Publications
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Sanders EJ, Price MA, Karita E, et al., 2017, Differences in acute retroviral syndrome by HIV-1 subtype in a multicentre cohort study in Africa, AIDS, Vol: 31, Pages: 2541-2546, ISSN: 0269-9370
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- Citations: 13
McLaren PJ, Pulit SL, Gurdasani D, et al., 2017, Evaluating the impact of functional genetic variation on HIV-1 control, Journal of Infectious Diseases, Vol: 216, Pages: 1063-1069, ISSN: 0022-1899
BackgroundPrevious genetic association studies of human immunodeficiency virus-1 (HIV-1) progression have focused on common human genetic variation ascertained through genome-wide genotyping.MethodsWe sought to systematically assess the full spectrum of functional variation in protein coding gene regions on HIV-1 progression through exome sequencing of 1327 individuals. Genetic variants were tested individually and in aggregate across genes and gene sets for an influence on HIV-1 viral load.ResultsMultiple single variants within the major histocompatibility complex (MHC) region were observed to be strongly associated with HIV-1 outcome, consistent with the known impact of classical HLA alleles. However, no single variant or gene located outside of the MHC region was significantly associated with HIV progression. Set-based association testing focusing on genes identified as being essential for HIV replication in genome-wide small interfering RNA (siRNA) and clustered regularly interspaced short palindromic repeats (CRISPR) studies did not reveal any novel associations.ConclusionsThese results suggest that exonic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection.
Ford TP, Wenden C, Mbekeani A, et al., 2017, CRYOPRESERVATION RELATED LOSS OF ANTIGEN SPECIFIC IFNγ PRODUCING CD4+T-CELLS: LESSONS FROM A MALARIA VACCINE TRIAL SUBSTUDY, 65th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 314-314, ISSN: 0002-9637
Ghosn J, Bayan T, Meixenberger K, et al., 2017, CD4 T cell decline following HIV seroconversion in individuals with and without CXCR4-tropic virus., J Antimicrob Chemother, Vol: 72, Pages: 2862-2868
BACKGROUND: The natural clinical and immunological courses following HIV seroconversion with CXCR4-tropic or dual-mixed (X4/DM) viruses are controversial. We compared spontaneous immunological outcome in patients harbouring an X4/DM virus at the time of seroconversion with those harbouring a CCR5-tropic (R5) virus. METHODS: Data were included from patients participating in CASCADE, a large cohort collaboration of HIV seroconverters, with ≥2 years of follow-up since seroconversion. The HIV envelope gene was sequenced from frozen plasma samples collected at enrolment, and HIV tropism was determined using Geno2Pheno (false-positive rate 10%). The spontaneous CD4 T cell evolution was compared by modelling CD4 kinetics using linear mixed-effects models with random intercept and random slope. RESULTS: A total of 1387 patients were eligible. Median time between seroconversion and enrolment was 1 month (range 0-3). At enrolment, 202 of 1387 (15%) harboured an X4/DM-tropic virus. CD4 decrease slopes were not significantly different according to HIV-1 tropism during the first 30 months after seroconversion. No marked change in these results was found after adjusting for age, year of seroconversion and baseline HIV viral load. Time to antiretroviral treatment initiation was not statistically different between patients harbouring an R5 (20.76 months) and those harbouring an X4/DM-tropic virus (22.86 months, logrank test P = 0.32). Conclusions: In this large cohort collaboration, 15% of the patients harboured an X4/DM virus close to HIV seroconversion. Patients harbouring X4/DM-tropic viruses close to seroconversion did not have an increased risk of disease progression, estimated by the decline in CD4 T cell count or time to combined ART initiation.
