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Article: Neutralization and beyond: Antibodies and HIV-1 acquisition.

Thomas, Allison S / Ghulam-Smith, Melissa / Sagar, Manish

2019 Volume 15, Page(s) 73–86

Abstract: It is widely accepted that an effective HIV-1 preventative vaccine must elicit antibodies that can block virus acquisition. Although, anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been isolated, unfortunately, no vaccine immunogens have been ... ...

Abstract	It is widely accepted that an effective HIV-1 preventative vaccine must elicit antibodies that can block virus acquisition. Although, anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been isolated, unfortunately, no vaccine immunogens have been designed that can elicit these bnAbs in uninfected at-risk individuals. Some studies have suggested that other antibody functionalities, besides neutralization, such as antibody-dependent cellular cytotoxicity (ADCC), may prevent HIV-1 acquisition. In contrast to bnAbs, ADCC-inducing antibodies may be more amenable to elicitation by current vaccine technologies. This review will provide clarity about the role of nAbs and ADCC-inducing antibodies in preventing transmission, highlight mechanisms that potentially explain how ADCC-mediating antibodies may work, and speculate about the generation of these novel protective antibodies. Anti-HIV-1 ADCC-inducing antibodies may provide a new avenue for developing an effective HIV-1 vaccine.
Language	English
Publishing date	2019-11-30
Publishing country	India
Document type	Journal Article
ZDB-ID	2475042-6
ISSN	0972-4591
ISSN	0972-4591
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Article ; Online: Developmental and behavioral phenotypes of pediatric patients with PTEN hamartoma tumor syndrome.

MacFarland, Suzanne P / Duvall, Melani / Kemajou, Raissa Tchetcho / Baldino, Sarah E / Zelley, Kristin / Black, Chelsea / Thomas, Allison / Thomas, Nina H / Ruffner, Melanie / Li, Yimei / Miller, Judith S / Brodeur, Garrett M / Shabason, Emily

American journal of medical genetics. Part A

2024 , Page(s) e63608

Abstract: Our study characterized the neurodevelopmental spectrum of individuals with PTEN Hamartoma Tumor Syndrome (PHTS), a syndrome that predisposes to both neurodevelopmental phenotypes and cancer risk. We aim to better understand life-impacting ... ...

Abstract	Our study characterized the neurodevelopmental spectrum of individuals with PTEN Hamartoma Tumor Syndrome (PHTS), a syndrome that predisposes to both neurodevelopmental phenotypes and cancer risk. We aim to better understand life-impacting neurodevelopmental features of PHTS. Our study recruited 20 children/adolescents with PHTS, who were then administered assessments for autism spectrum disorder (ASD) and other neurocognitive measures, including assessment of IQ, executive and adaptive functioning, and health-related quality of life. Thirteen individuals (65%) were identified as having ASD, of which five were newly diagnosed during the study. Of those, ASD symptom severity was in the mild-moderate range for 77%. Overall, IQ was in the average range, with a mean of 92.61 (SD 24.45, p = 0.5), though there was a non-statistically significant trend toward individuals without ASD having a higher mean IQ (102.7 vs 82.3; p = 0.1). Subjects had significant impairment in processing speed (mean 75.38, SD 24.75, p < 0.05), decreased adaptive functioning skills across all domains, and a trend toward having more executive functioning problems. Individuals with PHTS are at increased risk of neurodevelopmental disorders, including ASD and impaired executive and adaptive functioning. Although clear guidelines exist for cancer surveillance for individuals with PHTS, additional guidelines and screening for neurodevelopmental disorders are warranted.
Language	English
Publishing date	2024-03-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2108614-X
ISSN	1552-4833 ; 0148-7299 ; 1552-4825
ISSN (online)	1552-4833
ISSN	0148-7299 ; 1552-4825
DOI	10.1002/ajmg.a.63608
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Article ; Online: Antibody-dependent cellular cytotoxicity responses and susceptibility influence HIV-1 mother-to-child transmission.

