Possible clearance of transfusion-acquired nef/LTR-deleted attenuated HIV-1 infection by an elite controller with CCR5 Δ32 heterozygous and HLA-B57 genotype
John ZaundersWayne B. DyerMelissa J. ChurchillC. Mee Ling MunierPhilip CunninghamKazuo SuzukiKristin McBrideWill Hey-NguyenKersten K. KoelschBin WangBonnie HienerSarah PalmerPaul R. GorryMichelle BaileyYin XuMark DantaNabila SeddikiDavid A. CooperNitin K. SaksenaJohn S. SullivanSean RimintonJenny LearmontAnthony D. Kelleher
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Subject C135 is one of the members of the Sydney Blood Bank Cohort, infected in 1981 through transfusion with attenuated nef/3′ long terminal repeat (LTR)-deleted HIV-1, and has maintained undetectable plasma viral load and steady CD4 cell count, in the absence of therapy. Uniquely, C135 combines five factors separately associated with control of viraemia: nef/LTR-deleted HIV-1, HLA-B57, HLA-DR13, heterozygous CCR5 Δ32 genotype and vigorous p24-stimulated peripheral blood mononuclear cell (PBMC) proliferation. Therefore, we studied in detail viral burden and immunological responses in this individual. PBMC and gut and lymph node biopsy samples were analysed for proviral HIV-1 DNA by real-time and nested PCRs, and nef/LTR alleles by nested PCR. HIV-specific antibodies were studied by Western blotting, and CD4+ and CD8+ T lymphocyte responses were measured by proliferation and cytokine production in vitro. PBMC samples from 1996, but not since, showed amplification of nef alleles with gross deletions. Infectious HIV-1 was never recovered. Proviral HIV-1 DNA was not detected in recent PBMC or gut or lymph node biopsy samples. C135 has a consistently weak antibody response and a substantial CD4+ T cell proliferative response to a previously described HLA-DR13-restricted epitope of HIV-1 p24 in vitro, which augmented a CD8+ T cell response to an immunodominant HLA-B57-restricted epitope of p24, while his T cells show reduced levels of CCR5. Subject C135's early PCR and weak antibody results are consistent with limited infection with a poorly replicating nef/LTR-deleted strain of HIV-1. With his HLA-B57-restricted gag-specific CD8 and helper HLA-DR13-restricted CD4 T cell proliferative responses, C135 appears to have cleared his HIV-1 infection 37 years after transfusion.Keywords:
Viremia
Monoclonal antibody 2F5 recognizing the ELDKWA epitope on HIV-1 gp41 has a significant neutralization potency against 90% of the investigated viruses of African, Asian, American, and European strains, but the antibody responses to the epitope 2F5 in HIV-1-infected individuals were very low. We attempted to induce high levels of epitope-specific antibodies to ELDKWA and its three mutated epitopes by candidate epitope vaccines. The four candidate epitope vaccines all induced strong antibody responses at dilutions from about 1:6,400 to 1:25,600. We tested the cross-reactions between these antisera and four epitope peptides. The ELDKWA-specific antisera showed strong cross-reactivity with three neutralizing-resistant mutated epitopes which contain changes in the D or K positions of the epitope sequence. Virus variants containing these changes could escape neutralization by monoclonal antibody 2F5. In immunoblotting analysis, the ELDKWA, ELDEWA, and ELEKWA epitope specific antibodies all recognized rsgp41 which confirms that the antibodies against both mutated epitopes, ELDEWA and ELEKWA, could cross-react with the native epitope on rsgp41. Although it is not clear whether the polyclonal antibodies induced by the ELDKWA epitope vaccine could neutralize the mutated viruses containing these mutated epitopes, it is conceivable that epitope vaccines based on mutated epitopes could induce strong antibody responses with predefined epitope specificity to neutralize mutated viruse containing the mutated epitope. An epitope vaccine, using different epitopes including mutated epitopes, could provide a new concept for developing a new vaccine against HIV-1.
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HIV-1 viremia persists at low-levels despite clinically-effective antiretroviral therapy (ART). Here we review new methods to quantify and characterize persistent viremia at the single genome level, and discuss the mechanisms of persistence including clonal expansion of infected cells and tissue origins of virema. A deeper understanding of how viremia persists on ART is critically important to the design of therapies to eliminate viremia and achieve a functional cure for HIV-1.
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In conclusion, this case provided a unique illustration of de novo production of DSA following transplant from an HLA-A, -B, and -DR matched donor (eliminating the masking effect of these potential mismatches). The antibody generated could be tracked down not only to the allele level of the mismatched HLA antigen but also to the exact epitope that was conceived immunogenic by the recipient. Identifying this epitope also explained the presence of the additional non-donor-specific antibodies (NDSAs) that are actually the same antibody recognizing a shared epitope by multiple HLA-DP alleles. Finally, this information provided valuable information for selecting the most suitable donor for this patient. The concept of shared epitopes was first described by Parham et al. in 1980, and it was revisited recently by Piazza et al. This concept was further developed into a proposal for epitope matching rather than the conventional antigen matching. A simplified algorithm has been developed and implemented by Duquesnoy. The case presented in this manuscript provides a "poster child" example for the role of epitope matching. It is time that the community re-evaluates our nomenclature and scientific reasoning. Current nomenclature stems from historic events that led to the discovery of the HLA system. However, once molecular sequences and 3D structures of the HLA molecules have been elucidated and interactions between the HLA molecules and T-cell receptors have been deciphered, reclassification of the HLA system based on immunogenic epitopes is warranted.
