Jori Symons

University Medical Center Utrecht

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Sharon R. Lewin

Peter Doherty Institute

Paul Cameron

Peter Doherty Institute

Monique Nijhuis

University Medical Center Utrecht

Steven G. Deeks

University of California, San Francisco

Linos Vandekerckhove

Ghent University Hospital

Annemarie M. J. Wensing

University Medical Center Utrecht

Melissa J. Churchill

RMIT University

Abha Chopra

Murdoch University

Michael Roche

Peter Doherty Institute

S. Mallal

Murdoch University

Cooperative Institutions

Queen Mary University of London

Universidad de Londres

Royal London Hospital

British Medical Association

Royal Botanic Garden Edinburgh

National Institutes of Health

University of Melbourne

University of California, San Francisco

University of Washington

University Medical Center Utrecht

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HIV integration sites and implications for maintenance of the reservoir

Current Opinion in HIV and AIDS (2017)

Jori Symons Paul Cameron Sharon R. Lewin

To provide an overview of recent research of how HIV integration relates to productive and latent infection and implications for cure strategies.How and where HIV integrates provides new insights into how HIV persists on antiretroviral therapy (ART). Clonal expansion of infected cells with the same integration site demonstrates that T-cell proliferation is an important factor in HIV persistence, however, the driver of proliferation remains unclear. Clones with identical integration sites harbouring defective provirus can accumulate in HIV-infected individuals on ART and defective proviruses can express RNA and produce protein. HIV integration sites differ in clonally expanded and nonexpanded cells and in latently and productively infected cells and this influences basal and inducible transcription. There is a growing number of cellular proteins that can alter the pattern of integration to favour latency. Understanding these pathways may identify new interventions to eliminate latently infected cells.Using advances in analysing HIV integration sites, T-cell proliferation of latently infected cells is thought to play a major role in HIV persistence. Clonal expansion has been demonstrated with both defective and intact viruses. Production of viral RNA and protein from defective viruses may play a role in driving chronic immune activation. The site of integration may determine the likelihood of proliferation and the degree of basal and induced transcription. Finally, host factors and gene expression at the time of infection may determine the integration site. Together these new insights may lead to novel approaches to elimination of latently infected cells.

Provirus

Virus latency

10.1097/coh.0000000000000438

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Citations (33)

31 High prevalence of CXCR4-using virus and low clonal expansion in infected naïve and central memory CD4+ T cells in individuals on ART

Journal of Virus Eradication (2017)

Michael Roche Carolin Tumpach Jori Symons Paul Cameron Melissa J. Churchill

10.1016/s2055-6640(20)30736-6

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Citations (0)

Functional Constraints of Influenza A Virus Epitopes Limit Escape from Cytotoxic T Lymphocytes

Journal of Virology (2005)

E. G. M. Berkhoff Emmie de Wit Martina M. Geelhoed-Mieras Adrianus C. M. Boon Jori Symons

Viruses can exploit a variety of strategies to evade immune surveillance by cytotoxic T lymphocytes (CTL), including the acquisition of mutations in CTL epitopes. Also for influenza A viruses a number of amino acid substitutions in the nucleoprotein (NP) have been associated with escape from CTL. However, other previously identified influenza A virus CTL epitopes are highly conserved, including the immunodominant HLA-A*0201-restricted epitope from the matrix protein, M1(58-66). We hypothesized that functional constraints were responsible for the conserved nature of influenza A virus CTL epitopes, limiting escape from CTL. To assess the impact of amino acid substitutions in conserved epitopes on viral fitness and recognition by specific CTL, we performed a mutational analysis of CTL epitopes. Both alanine replacements and more conservative substitutions were introduced at various positions of different influenza A virus CTL epitopes. Alanine replacements for each of the nine amino acids of the M1(58-66) epitope were tolerated to various extents, except for the anchor residue at the second position. Substitution of anchor residues in other influenza A virus CTL epitopes also affected viral fitness. Viable mutant viruses were used in CTL recognition experiments. The results are discussed in the light of the possibility of influenza viruses to escape from specific CTL. It was speculated that functional constraints limit variation in certain epitopes, especially at anchor residues, explaining the conserved nature of these epitopes.

