Current HIV Research (v.11, #5)

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 (protectivenon-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-specificnNAbs have been highlighted as a positive correlate of immunity. Here, I briefly review some of the historical precedentswith many viruses other than HIV, along with the emergence of data over the course of some four decades, pointingemphatically to the importance of subsets of antiviral antibodies that operate by mechanisms other than classical virusneutralization. Foremost among suspected mechanisms of protection by PnNAbs is antibody-dependent cellularcytotoxicty (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 arerestricted to virus-infected cell surfaces or found on secreted proteins; others may be associated with virions butunavailable 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 neutralizationcan prevent infection, providing the impetus for current intense efforts to identify immunogens that elicit broadlyneutralizing antibodies in humans. Although Fc-mediated effector function may also contribute to protection byneutralizing antibodies, its role in protection by non-neutralizing antibodies is controversial. Here, I review the literaturesuggesting a role for Fc-mediated effector by non-neutralizing antibodies in protective immunity against HIV-1 with aprimary focus on antibody mediated cellular cytotoxicity (ADCC) and related responses such as antibody-dependentcellular viral inhibition (ADCVI). Special emphasis is placed on qualitative and quantitative variables including antibodyspecificity and dose-response behavior in vitro and in vivo, which I propose as key variables in future passiveimmunization studies. Properly configured, these studies should clarify the role of Fc-mediated effector function by nonneutralizingantibodies in protection against HIV-1.

Opportunities to Exploit Non-Neutralizing HIV-Specific Antibody Activity by Margaret E. Ackerman, Galit Alter (365-377).
Antibodies act as a nexus between innate and adaptive immunity: they provide a means to engage a spectrum ofinnate immune effector cells in order to clear viral particles and infected cells and prime antigen presentation. Thisfunctional landscape is remarkably complex, and depends on antibody isotype, subclass, and glycosylation; the expressionlevels and patterns of a suite of Fc receptors with both complementary and opposing activities; and a host of innateimmune cells capable of differential responses to opsonized particles and present at different sites. In vivo, evenneutralizing antibodies rely on their ability to act as molecular beacons and recruit innate immune effector cells in order toprovide protection, and results from both human and macaque studies have implicated these effector functions in vaccinemediatedprotection. Thus, while enhancing effector function is a tractable handle for potentiating antibody-mediatedprotection from HIV infection, success will depend critically on leveraging understanding of the means by whichantibodies 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.

Epitope Specificity of Human Immunodeficiency Virus-1 Antibody Dependent Cellular Cytotoxicity [ADCC] Responses by Justin Pollara, Mattia Bonsignori, M. Anthony Moody, Marzena Pazgier, Barton F. Haynes, Guido Ferrari (378-387).
Antibody dependent cellular cytotoxicity [ADCC] has been suggested to play an important role in control ofHuman Immunodeficiency Virus-1 [HIV-1] viral load and protection from infection. ADCC antibody responses have beenmapped to multiple linear and conformational epitopes within the HIV-1 envelope glycoproteins gp120 and gp41. Manyepitopes targeted by antibodies that mediate ADCC overlap with those recognized by antibodies capable of virusneutralization. In addition, recent studies conducted with human monoclonal antibodies derived from HIV-1 infectedindividuals and HIV-1 vaccine-candidate vaccinees have identified a number of antibodies that lack the ability to captureprimary HIV-1 isolates or mediate neutralizing activity, but are able to bind to the surface of infected CD4+ T cells andmediate ADCC. Of note, the conformational changes in the gp120 that may not exclusively relate to binding of the CD4molecule are important in exposing epitopes recognized by ADCC responses. Here we discuss the HIV-1 envelopeepitopes targeted by ADCC antibodies in the context of the potential protective capacities of ADCC.