Kratochvil S, McKay PF, Kopycinski JT, et al., 2017, A phase 1 human immunodeficiency virus vaccine Trial for cross-profiling the kinetics of serum and mucosal antibody responses to CN54gp140 modulated by two homologous prime-boost vaccine regimens, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
A key aspect to finding an efficacious human immunodeficiency virus (HIV) vaccine is the optimization of vaccine schedules that can mediate the efficient maturation of protective immune responses. In the present study, we investigated the effect of alternate booster regimens on the immune responses to a candidate HIV-1 clade C CN54gp140 envelope protein, which was coadministered with the TLR4-agonist glucopyranosyl lipid A-aqueous formulation. Twelve study participants received a common three-dose intramuscular priming series followed by a final booster at either 6 or 12 months. The two homologous prime-boost regimens were well tolerated and induced CN54gp140-specific responses that were observed in both the systemic and mucosal compartments. Levels of vaccine-induced IgG-subclass antibodies correlated significantly with FcγR engagement, and both vaccine regimens were associated with strikingly similar patterns in antibody titer and FcγR-binding profiles. In both groups, identical changes in the antigen (Ag)-specific IgG-subclass fingerprint, leading to a decrease in IgG1 and an increase in IgG4 levels, were modulated by booster injections. Here, the dissection of immune profiles further supports the notion that prime-boost strategies are essential for the induction of diverse Ag-specific HIV-1 responses. The results reported here clearly demonstrate that identical responses were effectively and safely induced by both vaccine regimens, indicating that an accelerated 6-month regimen could be employed for the rapid induction of immune responses against CN54gp140 with no apparent impact on the overall quality of the induced immune response. (This study has been registered at http://ClinicalTrials.gov under registration no. NCT01966900.)
Ford T, Wenden C, Mbekeani A, et al., 2017, Cryopreservation-related loss of antigen-specific IFN gamma producing CD4(+) T-cells can skew immunogenicity data in vaccine trials: Lessons from a malaria vaccine trial substudy, Vaccine, Vol: 35, Pages: 1898-1906, ISSN: 0264-410X
Ex vivo functional immunoassays such as ELISpot and intracellular cytokine staining (ICS) by flow cytometry are crucial tools in vaccine development both in the identification of novel immunogenic targets and in the immunological assessment of samples from clinical trials. Cryopreservation and subsequent thawing of PBMCs via validated processes has become a mainstay of clinical trials due to processing restrictions inherent in the disparate location and capacity of trial centres, and also in the need to standardize biological assays at central testing facilities. Logistical and financial requirement to batch process samples from multiple study timepoints are also key. We used ELISpot and ICS assays to assess antigen-specific immunogenicity in blood samples taken from subjects enrolled in a phase II malaria heterologous prime-boost vaccine trial and showed that the freeze thaw process can result in a 3–5-fold reduction of malaria antigen-specific IFNγ-producing CD3+CD4+ effector populations from PBMC samples taken post vaccination. We have also demonstrated that peptide responsive CD8+ T cells are relatively unaffected, as well as CD4+ T cell populations that do not produce IFNγ. These findings contribute to a growing body of data that could be consolidated and synthesised as guidelines for clinical trials with the aim of increasing the efficiency of vaccine development pipelines.
Joseph S, Quinn K, Greenwood A, et al., 2017, A comparative phase I study of combination, homologous subtype-C DNA, MVA, and Env gp140 protein/adjuvant HIV vaccines in two immunization regimes, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant—aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p = 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The ap
Nyombayire J, Anzala O, Gazzard B, et al., 2017, First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus-Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens, JOURNAL OF INFECTIOUS DISEASES, Vol: 215, Pages: 95-104, ISSN: 0022-1899
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- Citations: 28
Abujaber R, Shea PR, McLaren PJ, et al., 2017, No Evidence for Association of β-Defensin Genomic Copy Number with HIV Susceptibility, HIV Load during Clinical Latency, or Progression to AIDS, ANNALS OF HUMAN GENETICS, Vol: 81, Pages: 27-34, ISSN: 0003-4800
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- Citations: 3
Inzaule SC, Hamers RL, Paredes R, et al., 2017, The Evolving Landscape of HIV Drug Resistance Diagnostics for Expanding Testing in Resource-Limited Settings., AIDS Rev, Vol: 19, Pages: 219-230
Global scale-up of antiretroviral treatment has dramatically changed the prospects of HIV/AIDS disease, rendering life-long chronic care and treatment a reality for millions of HIV-infected patients. Affordable technologies to monitor antiretroviral treatment are needed to ensure long-term durability of limited available drug regimens. HIV drug resistance tests can complement existing strategies in optimizing clinical decision-making for patients with treatment failure, in addition to facilitating population-based surveillance of HIV drug resistance. This review assesses the current landscape of HIV drug resistance technologies and discusses the strengths and limitations of existing assays available for expanding testing in resource-limited settings. These include sequencing-based assays (Sanger sequencing assays and nextgeneration sequencing), point mutation assays, and genotype-free data-based prediction systems. Sanger assays are currently considered the gold standard genotyping technology, though only available at a limited number of resource-limited setting reference and regional laboratories, but high capital and test costs have limited their wide expansion. Point mutation assays present opportunities for simplified laboratory assays, but HIV genetic variability, extensive codon redundancy at or near the mutation target sites with limited multiplexing capability have restricted their utility. Next-generation sequencing, despite high costs, may have potential to reduce the testing cost significantly through multiplexing in high-throughput facilities, although the level of bioinformatics expertise required for data analysis is currently still complex and expensive and lacks standardization. Web-based genotype-free prediction systems may provide enhanced antiretroviral treatment decision-making without the need for laboratory testing, but require further clinical field evaluation and implementation scientific research in resource-limited settings.