CTL*

Nucleoprotein

10.1128/jvi.79.17.11239-11246.2005

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Citations (106)

PP 3.8 – 00137 Characterization of the HIV-1 subtype C reservoir during ART in South-African men and women

Journal of Virus Eradication (2022)

Ninée V.J.E. Buchholtz L. Hermans C. Umunnakwe T. De Jong A. Osman

Characterization

10.1016/j.jve.2022.100188

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Citations (0)

Persistence of envelopes in different CD4+ T-cell subsets in antiretroviral therapy-suppressed people with HIV

AIDS (2022)

Matthew J. Gartner Carolin Tumpach Ashanti Dantanarayana Jared Stern Jennifer M. Zerbato

Objectives: Despite suppressive antiretroviral therapy (ART), HIV can persist in a diverse range of CD4 + T-cell subsets. Through longitudinal env sampling from people with HIV (PWH) on ART, we characterized the persistence and phenotypic properties of HIV envs over two time-points (T1 and T2). Methods: Longitudinal blood and lymphoid tissue samples were obtained from eight PWH on suppressive ART. Single genome amplification (SGA) was performed on env to understand the genetic diversity and degree of clonal expansions over time. A subset of envs were used to generate pseudovirus particles to assess sensitivity to autologous plasma IgG and broadly neutralizing antibodies (bNAbs). Results: Identical env sequences indicating clonal expansion persisted between T1 and T2 and within multiple T-cell subsets. At both time-points, CXCR4-tropic (X4) Envs were more prevalent in naive and central memory cells; the proportion of X4 Envs did not significantly change in each subset between T1 and T2. Autologous purified plasma IgG showed variable neutralization of Envs, with no significant difference in neutralization between R5 and X4 Envs. X4 Envs were more sensitive to neutralization with clinical bNAbs, with CD4-binding site bNAbs demonstrating high breadth and potency against Envs. Conclusion: Our data suggest the viral reservoir in PWH on ART was predominantly maintained over time through proliferation and potentially differentiation of infected cells. We found the humoral immune response to Envs within the latent reservoir was variable between PWH. Finally, we identified coreceptor usage can influence bNAb sensitivity and may need to be considered for future bNAb immunotherapy approaches.

Persistence (discontinuity)

10.1097/qad.0000000000003424

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Citations (3)

CXCR4-Using HIV Strains Predominate in Naive and Central Memory CD4 ⁺ T Cells in People Living with HIV on Antiretroviral Therapy: Implications for How Latency Is Established and Maintained

Journal of Virology (2019)

Michael Roche Carolin Tumpach Jori Symons Matthew J. Gartner Jenny L. Anderson

In people living with HIV (PLWH) on suppressive ART, latent HIV can be found in a diverse range of CD4 + T cells, including quiescent naive and central memory cells that are typically difficult to infect in vitro . It is currently unclear how latency is established in these cells in vivo . We show that in CD4 + T cells from PLWH on suppressive ART, the use of the coreceptor CXCR4 was prevalent among viruses amplified from naive and central memory CD4 + T cells. Furthermore, we found that expanded numbers of identical viral sequences were most common in the effector memory population, and these identical sequences were also found in multiple different CD4 + T cell subsets. Our results help to shed light on how a range of CD4 + T cell subsets come to harbor HIV DNA, which is one of the major barriers to eradicating the virus from PLWH.

Virus latency

Cd4 t cell

10.1128/jvi.01736-19

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Citations (18)

Impact of triplicate testing on HIV genotypic tropism prediction in routine clinical practice

Clinical Microbiology and Infection (2011)

Jori Symons Linos Vandekerckhove Roger Paredes Chris Verhofstede R. Bellido

Clinical Practice

10.1111/j.1469-0691.2011.03631.x

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Citations (32)

Correction

BMJ (1963)

D. E. Fry Richard T. Johnson Claire Cameron I. J. Lord Jori Symons

10.1136/bmj.1.5345.1622

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Citations (0)

Development of a highly sensitive and specific intact proviral DNA assay for HIV-1 subtype B and C

Virology Journal (2024)