HIV-Specific Antibody Immunity Mediated Through NK Cells and Monocytes by Marit Kramski, Matthew S. Parsons, Ivan Stratov, Stephen J. Kent (388-406).
The partial success of the RV144 trial re-energized the field of HIV vaccine research, which had stalled aftervaccines based on neutralizing antibody and cytotoxic T cells had failed to induce protection. A large post-vaccineresearch effort has focused attention on the role of non-neutralizing antibodies in the protection afforded by the RV144vaccine. 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 immunesystem in the form of antibodies and effector cells (including NK cells, monocytes and granulocytes). A complexinterplay exists between the variable portion of the binding antibody and its HIV antigen target on one hand and theconstant region of the antibody and the Fcγ -receptor of the effector cell on the other hand. Technical advances haverevolutionized the abilities of scientist to detect the targets of non-neutralizing antibodies, including both envelope andnon-envelope epitopes, and their role in forcing escape. Our understanding of the antibody characteristics (including IgGsubclasses and Fc glycan profile) is providing valuable insights into their optimal structure and function. We expand oncritical research on ADCC effector cells, particularly education of NK cells. We introduce the concept of HIV antibodydependenttrogocytosis by monocytes as a potentially important aspect of HIV immunity. In summary, this reviewhighlights recent advances in HIV-specific antibody immunity mediated through NK cells and monocytes.

Fc Receptor-Mediated Immune Responses: New Tools But Increased Complexity in HIV Prevention by Diego A. Vargas-Inchaustegui, Marjorie Robert-Guroff (407-420).
The modest success of the RV144 HIV vaccine trial in Thailand and the ensuing suggestion that a Fc-receptormediatedantibody activity might have played a role in the protection observed have intensified investigations on Fcrelatedimmune responses. HIV neutralizing antibodies have been and continue to be the focal point of research intohumoral immune protection. However, recent knowledge that their protective efficacy can be augmented by Fc-FcRinteractions has increased the complexity of identifying immune correlates of protection. If anything, continued studies ofboth humoral and cellular immune mechanisms point to the lack of a single protective anti-HIV immune response. Herewe focus on humoral immunity, analyzing the role played by Fc receptor-related responses and discussing how newknowledge of their interactions requires further investigation, but may also spur novel vaccination approaches. Weinitially 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 interactionsthat 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 envelopespecificB cell memory. Overall, a spectrum of immune responses, reflecting the immune system's redundancy, will likelybe needed to prevent HIV infection and/or disease progression. Aside from elicitation of critical immune mechanisms, asuccessful vaccine will need to induce mature B cell responses and long-lasting immune memory.

Antibody-Dependent Enhancement and the Risk of HIV Infection by Andrea Gorlani, Donald N. Forthal (421-426).
Antibody-dependent enhancement (ADE) of infection has been described for a number of viruses includingHIV-1. However, the biological role of ADE in HIV disease pathogenesis or in increasing the risk of infection uponexposure is uncertain. In this review, we outline the mechanisms of ADE, as ascertained in vitro. We also discuss severalrecent human and non-human primate studies that raise concern about ADE resulting from vaccine-induced or passivelyinfused antibodies. Although biologically plausible, an important role for ADE in natural HIV infection has not beendirectly confirmed. Nonetheless, there is a need for further studies to pinpoint the exact mechanism or mechanisms at playin vivo and, more importantly, to develop assays that can predict the likelihood that a vaccine or antibody infusion willlead to enhanced infection or pathogenesis.

HIV-1 Variable Loop 2 and its Importance in HIV-1 Infection and Vaccine Development by Mangala Rao, Kristina K. Peachman, Jiae Kim, Guofen Gao, Carl R. Alving, Nelson L. Michael, Venigalla B. Rao (427-438).
A vaccine that can prevent the transmission of HIV-1 at the site of exposure to the host is one of the best hopesto control the HIV-1 pandemic. The trimeric envelope spike consisting of heterodimers, gp120 and gp41, is essential forvirus entry and thus has been a key target for HIV-1 vaccine development. However, it has been extremely difficult toidentify the types of antibodies required to block the transmission of various HIV-1 strains and the immunogens that canelicit such antibodies due to the high genetic diversity of the HIV-1 envelope. The modest efficacy of the gp120 HIV-1vaccine used in the RV144 Thai trial, including the studies on the immune correlates of protection, and the discovery ofvaccine-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 hostcell, and that this interaction might be important for virus capture, induction of antibodies against V2 loop could bepostulated as one of the mechanisms to prevent the acquisition of HIV-1. Immunogens that can induce these antibodiesshould therefore be taken into consideration when designing HIV-1 vaccine formulations.