Prentice HA, Lu H, Price MA, et al., 2016, Dynamics and Correlates of CD8 T-Cell Counts in Africans with Primary Human Immunodeficiency Virus Type 1 Infection, JOURNAL OF VIROLOGY, Vol: 90, Pages: 10423-10430, ISSN: 0022-538X
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- Citations: 2
Bergin P, Langat R, Omosa-Manyonyi G, et al., 2016, Assessment of anti-HIV-1 antibodies in oral and nasal compartments of volunteers from three different populations, JAIDS - Journal of Acquired Immune Deficiency Syndromes, Vol: 73, Pages: 130-137, ISSN: 1525-4135
In this study, we assessed the feasibility of collecting standardized nasal and salivary samples at centers in Nairobi (Kenya), Kigali (Rwanda) and London (UK) using different collection devices and media (Synthetic absorptive matrices versus flocked swabs, and Salimetrics Oral swabs versus whole oral fluid collection). We detected anti Gag (p24) and envelope (gp140) antibodies in both nasal fluid and salivary collections from all HIV-infected individuals, and cross-reactive anti-p24 antibodies were detected in 10% of HIV-uninfected individuals enrolled at one site. Collections from the nasal turbinates were comparable to samples collected deeper in the nasopharyngeal tract, and the yield of anti-p24 IgA in the whole oral fluid samples was higher than in samples collected from the parotid gland. We noted a trend toward reduced levels of anti-HIV antibody in the volunteers receiving anti-retroviral therapy (ART). Levels of antibodies were stable over multiple collection visits. Overall, this study shows that nasal and salivary samples can be collected in a standardized manner over repeated visits in both low and high resource settings. These methods may be used in support of future HIV vaccine clinical trials.
Joseph S, Quinn K, Greenwood A, et al., 2016, UK HVC 003: A Phase I Clinical Trial Exploring a Strategy to Maximise HIV Antibody Responses using Subtype C DNA, MVA and GLA Adjuvanted gp140, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 99-99, ISSN: 0889-2229
El-Badry E, Claiborne D, Prince J, et al., 2016, Gender Differences in Transmission of HIV-1 Viral Variants and Their Impact on Early Immune Activation, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 87-87, ISSN: 0889-2229
Kratochvil S, Gilmour J, Shattock R, et al., 2016, IgG1 Allotypic Variants G1m17 and G1m3 Influence the Vaccine-Antigen Specific IgG1: IgG2 Ratio in HIV Vaccine Recipients, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 273-273, ISSN: 0889-2229
Kratochvil S, McKay P, Kopycinski J, et al., 2016, Dissecting the Kinetic and Functional Immunoprofile of Antigen-specific B Cells in the Peripheral Blood and Mucosal Samples of HIV Vaccine Recipients, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 396-396, ISSN: 0889-2229
Cox J, Farah B, Langat R, et al., 2016, Broad HIV-1 Inhibition in Vitro by Vaccine-elicited CD8+T Cells in African Adults, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 77-77, ISSN: 0889-2229
Hare J, Streatfield C, Yates J, et al., 2016, CD4 T-cell Counts More Closely Associate with the Cytokine Profiles Observed in Acutely Infected Volunteers than Viral Load or Replicative Capacity, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 170-170, ISSN: 0889-2229
Nyombayire J, Anzala O, Gazzard B, et al., 2016, Recombinant Sendai Vaccine Delivered Mucosally Induces Gag-specific Functional T-cells or Antibody Responses in Prime-boost Regimens in Humans, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 108-108, ISSN: 0889-2229
Umviligihozo G, Lemon T, Uwera G, et al., 2016, Genetically Linked Transmission and ART Use in Discordant Couples in Rwanda, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 366-366, ISSN: 0889-2229
Macharia G, Yue L, Dilernia D, et al., 2016, Transmission of Multiple HIV-1 Founder Viruses and High Frequency of Unique Recombinant Forms among MSM in Kenya, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 88-88, ISSN: 0889-2229
Mutua G, Farah B, Langat R, et al., 2016, Broad HIV-1 inhibition in vitro by vaccine-elicited CD8(+) T cells in African adults., Molecular Therapy- Methods & Clinical Development, Vol: 3, ISSN: 2329-0501
