Publications
232 results found
McGowan E, Rosenthal R, Fiore-Gartland A, et al., 2021, Utilizing Computational Machine Learning Tools to Understand Immunogenic Breadth in the Context of a CD8 T-Cell Mediated HIV Response., Front Immunol, Vol: 12
Predictive models are becoming more and more commonplace as tools for candidate antigen discovery to meet the challenges of enabling epitope mapping of cohorts with diverse HLA properties. Here we build on the concept of using two key parameters, diversity metric of the HLA profile of individuals within a population and consideration of sequence diversity in the context of an individual's CD8 T-cell immune repertoire to assess the HIV proteome for defined regions of immunogenicity. Using this approach, analysis of HLA adaptation and functional immunogenicity data enabled the identification of regions within the proteome that offer significant conservation, HLA recognition within a population, low prevalence of HLA adaptation and demonstrated immunogenicity. We believe this unique and novel approach to vaccine design as a supplement to vitro functional assays, offers a bespoke pipeline for expedited and rational CD8 T-cell vaccine design for HIV and potentially other pathogens with the potential for both global and local coverage.
Macharia GN, Yue L, Staller E, et al., 2020, Infection with multiple HIV-1 founder variants is associated with lower viral replicative capacity, faster CD4(+)T cell decline and increased immune activation during acute infection, PLoS Pathogens, Vol: 16, Pages: 1-22, ISSN: 1553-7366
HIV-1 transmission is associated with a severe bottleneck in which a limited number of variants from a pool of genetically diverse quasispecies establishes infection. The IAVI protocol C cohort of discordant couples, female sex workers, other heterosexuals and men who have sex with men (MSM) present varying risks of HIV infection, diverse HIV-1 subtypes and represent a unique opportunity to characterize transmitted/founder viruses (TF) where disease outcome is known. To identify the TF, the HIV-1 repertoire of 38 MSM participants’ samples was sequenced close to transmission (median 21 days post infection, IQR 18–41) and assessment of multivariant infection done. Patient derived gag genes were cloned into an NL4.3 provirus to generate chimeric viruses which were characterized for replicative capacity (RC). Finally, an evaluation of how the TF virus predicted disease progression and modified the immune response at both acute and chronic HIV-1 infection was done. There was higher prevalence of multivariant infection compared with previously described heterosexual cohorts. A link was identified between multivariant infection and replicative capacity conferred by gag, whereby TF gag tended to be of lower replicative capacity in multivariant infection (p = 0.02) suggesting an overall lowering of fitness requirements during infection with multiple variants. Notwithstanding, multivariant infection was associated with rapid CD4+ T cell decline and perturbances in the CD4+ T cell and B cell compartments compared to single variant infection, which were reversible upon control of viremia. Strategies aimed at identifying and mitigating multivariant infection could contribute toward improving HIV-1 prognosis and this may involve strategies that tighten the stringency of the transmission bottleneck such as treatment of STI. Furthermore, the sequences and chimeric viruses help with TF based experimental vaccine immunogen design and can be used in functional assays to pr
El-Badry E, Macharia G, Claiborne D, et al., 2020, Better Viral Control despite Higher CD4<SUP>+</SUP> T Cell Activation during Acute HIV-1 Infection in Zambian Women Is Linked to the Sex Hormone Estradiol, JOURNAL OF VIROLOGY, Vol: 94, ISSN: 0022-538X
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- Citations: 8
Kasprowicz VO, Chopera D, Waddilove KD, et al., 2020, African-led health research and capacity building- is it working?, BMC PUBLIC HEALTH, Vol: 20
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- Citations: 44
Brooks K, Jones BR, Dilernia DA, et al., 2020, HIV-1 variants are archived throughout infection and persist in the reservoir, PLOS PATHOGENS, Vol: 16, ISSN: 1553-7366
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- Citations: 26
Debebe BJ, Boelen L, Lee JC, et al., 2020, Identifying the immune interactions underlying HLA class I disease associations, eLife, Vol: 9, Pages: 1-43, ISSN: 2050-084X
Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms in the HLA class I loci. These genetic associations provide a powerful opportunity for understanding the etiology of human disease. HLA class I associations are often interpreted in the light of 'protective' or 'detrimental' CD8+ T cell responses which are restricted by the host HLA class I allotype. However, given the diverse receptors which are bound by HLA class I molecules, alternative interpretations are possible. As well as binding T cell receptors on CD8+ T cells, HLA class I molecules are important ligands for inhibitory and activating killer immunoglobulin-like receptors (KIRs) which are found on natural killer cells and some T cells; for the CD94:NKG2 family of receptors also expressed mainly by NK cells and for leukocyte immunoglobulin-like receptors (LILRs) on myeloid cells. The aim of this study is to develop an immunogenetic approach for identifying and quantifying the relative contribution of different receptor-ligand interactions to a given HLA class I disease association and then to use this approach to investigate the immune interactions underlying HLA class I disease associations in three viral infections: Human T cell Leukemia Virus type 1, Human Immunodeficiency Virus type 1 and Hepatitis C Virus as well as in the inflammatory condition Crohn's disease.