Thomas, Allison S / Coote, Carolyn / Moreau, Yvetane / Isaac, John E / Ewing, Alexander C / Kourtis, Athena P / Sagar, Manish

JCI insight

2022 Volume 7, Issue 9

Abstract: HIV-1 vaccine efforts are primarily directed toward eliciting neutralizing antibodies (nAbs). However, vaccine trials and mother-to-child natural history cohort investigations indicate that antibody-dependent cellular cytotoxicity (ADCC), not nAbs, ... ...

Abstract	HIV-1 vaccine efforts are primarily directed toward eliciting neutralizing antibodies (nAbs). However, vaccine trials and mother-to-child natural history cohort investigations indicate that antibody-dependent cellular cytotoxicity (ADCC), not nAbs, correlate with prevention. The ADCC characteristics associated with lack of HIV-1 acquisition remain unclear. Here, we examine ADCC and nAb properties in pretransmission plasma from HIV-1-exposed infants and from the corresponding transmitting and nontransmitting mothers' breast milk and plasma. Breadth and potency (BP) were assessed against a panel of heterologous, nonmaternal variants. ADCC and neutralization sensitivity were estimated for the strains in the infected mothers. Infants who eventually acquired HIV-1 and those who remained uninfected had similar pretransmission ADCCBP. Viruses circulating in the transmitting and nontransmitting mothers had similar ADCC susceptibility. Infants with higher pretransmission ADCCBP and exposure to more ADCC-susceptible strains were less likely to acquire HIV-1. In contrast, higher preexisting infant neutralization BP and greater maternal virus neutralization sensitivity did not associate with transmission. Infants had higher ADCCBP closer to birth and in the presence of high plasma IgG relative to IgA levels. Mothers with potent humoral responses against their autologous viruses harbored more ADCC-sensitive strains. ADCC sensitivity of the exposure variants and preexisting ADCCBP influenced mother-to-child HIV-1 transmission during breastfeeding. Vaccination strategies that enhance ADCC are likely insufficient to prevent HIV-1 transmission because some strains may have low ADCC susceptibility.
MeSH term(s)	Antibodies, Neutralizing ; Antibody-Dependent Cell Cytotoxicity ; Female ; HIV Antibodies ; HIV Infections/complications ; HIV-1 ; Humans ; Infant ; Infectious Disease Transmission, Vertical/prevention & control ; Milk, Human
Chemical Substances	Antibodies, Neutralizing ; HIV Antibodies
Language	English
Publishing date	2022-05-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.159435
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: A new cell line for assessing HIV-1 antibody dependent cellular cytotoxicity against a broad range of variants

Thomas, Allison S / Ghulam-Smith, Melissa / Olson, Alex / Coote, Carolyn / Gonzales, Oscar / Sagar, Manish

Journal of immunological methods. 2020 May, v. 480

2020

Abstract: Human immunodeficiency virus type 1 (HIV-1) studies suggest that antibody-dependent cellular cytotoxicity (ADCC) influences both virus acquisition and subsequent disease outcome. Technical issues with currently available assays, however, have limited the ...

Abstract	Human immunodeficiency virus type 1 (HIV-1) studies suggest that antibody-dependent cellular cytotoxicity (ADCC) influences both virus acquisition and subsequent disease outcome. Technical issues with currently available assays, however, have limited the ability to comprehensively assess the impact of ADCC on transmission and disease progression. Commonly used ADCC assays use a target cell line, CEM.NKr-CCR5-Luc, that often does not support replication of relevant HIV-1 variants. Thus, the extent of ADCC responses against a large panel of HIV-1 strains often cannot be assessed using the currently available methods. We developed two new reporter cell-lines (MT4-CCR5-Luc and PM1-CCR5-Luc) to overcome these issues. MT4-CCR5-Luc cells are resistant, whereas PM1-CCR5-Luc cells are susceptible, to killing by a natural killer cell line, CD16+KHYG-1, in the absence of antibody. Polyclonal HIVIG gave similar ADCC estimates against HIV-1 isolate, NL4-3, regardless of which of the three cell lines were used as the targets. In contrast to CEM.NKr-CCR5-Luc and PM1-CCR5-Luc, however, MT4-CCR5-Luc target cells produce significantly higher luciferase after exposure to various HIV-1 strains, including transmitted founder variants and viruses incorporating specific envelopes of interest. This higher luciferase expression does not yield spurious results because ADCC estimates are similar when killing is assessed by both reporter protein expression and flow cytometry. Furthermore, ADCC estimates derived from MT4-CCR5-Luc cells are not skewed by non-antibody contents present in human plasma. In aggregate, the MT4-CCR5-Luc cell line can be used to estimate monoclonal antibody or plasma-induced ADCC responses against a diverse range of HIV-1 envelopes relevant for transmission and disease progression studies.
Keywords	Human immunodeficiency virus 1 ; cell lines ; cytotoxicity ; disease progression ; flow cytometry ; humans ; luciferase ; monoclonal antibodies ; natural killer cells ; protein synthesis ; viruses
Language	English
Dates of publication	2020-05
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	120142-6
ISSN	1872-7905 ; 0022-1759
ISSN (online)	1872-7905
ISSN	0022-1759
DOI	10.1016/j.jim.2020.112766
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 795: Show issues