We are developing a pan-clade HIV-1 T-cell vaccine HIVconsv, which could complement Env vaccines for prophylaxis and be a key to HIV cure. Our strategy focuses vaccine-elicited effector T-cells on functionally and structurally conserved regions (not full-length proteins and not only epitopes) of the HIV-1 proteome, which are common to most global variants and which, if mutated, cause a replicative fitness loss. Our first clinical trial in low risk HIV-1-negative adults in Oxford demonstrated the principle that naturally mostly subdominant epitopes, when taken out of the context of full-length proteins/virus and delivered by potent regimens involving combinations of simian adenovirus and poxvirus modified vaccinia virus Ankara, can induce robust CD8(+) T cells of broad specificities and functions capable of inhibiting in vitro HIV-1 replication. Here and for the first time, we tested this strategy in low risk HIV-1-negative adults in Africa. We showed that the vaccines were well tolerated and induced high frequencies of broadly HIVconsv-specific plurifunctional T cells, which inhibited in vitro viruses from four major clades A, B, C, and D. Because sub-Saharan Africa is globally the region most affected by HIV-1/AIDS, trial HIV-CORE 004 represents an important stage in the path toward efficacy evaluation of this highly rational and promising vaccine strategy.
Mónaco DC, Dilernia DA, Fiore-Gartland A, et al., 2016, Balance between transmitted HLA preadapted and nonassociated polymorphisms is a major determinant of HIV-1 disease progression, Journal of Experimental Medicine, Vol: 213, ISSN: 1540-9538
HIV-1 adapts to a new host through mutations that facilitate immune escape. Here, we evaluate the impact on viral control and disease progression of transmitted polymorphisms that were either preadapted to or nonassociated with the new host's HLA. In a cohort of 169 Zambian heterosexual transmission pairs, we found that almost one-third of possible HLA-linked target sites in the transmitted virus Gag protein are already adapted, and that this transmitted preadaptation significantly reduced early immune recognition of epitopes. Transmitted preadapted and nonassociated polymorphisms showed opposing effects on set-point VL and the balance between the two was significantly associated with higher set-point VLs in a multivariable model including other risk factors. Transmitted preadaptation was also significantly associated with faster CD4 decline (<350 cells/µl) and this association was stronger after accounting for nonassociated polymorphisms, which were linked with slower CD4 decline. Overall, the relative ratio of the two classes of polymorphisms was found to be the major determinant of CD4 decline in a multivariable model including other risk factors. This study reveals that, even before an immune response is mounted in the new host, the balance of these opposing factors can significantly influence the outcome of HIV-1 infection.
Carlson JM, Du VY, Pfeifer N, et al., 2016, Impact of pre-adapted HIV transmission, NATURE MEDICINE, Vol: 22, Pages: 606-+, ISSN: 1078-8956
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- Citations: 69
Hayes PJ, Cox JH, Coleman AR, et al., 2016, Adenovirus based HIV-1 vaccine candidates tested in efficacy trials elicit CD8 T-cells with limited breadth of HIV-1 inhibition., AIDS, Vol: 30, Pages: 1703-1712, ISSN: 0269-9370
OBJECTIVES: The ability of HIV-1 vaccine candidates; MRKAd5, VRC DNA/Ad5 and ALVAC/AIDSVAX to elicit CD8 T-cells with direct anti-viral function was assessed and compared with HIV-1 infected subjects. DESIGN: Adenovirus serotype 5 (Ad5)-based regimens MRKAd5 and VRC DNA/Ad5 designed to elicit HIV-1 specific T-cells, are immunogenic but failed to prevent infection or impact on viral loads in subjects infected subsequently. Failure may be due in part to a lack of CD8 T-cells with effective anti-viral functions. METHODS: An in vitro viral inhibition assay (VIA) tested the ability of bi-specific antibody expanded CD8 T-cells from peripheral blood mononuclear cells (PBMC) to inhibit replication of a multi-clade panel of HIV-1 isolates in autologous CD4 T-cells. HIV-1 proteins recognized by CD8 T-cells were assessed by IFNγ ELISpot assay. RESULTS: Ad5-based regimens elicited CD8 T-cells that inhibited replication of HIV-1 IIIB isolate with more limited inhibition of other isolates. IIIB isolate Gag and Pol genes have high sequence identities (>96%) to vector HIV-1 gene inserts and these were the predominant HIV-1 proteins recognized by CD8 T-cells. Virus inhibition breadth was greater in antiretroviral naïve HIV-1 infected subjects naturally controlling viremia (plasma viral load (pVL) < 10000/mL). HIV-1 inhibitory CD8 T-cells were not elicited by the ALVAC/AIDSVAX regimen. CONCLUSIONS: The Ad5-based regimens, although immunogenic, elicited CD8 T-cells with limited HIV-1 inhibition breadth. Effective T-cell based vaccines should presumably elicit broader HIV-1 inhibition profiles. The VIA can be used in vaccine design and to prioritise promising candidates with greater inhibition breadth for further clinical trials.