Ponnan SM, Hayes P, Fernandez N, et al., 2020, Evaluation of antiviral T cell responses and T<sub>SCM</sub> cells in volunteers enrolled in a phase I HIV-1 subtype C prophylactic vaccine trial in India, PLOS ONE, Vol: 15, ISSN: 1932-6203
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- Citations: 6
Price MA, Rida W, Kilembe W, et al., 2020, Control of the HIV-1 Load Varies by Viral Subtype in a Large Cohort of African Adults With Incident HIV-1 Infection (vol 220, pgf 432, 2019), JOURNAL OF INFECTIOUS DISEASES, Vol: 221, Pages: 493-493, ISSN: 0022-1899
Woodson E, Basu D, Olszewski H, et al., 2019, Reduced frequency of HIV superinfection in a high-risk cohort in Zambia, VIROLOGY, Vol: 535, Pages: 11-19, ISSN: 0042-6822
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- Citations: 1
Price MA, Rida W, Kilembe W, et al., 2019, Control of the HIV-1 Load Varies by Viral Subtype in a Large Cohort of African Adults With Incident HIV-1 Infection, JOURNAL OF INFECTIOUS DISEASES, Vol: 220, Pages: 432-441, ISSN: 0022-1899
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- Citations: 13
Claiborne DT, Scully EP, Palmer CD, et al., 2019, Protective HLA alleles are associated with reduced LPS levels in acute HIV infection with implications for immune activation and pathogenesis, PLOS PATHOGENS, Vol: 15, ISSN: 1553-7366
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- Citations: 8
Priddy FH, Lewis DJM, Gelderblom HC, et al., 2019, Adeno-associated virus vectored immunoprophylaxis to prevent HIV in healthy adults: a phase 1 randomised controlled trial, LANCET HIV, Vol: 6, Pages: E230-E239, ISSN: 2352-3018
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- Citations: 74
Ponnan SM, Pattabiram S, Thiruvengadam K, et al., 2019, Induction and maintenance of bi-functional (IFN-γ<SUP>+</SUP> IL-2<SUP>+</SUP> and IL-2<SUP>+</SUP> TNF-α<SUP>+</SUP>)T cell responses by DNA prime MVA boosted subtype C prophylactic vaccine tested in a Phase I trial in India, PLOS ONE, Vol: 14, ISSN: 1932-6203
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- Citations: 4
van Santen DK, van der Helm JJ, Touloumi G, et al., 2019, Effect of incident hepatitis C infection on CD4<SUP>+</SUP> cell count and HIV RNA trajectories based on a multinational HIV seroconversion cohort, AIDS, Vol: 33, Pages: 327-337, ISSN: 0269-9370
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- Citations: 4
Boelen L, Debebe B, Silveira M, et al., 2018, Inhibitory killer-cell immunoglobulin-like receptors strengthen CD8+ T cell-mediated control of HIV-1, HCV and HTLV-1, Science Immunology, Vol: 3, Pages: 1-16, ISSN: 2470-9468
Killer cell immunoglobulin-like receptors (KIRs) are expressed predominantly on natural killer cells, where they play a key role in the regulation of innate immune responses. Recent studies show that inhibitory KIRs can also affect adaptive T cell–mediated immunity. In mice and in human T cells in vitro, inhibitory KIR ligation enhanced CD8+ T cell survival. To investigate the clinical relevance of these observations, we conducted an extensive immunogenetic analysis of multiple independent cohorts of HIV-1–, hepatitis C virus (HCV)–, and human T cell leukemia virus type 1 (HTLV-1)–infected individuals in conjunction with in vitro assays of T cell survival, analysis of ex vivo KIR expression, and mathematical modeling of host-virus dynamics. Our data suggest that functional engagement of inhibitory KIRs enhances the CD8+ T cell response against HIV-1, HCV, and HTLV-1 and is a significant determinant of clinical outcome in all three viral infections.
