232 results found
van Duijn J, Stieh D, Fernandez N, et al., 2023, Mosaic HIV-1 vaccination induces anti-viral CD8+ T cell functionality in the phase 1/2a clinical trial APPROACH., J Virol, Vol: 97
The ability of vaccine-induced T cells to inhibit viral replication may contribute to protect against human immunodeficiency virus (HIV) acquisition. Here, we tested ex vivo viral inhibitory activity of T cell responses induced by a multivalent HIV vaccine based on the replication-incompetent recombinant adenovirus serotype 26 vector with a mosaic immunogen strategy (Ad26.Mos.HIV), designed for broad immune coverage of diverse HIV-1 strains. Using clinical trial samples with a diverse range of T cell responses measured by IFN-γ ELISpot, anti-viral function of vaccine-induced CD8+ T cells was assessed by inhibition of HIV-1 replication in autologous CD4+ T cells to a panel of HIV-1 isolates. Ex vivo expanded CD8+ T cells were able to inhibit replication of HIV in autologous CD4+ T cells, with 94% of vaccinees inhibiting at least one out of eight HIV isolates, and a median of 5 isolates inhibited at peak immunogenicity. Correlations between viral inhibition and ICS as well as ELISpot responses were explored, demonstrating positive correlations. Broad ELISpot responsiveness to different regions of the Env, Gag, and Pol proteins was associated with breadth of viral inhibitory responses. Moreover, polyfunctionality of CD8+ T cells correlated well with viral inhibition. These findings indicate that functional immunological breadth as well as antigenic breadth is important to induce antiviral activity. This study advances the understanding of vaccine-induced T cell functionality and demonstrates for the first time that Ad26.Mos.HIV vaccination in combination with adjuvanted gp140 can induce broad viral inhibitory activity toward a panel of diverse HIV-1 clades. IMPORTANCE The functionality of CD8+ T cells against human immunodeficiency virus-1 (HIV-1) antigens is indicative of HIV-progression in both animal models and people living with HIV. It is, therefore, of interest to assess CD8+ T cell responses in a prophylactic vaccination setting, as this may be an importan
Joyce C, Murrell S, Murrell B, et al., 2023, Antigen pressure from two founder viruses induces multiple insertions at a single antibody position to generate broadly neutralizing HIV antibodies., PLoS Pathog, Vol: 19
Vaccination strategies aimed at maturing broadly neutralizing antibodies (bnAbs) from naïve precursors are hindered by unusual features that characterize these Abs, including insertions and deletions (indels). Longitudinal studies of natural HIV infection cases shed light on the complex processes underlying bnAb development and have suggested a role for superinfection as a potential enhancer of neutralization breadth. Here we describe the development of a potent bnAb lineage that was elicited by two founder viruses to inform vaccine design. The V3-glycan targeting bnAb lineage (PC39-1) was isolated from subtype C-infected IAVI Protocol C elite neutralizer, donor PC39, and is defined by the presence of multiple independent insertions in CDRH1 that range from 1-11 amino acids in length. Memory B cell members of this lineage are predominantly atypical in phenotype yet also span the class-switched and antibody-secreting cell compartments. Development of neutralization breadth occurred concomitantly with extensive recombination between founder viruses before each virus separated into two distinct population "arms" that evolved independently to escape the PC39-1 lineage. Ab crystal structures show an extended CDRH1 that can help stabilize the CDRH3. Overall, these findings suggest that early exposure of the humoral system to multiple related Env molecules could promote the induction of bnAbs by focusing Ab responses to conserved epitopes.
