FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial

Li, Shuying S.; Gilbert, Peter B.; Tomaras, Georgia D.; Kijak, Gustavo H.; Ferrari, Guido; Thomas, Rasmi; Pyo, Chul Woo; Zolla‐Pazner, Susan; Montefiori, David C.; Liao, Hua Xin; Nabel, Gary J.; Pinter, Abraham; Evans, David T.; Gottardo, Raphaël; Dai, James Y.; Janes, Holly; Morris, Daryl E.; Fong, Youyi; Edlefsen, Paul T.; Li, Fusheng; Frahm, Nicole; Alpert, Michael D.; Prentice, Heather A.; Rerks-Ngarm, Supachai; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Robb, Merlin L.; O’Connell, Robert J.; Haynes, Barton F.; Michael, Nelson L.; Kim, Jerome H.; McElrath, M. Juliana; Geraghty, Daniel E.

doi:10.1172/jci75539

Cited by 100 publications

(131 citation statements)

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“…However, in a few donors possessing the known open reading frame for hFcgRIIC (37), as determined by multiplex ligation-dependent probe amplification (37) Cragg, and J.C. Strefford, submitted for publication), the hFcgRIIB mAb 7C07 gave a low level of staining in a small population of NK cells (data not shown) in accordance with their expression of hFcgRIIC (displaying an identical extracellular domain to hFcgRIIB). The regulation and functional relevance of hFcgRIIC expression has been reported previously (37)(38)(39)(40) and is the subject of our ongoing studies. B cells (CD3 2 CD19 + ) expressed high levels of hFcgRIIB, but did not express hFcgRI, -IIA, or -III (Fig.…”

Section: Expression Of Hfcgr In Blood Spleen and Tonsils Determinedmentioning

confidence: 66%

Development and Characterization of Monoclonal Antibodies Specific for Mouse and Human Fcγ Receptors

Tutt

James

Laversin

et al. 2015

The Journal of Immunology

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FcγRs are key regulators of the immune response, capable of binding to the Fc portion of IgG Abs and manipulating the behavior of numerous cell types. Through a variety of receptors, isoforms, and cellular expression patterns, they are able to fine-tune and direct appropriate responses. Furthermore, they are key determinants of mAb immunotherapy, with mAb isotype and FcγR interaction governing therapeutic efficacy. Critical to understanding the biology of this complex family of receptors are reagents that are robust and highly specific for each receptor. In this study, we describe the development and characterization of mAb panels specific for both mouse and human FcγR for use in flow cytometry, immunofluorescence, and immunocytochemistry. We highlight key differences in expression between the two species and also patterns of expression that will likely impact on immunotherapeutic efficacy and translation of therapeutic agents from mouse to clinic.

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Section: Expression Of Hfcgr In Blood Spleen and Tonsils Determinedmentioning

confidence: 66%

Development and Characterization of Monoclonal Antibodies Specific for Mouse and Human Fcγ Receptors

Tutt

James

Laversin

et al. 2015

The Journal of Immunology

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“…In the RV144 trial, sieve analyses focused on the V1V2 region of envelope were used to test the hypothesis generated in correlates-of-risk studies that antibodies against the V2 region of envelope mediated protection. The genetic sieve effect found in RV144 was then further corroborated by analyses of immune responses of subjects in the RV144 study, forming a cohesive picture of potential immune mechanisms of protection in RV144 (9)(10)(11)(12)(13). A more broadly applied genetic sieve analysis identified other genetic determinants associated with vaccine-mediated responses, thereby raising other testable hypotheses of the RV144 mechanism of action (3).…”

mentioning

confidence: 85%

Breakthrough Virus Neutralization Resistance as a Correlate of Protection in a Nonhuman Primate Heterologous Simian Immunodeficiency Virus Vaccine Challenge Study