Gelderblom HC, Lewis DJM, Streatfield C, et al., 2018, A Phase 1 Trial of AAV1 Vectored Immunoprophylaxis for HIV, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 183-183, ISSN: 0889-2229
Langat R, McRaven M, Joseph S, et al., 2018, Identification of HIV-1 Clade C Transmitted Founder Viruses that Replicate Efficiently in Human Rectal and Vaginal Tissue Explant Cultures, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 304-304, ISSN: 0889-2229
Farinre O, Gounder K, Tongo M, et al., 2018, HIV-1 Recombinant Viruses From West Africa Display Higher Replication Capacity Compared to Recombinants From East Africa, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 234-234, ISSN: 0889-2229
Peng BJ, Carlson JM, Liu MKP, et al., 2018, Antisense-Derived HIV-1 Cryptic Epitopes Are Not Major Drivers of Viral Evolution during the Acute Phase of Infection, JOURNAL OF VIROLOGY, Vol: 92, ISSN: 0022-538X
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- Citations: 3
Michelo CM, Dale JA, Fiore-Gartland A, et al., 2018, Unique and Expanded Breadth Estimate of CD8 T-cell Responses to Cohort-specific HIV-1 GAG Protein Peptides, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 385-385, ISSN: 0889-2229
Fernandez N, Makinde J, Black SL, et al., 2018, The Generation and Validation of Autologous CD8 and CD4 T Cell Lines for Use as Assay Controls in HIV Viral Inhibition Assays, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 247-247, ISSN: 0889-2229
Makinde J, Hayes P, Black SL, et al., 2018, A Rapid Protocol for Enriching Peptide-specific CD8 T Cell Lines to Determine Their Contribution to Viral Inhibition, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 246-246, ISSN: 0889-2229
Kibirige C, McGowan E, Hayes P, et al., 2018, Correlating HIV RNA Levels, Viral Replicative Capacity and Immune Control Within an Assay to Measure CD8 T Cell Mediated HIV-1 Inhibition In Vitro, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 176-176, ISSN: 0889-2229
Makinde J, Nduati EW, Kibirige C, et al., 2018, Classification of HIV Controllers in an Acute Infection Cohort to Enable Systems Investigation of Signatures Associated With Control of Infection, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 377-377, ISSN: 0889-2229
Balinda SN, Kapaata A, Ling Y, et al., 2018, Transmission of Unique Intersubtype HIV-1 Recombinants Predominate in Both Single and Multiple Variant Infections in Uganda, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 392-392, ISSN: 0889-2229
Ponnan SM, Swaminathan S, Tiruvengadam K, et al., 2018, Induction of circulating T follicular helper cells and regulatory T cells correlating with HIV-1 gp120 variable loop antibodies by a subtype C prophylactic vaccine tested in a Phase I trial in India, PLOS ONE, Vol: 13, ISSN: 1932-6203
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- Citations: 10
Macharia G, Staller E, Yue L, et al., 2018, Infection With Multiple Transmitted/Founder (TF) HIV-1 Viruses Impacts Peak VL and HIV-1 Pathogenesis, HIV Research for Prevention 2018: AIDS Vaccine, Microbicide and ARV-based Prevention Science (HIVR4P)
Powers KA, Price MA, Karita E, et al., 2018, Prediction of extended high viremia among newly HIV-1-infected persons in sub-Saharan Africa, PLOS ONE, Vol: 13, ISSN: 1932-6203
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- Citations: 3
Kratochvil S, McKay PF, Chung AW, et al., 2017, Immunoglobulin G1 Allotype Influences Antibody Subclass Distribution in Response to HIV gp140 Vaccination, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
Antibody subclasses exhibit extensive polymorphisms (allotypes) that could potentially impact the quality of HIV-vaccine induced B cell responses. Allotypes of immunoglobulin (Ig) G1, the most abundant serum antibody, have been shown to display altered functional properties in regard to serum half-life, Fc-receptor binding and FcRn-mediated mucosal transcytosis. To investigate the potential link between allotypic IgG1-variants and vaccine-generated humoral responses in a cohort of 14 HIV vaccine recipients, we developed a novel protocol for rapid IgG1-allotyping. We combined PCR and ELISA assays in a dual approach to determine the IgG1 allotype identity (G1m3 and/or G1m1) of trial participants, using human plasma and RNA isolated from PBMC. The IgG1-allotype distribution of our participants mirrored previously reported results for caucasoid populations. We observed elevated levels of HIV gp140-specific IgG1 and decreased IgG2 levels associated with the G1m1-allele, in contrast to G1m3 carriers. These data suggest that vaccinees homozygous for G1m1 are predisposed to develop elevated Ag-specific IgG1:IgG2 ratios compared to G1m3-carriers. This elevated IgG1:IgG2 ratio was further associated with higher FcγR-dimer engagement, a surrogate for potential antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) function. Although preliminary, these results suggest that IgG1 allotype may have a significant impact on IgG subclass distribution in response to vaccination and associated Fc-mediated effector functions. These results have important implications for ongoing HIV vaccine efficacy studies predicated on engagement of FcγR-mediated cellular functions including ADCC and ADCP, and warrant further investigation. Our novel allotyping protocol provides new tools to determine the potential impact of IgG1 allotypes on vaccine efficacy.
Gelderblom HC, Lewis DJ, Streatfield C, et al., 2017, A phase 1 trial of AAV1 vectored immunoprophylaxis for HIV, European-Society-of-Gene-and-Cell-Therapy (ESCGT) Congress, Publisher: MARY ANN LIEBERT, INC, Pages: A18-A19, ISSN: 1043-0342
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