Michelo CM, Fiore-Gartland A, Dalel JA, et al., 2023, Cohort-Specific Peptide Reagents Broaden Depth and Breadth Estimates of the CD8 T Cell Response to HIV-1 Gag Potential T Cell Epitopes, Vaccines, Vol: 11, ISSN: 2076-393X
An effective HIV vaccine will need to stimulate immune responses against the sequence diversity presented in circulating virus strains. In this study, we evaluate breadth and depth estimates of potential T-cell epitopes (PTEs) in transmitted founder virus sequence-derived cohort-specific peptide reagents against reagents representative of consensus and global sequences. CD8 T-cells from twenty-six HIV-1+ PBMC donor samples, obtained at 1-year post estimated date of infection, were evaluated. ELISpot assays compared responses to 15mer consensus (n = 121), multivalent-global (n = 320), and 10mer multivalent cohort-specific (n = 300) PTE peptides, all mapping to the Gag antigen. Responses to 38 consensus, 71 global, and 62 cohort-specific PTEs were confirmed, with sixty percent of common global and cohort-specific PTEs corresponding to consensus sequences. Both global and cohort-specific peptides exhibited broader epitope coverage compared to commonly used consensus reagents, with mean breadth estimates of 3.2 (global), 3.4 (cohort) and 2.2 (consensus) epitopes. Global or cohort peptides each identified unique epitope responses that would not be detected if these peptide pools were used alone. A peptide set designed around specific virologic and immunogenetic characteristics of a target cohort can expand the detection of CD8 T-cell responses to epitopes in circulating viruses, providing a novel way to better define the host response to HIV-1 with implications for vaccine development.
Fernandez N, Hayes P, Makinde J, et al., 2022, Assessment of a diverse panel of transmitted/founder HIV-1 infectious molecular clones in a luciferase based CD8 T-cell mediated viral inhibition assay, Frontiers in Immunology, Vol: 13, Pages: 1-15, ISSN: 1664-3224
Introduction: Immunological protection against human immunodeficiency virus-1 (HIV-1) infection is likely to require both humoral and cell-mediated immune responses, the latter involving cytotoxic CD8 T-cells. Characterisation of CD8 T-cell mediated direct anti-viral activity would provide understanding of potential correlates of immune protection and identification of critical epitopes associated with HIV-1 control.Methods: The present report describes a functional viral inhibition assay (VIA) to assess CD8 T-cell-mediated inhibition of replication of a large and diverse panel of 45 HIV-1 infectious molecular clones (IMC) engineered with a Renilla reniformis luciferase reporter gene (LucR), referred to as IMC-LucR. HIV-1 IMC replication in CD4 T-cells and CD8 T-cell mediated inhibition was characterised in both ART naive subjects living with HIV-1 covering a broad human leukocyte antigen (HLA) distribution and compared with uninfected subjects.Results & discussion: CD4 and CD8 T-cell lines were established from subjects vaccinated with a candidate HIV-1 vaccine and provided standard positive controls for both assay quality control and facilitating training and technology transfer. The assay was successfully established across 3 clinical research centres in Kenya, Uganda and the United Kingdom and shown to be reproducible. This IMC-LucR VIA enables characterisation of functional CD8 T-cell responses providing a tool for rational T-cell immunogen design of HIV-1 vaccine candidates and evaluation of vaccine-induced T-cell responses in HIV-1 clinical trials.
Kibirige CN, Manak M, King D, et al., 2022, Author Correction: Development of a sensitive, quantitative assay with broad subtype specificity for detection of total HIV-1 nucleic acids in plasma and PBMC, Scientific Reports, Vol: 12, ISSN: 2045-2322
Correction to: Scientific Reports https://doi.org/10.1038/s41598-021-03016-1, published online 28 January 2022
Kapaata A, Balinda SN, Hare J, et al., 2022, Infection with HIV-1 subtype D among acutely infected Ugandans is associated with higher median concentration of cytokines compared to subtype A, IJID Regions, Vol: 3, Pages: 89-95, ISSN: 2772-7076
OBJECTIVE: The observation that HIV-1 subtype D progresses faster to disease than subtype A prompted us to examine cytokine levels early after infection within the predominant viral subtypes that circulate in Uganda and address the following research questions: (1) Do cytokine levels vary between subtypes A1 and D? (2) Do cytokine profiles correlate with disease outcomes? METHODS: To address these questions, HIV-1 subtypes were determined by population sequencing of the HIV-1 pol gene and 37 plasma cytokine concentrations were evaluated using V-Plex kits on Meso Scale Discovery platform in 65 recent sero-converters. RESULTS: HIV-1 subtype D (pol) infections exhibited significantly higher median plasma concentrations of IL-5, IL-16, IL-1α, IL-7, IL-17A, CCL11 (Eotaxin-1), CXCL10 (IP-10), CCL13 (MCP-4) and VEGF-D compared to subtype A1 (pol) infections. We also found that IL-12/23p40 and IL-1α were associated with faster CD4+T cell count decline, while bFGF was associated with maintenance of CD4+ counts above 350 cells/microliter. CONCLUSION: Our results suggest that increased production of cytokines in early HIV infection may trigger a disruption of the immune environment and contribute to pathogenic mechanisms underlying the accelerated disease progression seen in individuals infected with HIV-1 subtype D in Uganda.