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bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: A new cell line for assessing HIV-1 antibody dependent cellular cytotoxicity against a broad range of variants.

Thomas, Allison S / Ghulam-Smith, Melissa / Olson, Alex / Coote, Carolyn / Gonzales, Oscar / Sagar, Manish

Journal of immunological methods

2020 Volume 480, Page(s) 112766

Abstract	Human immunodeficiency virus type 1 (HIV-1) studies suggest that antibody-dependent cellular cytotoxicity (ADCC) influences both virus acquisition and subsequent disease outcome. Technical issues with currently available assays, however, have limited the ability to comprehensively assess the impact of ADCC on transmission and disease progression. Commonly used ADCC assays use a target cell line, CEM.NKr-CCR5-Luc, that often does not support replication of relevant HIV-1 variants. Thus, the extent of ADCC responses against a large panel of HIV-1 strains often cannot be assessed using the currently available methods. We developed two new reporter cell-lines (MT4-CCR5-Luc and PM1-CCR5-Luc) to overcome these issues. MT4-CCR5-Luc cells are resistant, whereas PM1-CCR5-Luc cells are susceptible, to killing by a natural killer cell line, CD16
MeSH term(s)	Antibody-Dependent Cell Cytotoxicity ; Cell Line ; Coculture Techniques ; Genes, Reporter ; HIV Antibodies/immunology ; HIV Antigens/immunology ; HIV Infections/immunology ; HIV Infections/pathology ; HIV Infections/virology ; HIV-1/immunology ; HIV-1/pathogenicity ; Host-Pathogen Interactions ; Humans ; Killer Cells, Natural/immunology ; Killer Cells, Natural/virology ; Luciferases/biosynthesis ; Luciferases/genetics ; Lymphocytes/immunology ; Lymphocytes/virology ; env Gene Products, Human Immunodeficiency Virus/immunology
Chemical Substances	HIV Antibodies ; HIV Antigens ; env Gene Products, Human Immunodeficiency Virus ; Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2020-03-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	120142-6
ISSN	1872-7905 ; 0022-1759
ISSN (online)	1872-7905
ISSN	0022-1759
DOI	10.1016/j.jim.2020.112766
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 795: Show issues

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bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Book: DNA damage repair

Thomas, Allison E

repair mechanisms, and aging

(DNA : properties and modifications, functions and interactions, recombination and applications)

2010

Author's details	Allison E. Thomas, editor
Series title	DNA : properties and modifications, functions and interactions, recombination and applications
MeSH term(s)	DNA Repair ; DNA Damage ; Aging/physiology
Language	English
Size	xiii, 288 p. :, ill.
Publisher	Nova Science Publishers
Publishing place	New York
Document type	Book
ISBN	9781616689148 ; 1616689145
Database	Catalogue of the US National Library of Medicine (NLM)

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Article ; Online: Pre-existing infant antibody-dependent cellular cytotoxicity associates with reduced HIV-1 acquisition and lower morbidity.

