Humoral and Innate Antiviral Immunity as Tools to Clear Persistent HIV Infection

Ferrari, Guido; Pollara, Justin; Tomaras, Georgia D.; Haynes, Barton F.

doi:10.1093/infdis/jiw555

Cited by 22 publications

(24 citation statements)

References 120 publications

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“…In vitro studies with laboratory-adapted, tier 1 HIV-1 strains showed that Env-specific nnAbs can direct ADCC/ADCVI (reviewed in (Ferrari et al, 2017)). However, little evidence exists to demonstrate Fc-mediated nnAb activity against primary HIV-1 isolates and transmitted/founder viruses (Bruel et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Non-neutralizing Antibodies Alter the Course of HIV-1 Infection In Vivo

Horwitz

Bar-On

et al. 2017

Cell

122

132

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SUMMARY Non-neutralizing antibodies (nnAbs) to HIV-1 show little measurable activity in prevention or therapy in animal models, yet were the only correlate of protection in the RV144 vaccine trial. To investigate the role of nnAbs on HIV-1 infection in vivo, we devised a replication-competent HIV-1 reporter virus that expresses a heterologous HA-tag on the surface of infected cells and virions. Anti-HA antibodies bind to, but do not neutralize the reporter virus in vitro. However, anti-HA protects against infection in humanized mice and strongly selects for nnAb-resistant viruses in an entirely Fc-dependent manner. Similar results were also obtained with tier 2 HIV-1 viruses using a human anti-gp41 nnAb, 246D. While nnAbs are demonstrably less effective than broadly neutralizing antibodies (bNAbs) against HIV-1 in vitro and in vivo, the data show that nnAbs can protect against and alter the course of HIV-1 infection in vivo.

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Section: Discussionmentioning

confidence: 99%

Non-neutralizing Antibodies Alter the Course of HIV-1 Infection In Vivo

Horwitz

Bar-On

et al. 2017

Cell

122

132

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“…Evidence from in vitro latency models supports the hypothesis that these reservoirs can be eliminated by combining latency reversal agents (LRAs), which induce the expression of viral antigens, with enhanced immune effectors, in a paradigm referred to as "kick and kill" or "shock and kill" (4-7). One strategy for harnessing immune effectors for this purpose is to target reactivated infected cells with HIV-specific antibodies, resulting in the engagement of natural killer (NK) cells, monocytes, and granulocytes, which eliminate infected cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and/or antibodydependent cell-mediated phagocytosis (ADCP) (8)(9)(10). For this purpose, it will be crucial for the HIV-specific antibodies to bind to Env proteins expressed on the surfaces of the reactivated latently infected cells.…”

mentioning

confidence: 99%

Susceptibility to Neutralization by Broadly Neutralizing Antibodies Generally Correlates with Infected Cell Binding for a Panel of Clade B HIV Reactivated from Latent Reservoirs

Ren

Korom

Truong

et al. 2018

J Virol

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Efforts to cure human immunodeficiency virus (HIV) infection are obstructed by reservoirs of latently infected CD4 T cells that can reestablish viremia. HIV-specific broadly neutralizing antibodies (bNAbs), defined by unusually wide neutralization breadths against globally diverse viruses, may contribute to the elimination of these reservoirs by binding to reactivated cells, thus targeting them for immune clearance. However, the relationship between neutralization of reservoir isolates and binding to corresponding infected primary CD4 T cells has not been determined. Thus, the extent to which neutralization breadths and potencies can be used to infer the corresponding parameters of infected cell binding is currently unknown. We assessed the breadths and potencies of bNAbs against 36 viruses reactivated from peripheral blood CD4 T cells from antiretroviral (ARV)-treated HIV-infected individuals by using paired neutralization and infected cell binding assays. Single-antibody breadths ranged from 0 to 64% for neutralization (80% inhibitory concentration [IC] of ≤10 μg/ml) and from 0 to 89% for binding, with two-antibody combinations (results for antibody combinations are theoretical/predicted) reaching levels of 0 to 83% and 50 to 100%, respectively. Infected cell binding correlated with virus neutralization for 10 of 14 antibodies (e.g., for 3BNC117, = 0.82 and < 0.0001). Heterogeneity was observed, however, with a lack of significant correlation for 2G12, CAP256.VRC26.25, 2F5, and 4E10. Our results provide guidance on the selection of bNAbs for interventional cure studies, both by providing a direct assessment of intra- and interindividual variabilities in neutralization and infected cell binding in a novel cohort and by defining the relationships between these parameters for a panel of bNAbs. Although antiretroviral therapies have improved the lives of people who are living with HIV, they do not cure infection. Efforts are being directed towards harnessing the immune system to eliminate the virus that persists, potentially resulting in virus-free remission without medication. HIV-specific antibodies hold promise for such therapies owing to their ability to both prevent the infection of new cells (neutralization) and direct the killing of infected cells. We isolated 36 HIV strains from individuals whose virus was suppressed by medication and tested 14 different antibodies for neutralization of these viruses and for binding to cells infected with the same viruses (critical for engaging natural killer cells). For both neutralization and infected cell binding, we observed variation both between individuals and amongst different viruses within an individual. For most antibodies, neutralization activity correlated with infected cell binding. These data provide guidance on the selection of antibodies for clinical trials.

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“…This in turn triggers signaling through NFκB, IRF3/7, and MAPK pathways among others. Signaling through these well-studied pathways produces a host of pro-inflammatory cytokines, chemokines, and viral restriction factors to help combat early infection [14]. Importantly, myeloid cell responses to PRR activation can be tuned based on signaling from SLAMF1, SLAMF5, SLAMF7, SLAMF8, and SLAMF9 [15][16][17][18][19][20][21].…”

Section: Immune Responses To Viral Infectionsmentioning

confidence: 99%

SLAM Family Receptor Signaling in Viral Infections: HIV and Beyond

2019

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The signaling lymphocytic activation molecule (SLAM) family of receptors are expressed on the majority of immune cells. These receptors often serve as self-ligands, and play important roles in cellular communication and adhesion, thus modulating immune responses. SLAM family receptor signaling is differentially regulated in various immune cell types, with responses generally being determined by the presence or absence of two SLAM family adaptor proteins—Ewing’s sarcoma-associated transcript 2 (EAT-2) and SLAM-associated adaptor protein (SAP). In addition to serving as direct regulators of the immune system, certain SLAM family members have also been identified as direct targets for specific microbes and viruses. Here, we will discuss the known roles for these receptors in the setting of viral infection, with special emphasis placed on HIV infection. Because HIV causes such complex dysregulation of the immune system, studies of the roles for SLAM family receptors in this context are particularly exciting.

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Humoral and Innate Antiviral Immunity as Tools to Clear Persistent HIV Infection

Cited by 22 publications

References 120 publications

Non-neutralizing Antibodies Alter the Course of HIV-1 Infection In Vivo

Non-neutralizing Antibodies Alter the Course of HIV-1 Infection In Vivo

Susceptibility to Neutralization by Broadly Neutralizing Antibodies Generally Correlates with Infected Cell Binding for a Panel of Clade B HIV Reactivated from Latent Reservoirs

SLAM Family Receptor Signaling in Viral Infections: HIV and Beyond

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