Alrubayyi A, Hassan AS, Hare J, et al., 2022, Evolution of natural killer (NK) cell responses during acute HIV-1 infection with distinct viral subtypes, Publisher: WILEY, Pages: 38-39, ISSN: 1464-2662
Huettner I, Krumm SA, Serna S, et al., 2022, Cross-reactivity of glycan-reactive HIV-1 broadly neutralizing antibodies with parasite glycans., Cell Rep, Vol: 38
The HIV-1 Envelope glycoprotein (Env) is the sole target for broadly neutralizing antibodies (bnAbs). Env is heavily glycosylated with host-derived N-glycans, and many bnAbs bind to, or are dependent upon, Env glycans for neutralization. Although glycan-binding bnAbs are frequently detected in HIV-infected individuals, attempts to elicit them have been unsuccessful because of the poor immunogenicity of Env N-glycans. Here, we report cross-reactivity of glycan-binding bnAbs with self- and non-self N-glycans and glycoprotein antigens from different life-stages of Schistosoma mansoni. Using the IAVI Protocol C HIV infection cohort, we examine the relationship between S. mansoni seropositivity and development of bnAbs targeting glycan-dependent epitopes. We show that the unmutated common ancestor of the N332/V3-specific bnAb lineage PCDN76, isolated from an HIV-infected donor with S. mansoni seropositivity, binds to S. mansoni cercariae while lacking reactivity to gp120. Overall, these results present a strategy for elicitation of glycan-reactive bnAbs which could be exploited in HIV-1 vaccine development.
Balinda SN, Kapaata A, Xu R, et al., 2022, Characterization of Near Full-Length Transmitted/Founder HIV-1 Subtype D and A/D Recombinant Genomes in a Heterosexual Ugandan Population (2006-2011), VIRUSES-BASEL, Vol: 14
Kibirige C, Manak M, King D, et al., 2022, Development of a Sensitive, Quantitative Assay with Broad Subtype Specificity for Detection of Total HIV-1 Nucleic Acids in Plasma and PBMC, Scientific Reports, Vol: 12, ISSN: 2045-2322
An LTR-based Quantitative PCR (qPCR) assay was modified and optimized for the quantification of total HIV-1 nucleic acids in plasma and PBMC. TaqMan qPCR primers and probes were designed against the NCBI/LANL HIV-1 compendium database by analyzing sequences used in assays for sensitive cross-clade detection of HIV-1 as reported in the literature and elucidating regions of improved cross-subtype specificity. Inosine and mixed nucleotide bases were included at polymorphic sites. Real-time RT-qPCR and qPCR were performed on plasma viral RNA and cellular lysates. A step-up amplification approach to allow binding of primers across polymorphic regions showed improved sensitivity compared to universal cycling. Unlike a lead competing laboratory-developed assay, all major HIV-1 subtypes, and a wide range of recombinants from a 127-member diversity panel were detected and accurately quantified in spiked plasmas. Semi-nested PCR increased detection sensitivity even further. The assay was able to detect down to 88 copies/mL of HIV-1 in plasma with 95% efficiency or the equivalent of a single infected cell. The PCR assay will be valuable in studies that monitor very low viral levels including residual or break through HIV-1 in patients receiving antiretroviral therapy, in HIV-1 cure, and in other research studies.