Thomas, Allison S / Moreau, Yvetane / Jiang, Wenqing / Isaac, John E / Ewing, Alexander / White, Laura F / Kourtis, Athena P / Sagar, Manish

Cell reports. Medicine

2021 Volume 2, Issue 10, Page(s) 100412

Abstract: In humans, pre-existing anti-HIV-1 neutralizing antibodies (nAbs) have not been associated with decreased HIV-1 acquisition. Here, we evaluate antibody-dependent cellular cytotoxicity (ADCC) present in pre-transmission infant and maternal plasma and ... ...

Abstract	In humans, pre-existing anti-HIV-1 neutralizing antibodies (nAbs) have not been associated with decreased HIV-1 acquisition. Here, we evaluate antibody-dependent cellular cytotoxicity (ADCC) present in pre-transmission infant and maternal plasma and breast milk (BM) against the contemporaneous maternal HIV-1 variants. HIV-1-exposed uninfected compared with HIV-1-exposed infected infants have higher ADCC and a combination of ADCC and nAb responses against their corresponding mother's strains. ADCC does not correlate with nAbs, suggesting they are independent activities. The infected infants with high ADCC compared with low ADCC, but not those with higher ADCC plus nAbs, have lower morbidity up to 1 year after birth. A higher IgA to IgG ratio, observed in BM supernatants and in a higher proportion of the infected compared with the uninfected infants, associates with lower ADCC. Against the exposure strains, ADCC, more than nAbs, associates with both lower mother-to-child transmission and decreased post-infection infant morbidity.
MeSH term(s)	Adult ; Antibodies, Neutralizing/blood ; Antibody-Dependent Cell Cytotoxicity ; Cytotoxicity, Immunologic ; Female ; HIV Antibodies/blood ; HIV Infections/genetics ; HIV Infections/immunology ; HIV Infections/pathology ; HIV Infections/virology ; HIV-1/genetics ; HIV-1/immunology ; HIV-1/pathogenicity ; Humans ; Immune Sera/chemistry ; Immunoglobulin A/blood ; Immunoglobulin G/blood ; Infant ; Infectious Disease Transmission, Vertical ; Milk, Human/chemistry ; Milk, Human/immunology ; Pregnancy
Chemical Substances	Antibodies, Neutralizing ; HIV Antibodies ; Immune Sera ; Immunoglobulin A ; Immunoglobulin G
Language	English
Publishing date	2021-10-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2021.100412
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Correction: Characterizing the neurological phenotype of the hyperinsulinism hyperammonemia syndrome.

Rosenfeld, Elizabeth / Nanga, Ravi Prakash Reddy / Lucas, Alfredo / Revell, Andrew Y / Thomas, Allison / Thomas, Nina H / Roalf, David R / Shinohara, Russell T / Reddy, Ravinder / Davis, Kathryn A / De León, Diva D

Orphanet journal of rare diseases

2022 Volume 17, Issue 1, Page(s) 315

Language	English
Publishing date	2022-08-18
Publishing country	England
Document type	Published Erratum
ZDB-ID	2225857-7
ISSN	1750-1172 ; 1750-1172
ISSN (online)	1750-1172
ISSN	1750-1172
DOI	10.1186/s13023-022-02466-8
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Article ; Online: Characterizing the neurological phenotype of the hyperinsulinism hyperammonemia syndrome.

Orphanet journal of rare diseases

2022 Volume 17, Issue 1, Page(s) 248

Abstract: Background: Hyperinsulinism hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1, encoding glutamate dehydrogenase (GDH). Atypical absence seizures and neuropsychological disorders occur at high rates in this form of ... ...