Baden LR, Karita E, Mutua G, et al., 2016, Assessment of the Safety and Immunogenicity of 2 Novel Vaccine Platforms for HIV-1 Prevention: A Randomized Trial., Annals of Internal Medicine, Vol: 164, Pages: 313-322, ISSN: 1539-3704
BACKGROUND: A prophylactic HIV-1 vaccine is a global health priority. OBJECTIVE: To assess a novel vaccine platform as a prophylactic HIV-1 regimen. DESIGN: Randomized, double-blind, placebo-controlled trial. Both participants and study personnel were blinded to treatment allocation. (ClinicalTrials.gov: NCT01215149). SETTING: United States, East Africa, and South Africa. PATIENTS: Healthy adults without HIV infection. INTERVENTION: 2 HIV-1 vaccines (adenovirus serotype 26 with an HIV-1 envelope A insert [Ad26.EnvA] and adenovirus serotype 35 with an HIV-1 envelope A insert [Ad35.Env], both administered at a dose of 5 × 1010 viral particles) in homologous and heterologous combinations. MEASUREMENTS: Safety and immunogenicity and the effect of baseline vector immunity. RESULTS: 217 participants received at least 1 vaccination, and 210 (>96%) completed follow-up. No vaccine-associated serious adverse events occurred. All regimens were generally well-tolerated. All regimens elicited humoral and cellular immune responses in nearly all participants. Preexisting Ad26- or Ad35-neutralizing antibody titers had no effect on vaccine safety and little effect on immunogenicity. In both homologous and heterologous regimens, the second vaccination significantly increased EnvA antibody titers (approximately 20-fold from the median enzyme-linked immunosorbent assay titers of 30-300 to 3000). The heterologous regimen of Ad26-Ad35 elicited significantly higher EnvA antibody titers than Ad35-Ad26. T-cell responses were modest and lower in East Africa than in South Africa and the United States. LIMITATIONS: Because the 2 envelope inserts were not identical, the boosting responses were complex to interpret. Durability of the immune responses elicited beyond 1 year is unknown. CONCLUSION: Both vaccines elicited significant immune responses in all populations. Baseline vector immunity did not significantly affect responses. Second vaccinations in all regimens significan
Pennington SH, Thompson AL, Wright AK, et al., 2016, Oral typhoid vaccination with Ty21a generates Ty21a-responsive and heterologous influenza-responsive CD4+ and CD8+ T-cells at the human intestinal mucosa, Journal of Infectious Diseases, Vol: 2016, ISSN: 1537-6613
BACKGROUND: Oral vaccination with live-attenuated Salmonella Typhi strain Ty21a is modestly efficacious, but the mechanisms of protection are currently unknown. While humoral and cellular immune responses are well described in peripheral blood, the cellular response at the intestinal mucosa has never been directly assessed. METHODS: We vaccinated healthy adults with Ty21a and assessed humoral and cellular immunity in vaccinated volunteers and controls after 18 days. Immunoglobulin levels were assessed in peripheral blood by an enzyme-linked immunosorbent assay. Cellular responses were assessed in peripheral blood and at the duodenal and colonic mucosa by flow cytometry. RESULTS: We demonstrate the generation of Ty21a-responsive and heterologous influenza virus-responsive CD4(+) and CD8(+) T cells at the duodenal mucosa. All duodenal responses were consistently correlated, and no responses were observed at the colonic mucosa. Peripheral anti-lipopolysaccharide immunoglobulin G and immunoglobulin A responses were significantly correlated with duodenal responses. The assessment of integrin β7 expression intensity among peripheral and duodenal T-cell subsets revealed varied capacities for mucosal homing and residence. CONCLUSIONS: The breadth of duodenal cellular responses was not reflected peripherally. The direct evaluation of mucosal immune defense may yield functional correlates of protection and could provide insight into mechanisms that may be manipulated to enhance vaccine immunogenicity.