Farah B, Maraka M, Mshai M, et al., 2022, Strengthening laboratory capacity for HIV vaccine clinical trials and epidemiological studies in Eastern and Southern Africa, F1000Research, Vol: 11, ISSN: 2046-1402
Background: Conducting successful HIV vaccine clinical trials in resource-limited settings is hampered by lack of adequate laboratory capacity at trial sites, poor infrastructure, lack of well-trained technical personnel, and inadequate laboratory quality management Systems. We describe our approach to establishing sustainable laboratory capacity for clinical trials in Africa. Methods: IAVI identified 9 CRCs where a capacity building program that supports immunology and clinical testing was established. Information from the 9 CRCs was collected retrospectively and compiled in Microsoft excel for descriptive statistics. Mapping was done in Quantum Geographic information system. Results: Newly built and refurbished laboratories have been equipped with the required testing laboratory equipment. All CRC laboratories (n=10, 100%) received Good Clinical Laboratory Practice (GCLP) accreditation between 2004 and 2016, and accreditation maintained annually. A total of 89 audits were done between 2005-2019. KAVI and KEMRI had the highest number of audits (n=11, 12.4%). IAVI successfully trained a total of 1811 individual, of which (n=1130, 62.7%) trained on GCLP, (n=330, 18.3%) Quality Management Systems, (n=311, 17,2%) laboratory techniques and (n=32,1.8%) between 2004 and 2021. All the 13 Assays were registered in either College of American pathologist (CAP) or Royal college of pathologists of Australasia (RCPA) for Proficiency testing. Conclusion: The establishment of GCLP accredited laboratories and well-trained personnel has created centers of excellence and it has enabled them to attract independent competitive research funding. The GCLP accreditation and standardized testing procedures ensured reliable and accurate data, especially important for multi-country and multi-center studies.
Hayes P, Fernandez N, Ochsenbauer C, et al., 2021, Breadth of CD8 T-cell mediated inhibition of replication of diverse HIV-1 transmitted-founder isolates correlates with the breadth of recognition within a comprehensive HIV-1 Gag, Nef, Env and Pol potential T-cell epitope (PTE) peptide set., PLoS One, Vol: 16, Pages: 1-24, ISSN: 1932-6203
Full characterisation of functional HIV-1-specific T-cell responses, including identification of recognised epitopes linked with functional antiviral responses, would aid development of effective vaccines but is hampered by HIV-1 sequence diversity. Typical approaches to identify T-cell epitopes utilising extensive peptide sets require subjects' cell numbers that exceed feasible sample volumes. To address this, CD8 T-cells were polyclonally expanded from PBMC from 13 anti-retroviral naïve subjects living with HIV using CD3/CD4 bi-specific antibody. Assessment of recognition of individual peptides within a set of 1408 HIV-1 Gag, Nef, Pol and Env potential T-cell epitope peptides was achieved by sequential IFNγ ELISpot assays using peptides pooled in 3-D matrices followed by confirmation with single peptides. A Renilla reniformis luciferase viral inhibition assay assessed CD8 T-cell-mediated inhibition of replication of a cross-clade panel of 10 HIV-1 isolates, including 9 transmitted-founder isolates. Polyclonal expansion from one frozen PBMC vial provided sufficient CD8 T-cells for both ELISpot steps in 12 of 13 subjects. A median of 33 peptides in 16 epitope regions were recognised including peptides located in previously characterised HIV-1 epitope-rich regions. There was no