-dependent cellular viral inhibition (ADCVI). Special emphasis is placed on qualitative and quantitative variables including antibody specificity and dose-response behavior in vitro and in vivo, which I propose as key variables in future passive immunization studies. Properly configured, these studies should clarify the role of Fc-mediated effector function by nonneutralizing antibodies in protection against HIV-1.

Antibodies act as a nexus between innate and adaptive immunity: they provide a means to engage a spectrum of innate immune effector cells in order to clear viral particles and infected cells and prime antigen presentation. This functional landscape is remarkably complex, and depends on antibody isotype, subclass, and glycosylation; the expression levels and patterns of a suite of Fc receptors with both complementary and opposing activities; and a host of innate immune cells capable of differential responses to opsonized particles and present at different sites. In vivo, even neutralizing antibodies rely on their ability to act as molecular beacons and recruit innate immune effector cells in order to provide protection, and results from both human and macaque studies have implicated these effector functions in vaccinemediated protection. Thus, while enhancing effector function is a tractable handle for potentiating antibody-mediated protection from HIV infection, success will depend critically on leveraging understanding of the means by which antibodies with specific functional profiles could be elicited, which effector functions could provide optimal protection, and perhaps most critically, how to efficiently recruit the innate effector cells present at sites of infection.

Antibody dependent cellular cytotoxicity [ADCC] has been suggested to play an important role in control of Human Immunodeficiency Virus-1 [HIV-1] viral load and protection from infection. ADCC antibody responses have been mapped to multiple linear and conformational epitopes within the HIV-1 envelope glycoproteins gp120 and gp41. Many epitopes targeted by antibodies that mediate ADCC overlap with those recognized by antibodies capable of virus neutralization. In addition, recent studies conducted with human monoclonal antibodies derived from HIV-1 infected individuals and HIV-1 vaccine-candidate vaccinees have identified a number of antibodies that lack the ability to capture primary HIV-1 isolates or mediate neutralizing activity, but are able to bind to the surface of infected CD4+ T cells and mediate ADCC. Of note, the conformational changes in the gp120 that may not exclusively relate to binding of the CD4 molecule are important in exposing epitopes recognized by ADCC responses. Here we discuss the HIV-1 envelope epitopes targeted by ADCC antibodies in the context of the potential protective capacities of ADCC.

The partial success of the RV144 trial re-energized the field of HIV vaccine research, which had stalled after vaccines based on neutralizing antibody and cytotoxic T cells had failed to induce protection. A large post-vaccine research effort has focused attention on the role of non-neutralizing antibodies in the protection afforded by the RV144 vaccine. These binding antibodies can initiate immune responses such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) and combine elements of the adaptive and innate immune system in the form of antibodies and effector cells (including NK cells, monocytes and granulocytes). A complex interplay exists between the variable portion of the binding antibody and its HIV antigen target on one hand and the constant region of the antibody and the Fcγ-receptor of the effector cell on the other hand. Technical advances have revolutionized the abilities of scientist to detect the targets of non-neutralizing antibodies, including both envelope and non-envelope epitopes, and their role in forcing escape. Our understanding of the antibody characteristics (including IgG subclasses and Fc glycan profile) is providing valuable insights into their optimal structure and function. We expand on critical research on ADCC effector cells, particularly education of NK cells. We introduce the concept of HIV antibodydependent trogocytosis by monocytes as a potentially important aspect of HIV immunity. In summary, this review highlights recent advances in HIV-specific antibody immunity mediated through NK cells and monocytes.

The modest success of the RV144 HIV vaccine trial in Thailand and the ensuing suggestion that a Fc-receptormediated antibody activity might have played a role in the protection observed have intensified investigations on Fcrelated immune responses. HIV neutralizing antibodies have been and continue to be the focal point of research into humoral immune protection. However, recent knowledge that their protective efficacy can be augmented by Fc-FcR interactions has increased the complexity of identifying immune correlates of protection. If anything, continued studies of both humoral and cellular immune mechanisms point to the lack of a single protective anti-HIV immune response. Here we focus on humoral immunity, analyzing the role played by Fc receptor-related responses and discussing how new knowledge of their interactions requires further investigation, but may also spur novel vaccination approaches. We initially address classical Fc-receptor mediated anti-viral mechanisms including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell mediated viral inhibition (ADCVI), and antibody-dependent cellular phagocytosis (ADCP), as well as the effector cells that mediate these functions. Next, we summarize key aspects of FcR-Fc interactions that are important for potential control of HIV/SIV such as FcR polymorphisms and post-transcriptional modifications. Finally we discuss less commonly studied non-mechanistic anti-HIV immune functions: antibody avidity and envelopespecific B cell memory. Overall, a spectrum of immune responses, reflecting the immune system’s redundancy, will likely be needed to prevent HIV infection and/or disease progression. Aside from elicitation of critical immune mechanisms, a successful vaccine will need to induce mature B cell responses and long-lasting immune memory.

Antibody-dependent enhancement (ADE) of infection has been described for a number of viruses including HIV-1. However, the biological role of ADE in HIV disease pathogenesis or in increasing the risk of infection upon exposure is uncertain. In this review, we outline the mechanisms of ADE, as ascertained in vitro. We also discuss several recent human and non-human primate studies that raise concern about ADE resulting from vaccine-induced or passively infused antibodies. Although biologically plausible, an important role for ADE in natural HIV infection has not been directly confirmed. Nonetheless, there is a need for further studies to pinpoint the exact mechanism or mechanisms at play in vivo and, more importantly, to develop assays that can predict the likelihood that a vaccine or antibody infusion will lead to enhanced infection or pathogenesis.

A vaccine that can prevent the transmission of HIV-1 at the site of exposure to the host is one of the best hopes to control the HIV-1 pandemic. The trimeric envelope spike consisting of heterodimers, gp120 and gp41, is essential for virus entry and thus has been a key target for HIV-1 vaccine development. However, it has been extremely difficult to identify the types of antibodies required to block the transmission of various HIV-1 strains and the immunogens that can elicit such antibodies due to the high genetic diversity of the HIV-1 envelope. The modest efficacy of the gp120 HIV-1 vaccine used in the RV144 Thai trial, including the studies on the immune correlates of protection, and the discovery of vaccine-induced immune responses to certain signature regions of the envelope have shown that the gp120 variable loop 2 (V2) is an important region. Since there is evidence that the V2 region interacts with the integrin α4β7 receptor of the host cell, and that this interaction might be important for virus capture, induction of antibodies against V2 loop could be postulated as one of the mechanisms to prevent the acquisition of HIV-1. Immunogens that can induce these antibodies should therefore be taken into consideration when designing HIV-1 vaccine formulations.