Ahmed T, Borthwick NJ, Gilmour J, et al., 2016, Control of HIV-1 replication in vitro by vaccine-induced human CD8(+) T cells through conserved subdominant Pol epitopes., Vaccine, Vol: 34, Pages: 1215-1224, ISSN: 1873-2518
OBJECTIVE: The specificity of CD8(+) T cells is critical for early control of founder/transmitted and reactivated HIV-1. To tackle HIV-1 variability and escape, we designed vaccine immunogen HIVconsv assembled from 14 highly conserved regions of mainly Gag and Pol proteins. When administered to HIV-1-negative human volunteers in trial HIV-CORE 002, HIVconsv vaccines elicited CD8(+) effector T cells which inhibited replication of up to 8 HIV-1 isolates in autologous CD4(+) cells. This inhibition correlated with interferon-γ production in response to Gag and Pol peptide pools, but direct evidence of the inhibitory specificity was missing. Here, we aimed to define through which epitopes these effectors inhibit HIV-1 replication. DESIGN: CD8(+) T-cells from the 3 broadest HIV-1 inhibitors out of 23 vaccine recipients were expanded in culture by Gag or Pol peptide restimulation and tested in viral inhibition assay (VIA) using HIV-1 clade B and A isolates. METHODS: Frozen PBMCs were expanded first using peptide pools from Gag or Pol conserved regions and tested on HIV-1-infected cells in VIA or by individual peptides for their effector functions. Single peptide specificities responsible for inhibition of HIV-1 replication were then confirmed by single-peptide expanded effectors tested on HIV-1-infected cells. RESULTS: We formally demonstrated that the vaccine-elicited inhibitory human CD8(+) T cells recognized conserved epitopes of both Pol and Gag proteins. We defined 7 minimum epitopes, of which 3 were novel, presumably naturally subdominant. The effectors were oligofunctional producing several cytokines and chemokines and killing peptide-pulsed target cells. CONCLUSIONS: These results implicate the use of functionally conserved regions of Pol in addition to the widely used Gag for T-cell vaccine design. Proportion of volunteers developing these effectors and their frequency in circulation are separate issues, which can be addressed, if needed, by more efficient v
Landais E, Huang X, Havenar-Daughton C, et al., 2016, Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort., PLOS Pathogens, Vol: 12, ISSN: 1553-7366
Broadly neutralizing antibodies (bnAbs) are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(-) genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design.
Erdmann N, Du VY, Carlson J, et al., 2015, HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses., Plos Pathogens, Vol: 11, ISSN: 1553-7374
Antiretroviral therapy, antibody and CD8+ T cell-mediated responses targeting human immunodeficiency virus-1 (HIV-1) exert selection pressure on the virus necessitating escape; however, the ability of CD4+ T cells to exert selective pressure remains unclear. Using a computational approach on HIV gag/pol/nef sequences and HLA-II allelic data, we identified 29 HLA-II associated HIV sequence polymorphisms or adaptations (HLA-AP) in an African cohort of chronically HIV-infected individuals. Epitopes encompassing the predicted adaptation (AE) or its non-adapted (NAE) version were evaluated for immunogenicity. Using a CD8-depleted IFN-γ ELISpot assay, we determined that the magnitude of CD4+ T cell responses to the predicted epitopes in controllers was higher compared to non-controllers (p<0.0001). However, regardless of the group, the magnitude of responses to AE was lower as compared to NAE (p<0.0001). CD4+ T cell responses in patients with acute HIV infection (AHI) demonstrated poor immunogenicity towards AE as compared to NAE encoded by their transmitted founder virus. Longitudinal data in AHI off antiretroviral therapy demonstrated sequence changes that were biologically confirmed to represent CD4+ escape mutations. These data demonstrate an innovative application of HLA-associated polymorphisms to identify biologically relevant CD4+ epitopes and suggests CD4+ T cells are active participants in driving HIV evolution.
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