Ninée V.E.J. Buchholtz Marieke M. Nühn T. C. M. de Jong T. A. T. Stienstra Kavidha Reddy

Abstract Introduction HIV reservoir quantification is essential for evaluation of HIV curative strategies and may provide valuable insights about reservoir dynamics during antiretroviral therapy. The Intact Proviral DNA Assay (IPDA) provides the unique opportunity to quantify the intact and defective reservoir. The current IPDA is optimized for HIV-1 subtype B, the dominant subtype in resource-rich settings. However, subtype C is dominant in Sub-Saharan Africa, jointly accounting for around 60% of the pandemic. We developed an assay capable of quantifying intact and defective proviral HIV-1 DNA of subtype B and C. Methods Primer and probe sequences were strategically positioned at conserved regions in psi and env and adapted to subtype B&C. In silico analysis of 752 subtype B and 697 subtype C near-full length genome sequences (nFGS) was performed to predict the specificity and sensitivity. Gblocks were used to determine the limit of blank (LoB), limit of detection (LoD), and different annealing temperatures were tested to address impact of sequence variability. Results The in silico analysis showed that the HIV-1 B&C IPDA correctly identified 100% of the intact subtype B, and 86% of the subtype C sequences. In contrast, the original IPDA identified 86% and 12% of these subtype B and C sequences as intact. Furthermore, the HIV-1 B&C IPDA correctly identified hypermutated (87% and 88%) and other defective sequences (73% and 66%) for subtype B and C with comparable specificity as the original IPDA for subtype B (59% and 63%). Subtype B cis-acting sequences were more frequently identified as intact by the HIV-1 B&C IPDA compared to the original IPDA (39% and 2%). The LoB for intact proviral DNA copies was 0, and the LoD for intact proviral DNA copies was 6 (> 95% certainty) at 60 °C. Quantification of 2–6 copies can be performed with > 80% certainty. Lowering the annealing temperature to 55 °C slightly lowered the specificity but prevented exclusion of samples with single mutations in the primer/probe region. Conclusions We developed a robust and sensitive assay for the quantification of intact and defective HIV-1 subtype B and C proviral DNA, making this a suitable tool to monitor the impact of (large-scale) curative interventions.

Primer (cosmetics)

10.1186/s12985-024-02300-6

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Citations (6)

Efficacy and safety of an attenuated live QX-like infectious bronchitis virus strain as a vaccine for chickens

Avian Pathology (2011)

H.J. Geerligs G. J. Boelm C. A. M. Meinders B. G. E. Stuurman Jori Symons

The attenuation of infectious bronchitis (IB) QX-like virus strain L1148 is described. The virus was passaged multiple times in embryonated specific pathogen free (SPF) chicken eggs, and at different passage levels samples were tested for safety for the respiratory tract and kidneys in 1-day-old SPF chickens. There was a clear decrease in pathogenicity for the respiratory tract and kidneys when the virus had undergone a large number of passages. Passage level 80 was investigated for safety for the reproductive tract in 1-day-old and 7-day-old SPF chickens. In 1-day-old chickens, 12.5% of the vaccinated birds had macroscopic lesions. No lesions were observed if the chickens had been vaccinated at 7 days of age. Passage level 80 was investigated for its ability to spread from vaccinated to non-vaccinated chickens and for dissemination in the body. The virus was able to spread from vaccinated chickens to groups of non-vaccinated chickens, and in the vaccinated birds the virus was found frequently in oro-pharyngeal and cloacal swabs. A fragment of the hypervariable region of the S1 protein of passage level 80 was sequenced and revealed nucleotide changes resulting in two amino acid substitutions. Passage level 80 was given additional passages to levels 82 and 85. Both passage levels were tested for efficacy in SPF chickens and passage level 85 was tested for efficacy in commercial chickens with maternally derived antibodies (MDA) against a challenge with QX-like strain IB D388. In both SPF chickens and chickens with MDA, the vaccines based on strain IB L1148 were efficacious against challenge.

Embryonated

Specific-pathogen-free

Attenuated vaccine

Strain (injury)

Infectious dose

Viral Shedding

Respiratory tract

10.1080/03079457.2010.542742

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Citations (35)