Abstract	Background: Hyperinsulinism hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1, encoding glutamate dehydrogenase (GDH). Atypical absence seizures and neuropsychological disorders occur at high rates in this form of hyperinsulinism. Dysregulated central nervous system (CNS) glutamate balance, due to GDH overactivity in the brain, has been hypothesized to play a role. This study aimed to describe the neurologic phenotype in HI/HA syndrome and investigate CNS glutamate levels using glutamate weighted chemical exchange saturation transfer magnetic resonance imaging (GluCEST MRI). In this cross-sectional study, 12 subjects with HI/HA syndrome had plasma ammonia measurement, self- or parent-completed neurocognitive assessments, electroencephalogram (EEG), and GluCEST MRI at 7 T performed. GluCEST MRI measures were compared to a historic reference population of 10 healthy adults. Results: Subjects were five males and seven females with median age of 25.5 years. Seventy-five percent of subjects reported a history of neurodevelopmental problems and 42% had neurocognitive assessment scores outside the normal range. Fifty percent had interictal EEG findings of generalized, irregular spike and wave discharges. Higher variability in hippocampal GluCEST asymmetry (p = 0.002), and in peak hippocampal GluCEST values (p = 0.008), was observed in HI/HA subjects (n = 9 with interpretable MRI) compared to the healthy reference population (n = 10). Conclusions: The high prevalence of abnormal neurocognitive assessment scores and interictal EEG findings observed highlights the importance of longitudinal neuropsychological assessment for individuals with HI/HA syndrome. Our findings demonstrate the potential application of GluCEST to investigate persistent knowledge gaps in the mechanisms underlying the unique neurophenotype of this disorder.
MeSH term(s)	Cross-Sectional Studies ; Female ; Glutamate Dehydrogenase/genetics ; Glutamates ; Humans ; Hyperammonemia/genetics ; Hyperinsulinism/genetics ; Hypoglycemia ; Male ; Phenotype
Chemical Substances	Glutamates ; Glutamate Dehydrogenase (EC 1.4.1.2)
Language	English
Publishing date	2022-06-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2225857-7
ISSN	1750-1172 ; 1750-1172
ISSN (online)	1750-1172
ISSN	1750-1172
DOI	10.1186/s13023-022-02398-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Vertical HIV-1 Transmission in the Setting of Maternal Broad and Potent Antibody Responses.

Tu, Joshua J / Kumar, Amit / Giorgi, Elena E / Eudailey, Joshua / LaBranche, Celia C / Martinez, David R / Fouda, Genevieve G / Moreau, Yvetane / Thomas, Allison / Montefiori, David / Gao, Feng / Sagar, Manish / Permar, Sallie R

Journal of virology

2022 Volume 96, Issue 11, Page(s) e0023122

Abstract: Despite the worldwide availability of antiretroviral therapy (ART), approximately 150,000 pediatric HIV infections continue to occur annually. ART can dramatically reduce HIV mother-to-child transmission (MTCT), but inconsistent drug access and adherence, ...

Abstract	Despite the worldwide availability of antiretroviral therapy (ART), approximately 150,000 pediatric HIV infections continue to occur annually. ART can dramatically reduce HIV mother-to-child transmission (MTCT), but inconsistent drug access and adherence, as well as primary maternal HIV infection during pregnancy and lactation are major barriers to eliminating vertical HIV transmission. Thus, immunologic strategies to prevent MTCT, such as an HIV vaccine, will be required to attain an HIV-free generation. A primary goal of HIV vaccine research has been to elicit broadly neutralizing antibodies (bnAbs) given the ability of passive bnAb immunization to protect against sensitive strains, yet we previously observed that HIV-transmitting mothers have more plasma neutralization breadth than nontransmitting mothers. Additionally, we have identified infant transmitted/founder (T/F) viruses that escape maternal bnAb responses. In this study, we examine a cohort of postpartum HIV-transmitting women with neutralization breadth to determine if certain maternal bnAb specificities drive the selection of infant T/F viruses. Using HIV pseudoviruses that are resistant to neutralizing antibodies targeting common bnAb epitopes, we mapped the plasma bnAb specificities of this cohort. Significantly more transmitting women with plasma bnAb activity had a mappable plasma bnAb specificity (six of seven, or 85.7%) compared to that of nontransmitting women with plasma bnAb activity (7 of 21, or 33.3%,
MeSH term(s)	AIDS Vaccines ; Antibody Formation ; Broadly Neutralizing Antibodies ; Epitopes ; Female ; HIV Antibodies/immunology ; HIV Infections/transmission ; HIV Seropositivity ; HIV-1 ; Humans ; Infant ; Infectious Disease Transmission, Vertical/prevention & control ; Pregnancy
Chemical Substances	AIDS Vaccines ; Broadly Neutralizing Antibodies ; Epitopes ; HIV Antibodies
Language	English
Publishing date	2022-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00231-22
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