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Epitope-vaccine is a newly developing vaccine which has many advantages comparied with to the traditional vaccine.The key step for designing epitope-vaccine is to screen epitopes.The epitope-screening methods include protein degration,peptide-probing scanning,epitope prediction by computer,et al.Usually,the epitope-vaccine needs combine some carriers to display immunologic activity,for example,lipid carriers,protein carriers,and adjuvant.In addition,researchers also use tandem repeat epitopes,conformational multiple antigen peptide(MAP) and epitope modifying to strengthen the immunological efficacity.The epitope-vaccine mainly contains viral epitope-vaccine,bacterial epitope-vaccine and epitope-vaccine for parasites.Although the researches on epitope-vaccine develop fast,some problems and challenges need to resolve impendingly.
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Turkey herpesvirus (HVT) viremia was studied at 3-week intervals through 21 weeks of age in individual chickens of experimental (WSU-VS) and commercial strains (C-WL) of White Leghorns vaccinated with graded doses of HVT. HVT viremia was consistently detectable in all WSU-VS birds through 21 weeks postvaccination (PV) regardless of vaccine dose employed, whereas the viremia could not be detected in some of the C-WL birds 9 to 15 weeks PV and thereafter. C-WL birds that lost detectable viremia remained so up to 21 weeks PV, or returned to low levels of viremia which was followed in some birds again by no detectable viremia. Viremia titers were significantly lower in the C-WL than in the WSU-VS birds despite the same vaccination. Both strains of chickens exhibited significantly lower viremia titers when vaccinated with 240 plaqueforming units (PFU) than with 1,480 or 6,600 PFU of HVT, and other C-WL birds lost detectable viremia earlier and more frequently with smaller vaccine doses. This observation indicated a possible genetic difference between the two strains of chickens in susceptibility and viremic response to HVT as well as dose-dependence of HVT viremia.
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Serial samples from source plasma donors with confirmed new HIV infection were investigated for low-level viremia (LLV) (ie, < 100 genome copies [cp]/mL) at time points preceding the period of steadily rising viremia above 100 cp/mL (ramp-up viremia). Fifteen of 44 plasma donor panels previously studied for the dynamics of HIV viremia during primary infection contained 70 samples with undetectable HIV-1 RNA by quantitative polymerase chain reaction (PCR). On retesting with a sensitive qualitative reverse transcriptase PCR assay (95% detection at 4 cp/mL), we identified LLV in 13 of 15 panels and 23 of 69 retested samples. In 6 panels, a total of 11 samples (1-3 per panel) were consistent with LLV before ramp-up viremia. These samples preceded the first sample with >100 cp/mL HIV by 9 to 25 days (median = 18 days) and were separated from the latter by at least 1 sample with undetectable viremia by the qualitative PCR assay. We conclude that LLV is not uncommon during the very early period of primary HIV infection preceding ramp-up viremia. It is not known if blood is infectious during this period; however, given the low viral concentrations and transient nature of the observed viremic "blips," the risk of infectivity can be assumed to be small.
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The HIV-1 reservoir is composed of cells harboring latent proviruses that have the potential to contribute to viremia upon antiretroviral treatment (ART) interruption. While this reservoir is known to be maintained by clonal expansion of infected cells, the contribution of these cell clones to residual viremia and viral rebound remains underexplored. Here, we conducted an extensive analysis on four ART-treated individuals who underwent an analytical treatment interruption (ATI), characterizing the proviral genomes and associated integration sites of large infected clones and phylogenetically linking these to plasma viremia. We show discrepancies between different assays in their ability to assess clonal expansion. Furthermore, we demonstrate that proviruses could phylogenetically be linked to plasma virus obtained before or during an ATI. This study highlights a role for HIV-infected cell clones in the maintenance of the replication-competent reservoir and suggests that infected cell clones can directly contribute to rebound viremia upon ATI.
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The development and persistence of viremia were followed in two lines of Single-Comb White Leghorns: one experimental line (WSU-VS) highly susceptible, and one commercial line (C-WL) relatively resistant to Marek's disease(MD). In the resistant C-WL chicken, viremia with a mild strain of MD herpesvirus (MDHV) persisted in all viremic birds through 8 weeks postinoculation (PI), while viremia with an acute strain of MDHV did not, resulting in a decrease in number of viremic birds after 2 weeks PI. In the susceptible WSU-VS chicken, viremia with acute MDHV persisted in all viremic birds whereas viremia with mild MDHV was detected in a decreasing number of birds after 6 weeks PI. The pattern of viremia observed in the dually infected groups simulated a combination of the responses of the two groups respectively inoculated with mild and acute MDHV. Whether inoculation was with acute MDHV alone, or together with mild MDHV, levels of viremia with acute MDHV were appreciably higher in the WSU-VS than in the C-WL chicken. In both lines, levels of viremia were higher with acute MDHV than with mild MDHV but viremia with acute MDHV could not be demonstrated in the C-WL bird at 6-8 weeks PI. Levels of viremia with mild MDHV were consistently and similarly low in both WSU-VS and C-WL chickens.
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