significant difference between ELISpot magnitudes for in vitro expanded CD8 T-cells and CD8 T-cells directly isolated from PBMCs. CD8 T-cells from all subjects inhibited a median of 7 HIV-1 isolates (range 4 to 10). The breadth of CD8 T-cell mediated HIV-1 inhibition was significantly positively correlated with CD8 T-cell breadth of peptide recognition. Polyclonal CD8 T-cell expansion allowed identification of HIV-1 isolates inhibited and peptides recognised within a large peptide set spanning the major HIV-1 proteins. This approach overcomes limitations associated with obtaining sufficient cell numbers to fully characterise HIV-1-specific CD8 T-cell responses by different functiona
Umviligihozo G, Muok E, Gisa EN, et al., 2021, Increased Frequency of Inter-Subtype HIV-1 Recombinants Identified by Near Full-Length Virus Sequencing in Rwandan Acute Transmission Cohorts, FRONTIERS IN MICROBIOLOGY, Vol: 12
Hassan AS, Hare J, Gounder K, et al., 2021, A Stronger Innate Immune Response During Hyperacute Human Immunodeficiency Virus Type 1 (HIV-1) Infection Is Associated With Acute Retroviral Syndrome, CLINICAL INFECTIOUS DISEASES, Vol: 73, Pages: 832-841, ISSN: 1058-4838
Hare J, Macharia G, Yue L, et al., 2021, Direct identification of HLA-presented CD8 T cell epitopes from transmitted founder HIV-1 variants, PROTEOMICS, Vol: 21, ISSN: 1615-9853
Hare J, Fiore-Gartland A, McGowan E, et al., 2021, Selective HLA restriction enables the evaluation and interpretation of immunogenic breadth at comparable levels to that observed with broader HLA distribution, PROTEOMICS, Vol: 21, ISSN: 1615-9853
Dalel J, Ung SK, Hayes P, et al., 2021, HIV-1 infection and the lack of viral control are associated with greater expression of interleukin-21 receptor on CD8(+) T cells, AIDS, Vol: 35, Pages: 1167-1177, ISSN: 0269-9370
Objectives: Interleukin-21 (IL-21) has been linked with the generation of virus-specific memory CD8+ T cells following acute infection with HIV-1 and reduced exhaustion of CD8+ T cells. IL-21 has also been implicated in the promotion of CD8+ T-cell effector functions during viral infection. Little is known about the expression of interleukin-21 receptor (IL-21R) during HIV-1 infection or its role in HIV-1-specific CD8+ T-cell maintenance and subsequent viral control.Methods: We compared levels of IL-21R expression on total and memory subsets of CD8+ T cells from HIV-1-negative and HIV-1-positive donors. We also measured IL-21R on antigen-specific CD8+ T cells in volunteers who were positive for HIV-1 and had cytomegalovirus-responding T cells. Finally, we quantified plasma IL-21 in treatment-naive HIV-1-positive individuals and compared this with IL-21R expression.Results: IL-21R expression was significantly higher on CD8+ T cells (P = 0.0256), and on central memory (P = 0.0055) and effector memory (P = 0.0487) CD8+ T-cell subsets from HIV-1-positive individuals relative to HIV-1-negative individuals. For those infected with HIV-1, the levels of IL-21R expression on HIV-1-specific CD8+ T cells correlated significantly with visit viral load (r = 0.6667, P = 0.0152, n = 13) and inversely correlated with plasma IL-21 (r = −0.6273, P = 0.0440, n = 11). Lastly, CD8+ T cells from individuals with lower set point viral load who demonstrated better viral control had the lowest levels of IL-21R expression and highest levels of plasma IL-21.Conclusion: Our data demonstrates significant associations between IL-21R expression on peripheral CD8+ T cells and viral load, as well as disease trajectory. This suggests that the IL-21 receptor could be a novel marker of CD8+ T-cell dysfunction during HIV-1 infection.