Lee

Mason²,

Welles³

et al. 2015

J Virol

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Comprehensive assessments of immune correlates of protection in human immunodeficiency virus (HIV) vaccine trials are essential to vaccine design. Neutralization sieve analysis compares the neutralization sensitivity of the breakthrough transmitted/ founder (TF) viruses from vaccinated and control animals to infer the molecular mechanisms of vaccine protection. Here, we report a robust neutralization sieve effect in a nonhuman primate simian immunodeficiency virus (SIV) vaccine trial (DNA prime/recombinant adenovirus type 5 [rAd5] boost) (VRC-10-332) that demonstrated substantial protective efficacy and revealed a genetic signature of neutralization resistance in the C1 region of env. We found significant enrichment for neutralization resistance in the vaccine compared to control breakthrough TF viruses when tested with plasma from vaccinated study animals, plasma from chronically SIV-infected animals, and a panel of SIV-specific monoclonal antibodies targeting six discrete Env epitopes (P < 0.008 for all comparisons). Neutralization resistance was significantly associated with the previously identified genetic signature of resistance (P < 0.0001), and together, the results identify virus neutralization as a correlate of protection. These findings further demonstrate the in vivo relevance of our previous in vitro analyses of the SIVsmE660 challenge stock, which revealed a broad range of neutralization sensitivities of its component viruses. In sum, this report demonstrates proof-of-concept that phenotypic sieve analyses can elucidate mechanistic correlates of immune protection following vaccination and raises a cautionary note for SIV and SHIV (simian-human immunodeficiency virus) vaccine studies that employ challenge strains with envelope glycoproteins that fail to exhibit neutralization resistance profiles typical of TF viruses. IMPORTANCEWith more than 2 million new infections annually, the development of an effective vaccine against HIV-1 is a global health priority. Understanding immunologic correlates of protection generated in vaccine trials is critical to advance vaccine development. Here, we assessed the role of vaccine-elicited neutralizing antibodies in a recent nonhuman primate study of a vaccine that showed significant protection against simian immunodeficiency virus (SIV) challenge and suggested a genetic signature of neutralization sensitivity. We found that breakthrough viruses able to establish infection in vaccinated animals were substantially more resistant to antibody-mediated neutralization than were viruses from controls. These findings suggest that vaccine-elicited neutralizing antibodies selectively blocked the transmission of more sensitive challenge viruses. Sieve analysis also corroborated a genetic signature of neutralization sensitivity and highlighted the impact of challenge swarm diversity. Our findings suggest an important role for neutralization sieve analyses as an informative component of comprehensive immune-correlates analyses. Substantial efforts toward the developme...

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“…The protective efficacy of these IgG antibodies was not associated with their avidity (39-43) but rather with FcR-mediated functions, such as ADCC (44). Conversely, high levels of gp120-specific plasma IgA were positively correlated with an increased risk of HIV infection in RV144 vaccine recipients (39) expressing a nonfunctional Fc␥RIIc receptor (45), which has been associated with reduced IgG/NK cellmediated ADCC (46). Presumably, IgA interfered with IgG-mediated ADCC in these subjects (47).…”

Section: Figmentioning

confidence: 99%

Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques

Jensen

Nabi

Rompay

et al. 2016

J Virol

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Despite significant progress in reducing peripartum mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV)with antiretroviral therapy (ART), continued access to ART throughout the breastfeeding period is still a limiting factor, and breast milk exposure to HIV accounts for up to 44% of MTCT. As abstinence from breastfeeding is not recommended, alternative means are needed to prevent MTCT of HIV. We have previously shown that oral vaccination at birth with live attenuated Mycobacterium tuberculosis strains expressing simian immunodeficiency virus (SIV) genes safely induces persistent SIV-specific cellular and humoral immune responses both systemically and at the oral and intestinal mucosa. Here, we tested the ability of oral M. tuberculosis vaccine strains expressing SIV Env and Gag proteins, followed by systemic heterologous (MVA-SIV Env/Gag/Pol) boosting, to protect neonatal macaques against oral SIV challenge. While vaccination did not protect infant macaques against oral SIV acquisition, a subset of immunized animals had significantly lower peak viremia which inversely correlated with prechallenge SIV Env-specific salivary and intestinal IgA responses and higher-avidity SIV Env-specific IgG in plasma. These controller animals also maintained CD4؉ T cell populations better and showed reduced tissue pathology compared to noncontroller animals. We show that infants vaccinated at birth can

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FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial

Cited by 100 publications

References 50 publications

Development and Characterization of Monoclonal Antibodies Specific for Mouse and Human Fcγ Receptors

Development and Characterization of Monoclonal Antibodies Specific for Mouse and Human Fcγ Receptors

Breakthrough Virus Neutralization Resistance as a Correlate of Protection in a Nonhuman Primate Heterologous Simian Immunodeficiency Virus Vaccine Challenge Study

Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques

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