Farinre O, Gounder K, Reddy T, et al., 2021, Subtype-specific differences in Gag-protease replication capacity of HIV-1 isolates from East and West Africa, RETROVIROLOGY, Vol: 18
Michelo CM, Dalel JA, Hayes P, et al., 2021, Comprehensive epitope mapping using polyclonally expanded human CD8 T cells and a two-step ELISpot assay for testing large peptide libraries, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 491, ISSN: 0022-1759
McInally S, Wall K, Yu T, et al., 2021, Elevated levels of inflammatory plasma biomarkers are associated with risk of HIV infection, RETROVIROLOGY, Vol: 18
Makinde J, Nduati EW, Freni-Sterrantino A, et al., 2021, A novel sample selection approach to aid the identification of factors that correlate wth the control of HIV-1 infection, Frontiers in Immunology, Vol: 12, Pages: 1-12, ISSN: 1664-3224
Individuals infected with HIV display varying rates of viral control and disease progression, with a small percentage of individuals being able to spontaneously control infection in the absence of treatment. In attempting to define the correlates associated with natural protection against HIV, extreme heterogeneity in the datasets generated from systems methodologies can be further complicated by the inherent variability encountered at the population, individual, cellular and molecular levels. Furthermore, such studies have been limited by the paucity of well-characterised samples and linked epidemiological data, including duration of infection and clinical outcomes. To address this, we selected 10 volunteers who rapidly and persistently controlled HIV, and 10 volunteers each, from two control groups who failed to control (based on set point viral loads) from an acute and early HIV prospective cohort from East and Southern Africa. A propensity score matching approach was applied to control for the influence of five factors (age, risk group, virus subtype, gender, and country) known to influence disease progression on causal observations. Fifty-two plasma proteins were assessed at two timepoints in the 1st year of infection. We independently confirmed factors known to influence disease progression such as the B*57 HLA Class I allele, and infecting virus Subtype. We demonstrated associations between circulating levels of MIP-1α and IL-17C, and the ability to control infection. IL-17C has not been described previously within the context of HIV control, making it an interesting target for future studies to understand HIV infection and transmission. An in-depth systems analysis is now underway to fully characterise host, viral and immunological factors contributing to control.
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, FRONTIERS IN IMMUNOLOGY, Vol: 12, Pages: 32-32, ISSN: 1664-3224
Langat RK, Farah B, Indangasi J, et al., 2021, Performance of International AIDS Vaccine Initiative African clinical research laboratories in standardised ELISpot and peripheral blood mononuclear cell processing in support of HIV vaccine clinical trials, AFRICAN JOURNAL OF LABORATORY MEDICINE, Vol: 10, ISSN: 2225-2002
Langat R, McRaven M, Joseph S, et al., 2021, The impact of human immunodeficiency virus-1 viral replicative capacity on infection of human cervical and rectal tissue explants ex vivo, Publisher: JOHN WILEY & SONS LTD
Yue L, Umviligihozo G, Muok E, et al., 2021, Increased frequency of inter-subtype HIV-1 recombinants identified by near full-length virus sequencing in a Rwanda acute heterosexual transmission cohort, Publisher: JOHN WILEY & SONS LTD
Fernandez N, Makinde J, Hayes P, et al., 2021, Generation of HIV-specific CD4 and CD8 T-cell clones for use in HIV viral inhibition assays, Publisher: JOHN WILEY & SONS LTD
Fernandez N, Hayes P, Dalel J, et al., 2021, Breadth of CD8 T-cell mediated inhibition of HIV-1 replication correlates with breadth of epitope recognition mapped with a comprehensive Gag, Nef, Env and Pol potential T-cell Epitope (PTE) peptide set, Publisher: JOHN WILEY & SONS LTD
Makinde J, Fernandez N, Hayes P, et al., 2021, Spontaneous <i>in vivo</i> control of HIV replication is underpinned by the cross-clade antiviral potency of HIV-specific CD8 T cells, Publisher: JOHN WILEY & SONS LTD
Kapaata A, Balinda SN, Xu R, et al., 2021, HIV-1 <i>Gag-Pol</i> Sequences from Ugandan Early Infections Reveal Sequence Variants Associated with Elevated Replication Capacity, VIRUSES-BASEL, Vol: 13
Price MA, Kilembe W, Ruzagira E, et al., 2021, Cohort Profile: IAVI's HIV epidemiology and early infection cohort studies in Africa to support vaccine discovery, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, Vol: 50, Pages: 29-+, ISSN: 0300-5771
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