13 results on '"Hemashettar G"'
Search Results
2. Passive immunization with polyclonal anti-SHIV IgG: partial protection or increased acquisition of heterologous tier 2 SHIV – depending on IgG dose
- Author
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Sholukh, AM, Sholukh, AM, Siddappa, NB, Shanmuganathan, V, Lakhashe, SK, Rasmussen, RA, Watkins, JD, Vyas, HK, Mukhtar, MM, Hemashettar, G, Thorat, S, Yoon, JK, Villinger, F, Novembre, FJ, Landucci, G, Forthal, DN, Ratcliffe, S, Robert-Guroff, M, Polonis, V, Montefiori, DC, Ertl, HC, Ruprecht, RM, Sholukh, AM, Sholukh, AM, Siddappa, NB, Shanmuganathan, V, Lakhashe, SK, Rasmussen, RA, Watkins, JD, Vyas, HK, Mukhtar, MM, Hemashettar, G, Thorat, S, Yoon, JK, Villinger, F, Novembre, FJ, Landucci, G, Forthal, DN, Ratcliffe, S, Robert-Guroff, M, Polonis, V, Montefiori, DC, Ertl, HC, and Ruprecht, RM
- Published
- 2012
3. Passive immunization with polyclonal anti-SHIV IgG: partial protection or increased acquisition of heterologous tier 2 SHIV – depending on IgG dose
- Author
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Siddappa, NB, Shanmuganathan, V, Hemashettar, G, Yoon, JK, Villinger, F, Novembre, FJ, Landucci, G, Forthal, DN, Ratcliffe, S, Robert-Guroff, M, Polonis, V, Montefiori, DC, Ertl, HC, Sholukh, Anton M, Lakhashe, Samir, Rasmussen, Robert Anthony, Watkins, Jennifer D, Vyas, Hemant Kumar, Mukhtar, Muhammad Mahmood, Thorat, Swati, and Ruprecht, Ruth Margrit
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- 2012
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4. Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: complete protection of rhesus monkeys from mucosal SHIV challenge.
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Sholukh AM, Watkins JD, Vyas HK, Gupta S, Lakhashe SK, Thorat S, Zhou M, Hemashettar G, Bachler BC, Forthal DN, Villinger F, Sattentau QJ, Weiss RA, Agatic G, Corti D, Lanzavecchia A, Heeney JL, and Ruprecht RM
- Subjects
- Administration, Intravenous, Administration, Mucosal, Animals, Antibodies, Monoclonal immunology, Antibodies, Neutralizing administration & dosage, HIV Antibodies blood, Humans, Immunity, Cellular, Immunity, Mucosal, Immunoglobulin A administration & dosage, Immunoglobulin A blood, Immunoglobulin A immunology, Immunoglobulin G administration & dosage, Immunoglobulin G blood, Immunoglobulin G immunology, Macaca mulatta, Mucous Membrane immunology, RNA, Viral blood, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus pathogenicity, T-Lymphocytes immunology, Antibodies, Monoclonal administration & dosage, HIV Antibodies administration & dosage, HIV-1 immunology, Immunization, Passive, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus immunology
- Abstract
Although IgA is the most abundantly produced immunoglobulin in humans, its role in preventing HIV-1 acquisition, which occurs mostly via mucosal routes, remains unclear. In our passive mucosal immunizations of rhesus macaques (RMs), the anti-HIV-1 neutralizing monoclonal antibody (nmAb) HGN194, given either as dimeric IgA1 (dIgA1) or dIgA2 intrarectally (i.r.), protected 83% or 17% of the RMs against i.r. simian-human immunodeficiency virus (SHIV) challenge, respectively. Data from the RV144 trial implied that vaccine-induced plasma IgA counteracted the protective effector mechanisms of IgG1 with the same epitope specificity. We thus hypothesized that mucosal dIgA2 might diminish the protection provided by IgG1 mAbs targeting the same epitope. To test our hypothesis, we administered HGN194 IgG1 intravenously (i.v.) either alone or combined with i.r. HGN194 dIgA2. We enrolled SHIV-exposed, persistently aviremic RMs protected by previously administered nmAbs; RM anti-human IgG responses were undetectable. However, low-level SIV Gag-specific proliferative T-cell responses were found. These animals resemble HIV-exposed, uninfected humans, in which local and systemic cellular immune responses have been observed. HGN194 IgG1 and dIgA2 used alone and the combination of the two neutralized the challenge virus equally well in vitro. All RMs given only i.v. HGN194 IgG1 became infected. In contrast, all RMs given HGN194 IgG1+dIgA2 were completely protected against high-dose i.r. SHIV-1157ipEL-p challenge. These data imply that combining suboptimal defenses at the mucosal and systemic levels can completely prevent virus acquisition. Consequently, active vaccination should focus on defense-in-depth, a strategy that seeks to build up defensive fall-back positions well behind the fortified frontline., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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5. Multimodality vaccination against clade C SHIV: partial protection against mucosal challenges with a heterologous tier 2 virus.
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Lakhashe SK, Byrareddy SN, Zhou M, Bachler BC, Hemashettar G, Hu SL, Villinger F, Else JG, Stock S, Lee SJ, Vargas-Inchaustegui DA, Cofano EB, Robert-Guroff M, Johnson WE, Polonis VR, Forthal DN, Loret EP, Rasmussen RA, and Ruprecht RM
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- Animals, Antibodies, Neutralizing blood, Gene Products, gag immunology, Gene Products, nef immunology, HIV Antibodies blood, HIV Envelope Protein gp160 immunology, HIV-1, Immunity, Cellular, Immunity, Humoral, Macaca mulatta immunology, Recombinant Proteins immunology, Simian Immunodeficiency Virus, Vaccines, Synthetic immunology, Viremia prevention & control, tat Gene Products, Human Immunodeficiency Virus immunology, AIDS Vaccines immunology, Immunity, Mucosal, Vaccination methods
- Abstract
We sought to test whether vaccine-induced immune responses could protect rhesus macaques (RMs) against upfront heterologous challenges with an R5 simian-human immunodeficiency virus, SHIV-2873Nip. This SHIV strain exhibits many properties of transmitted HIV-1, such as tier 2 phenotype (relatively difficult to neutralize), exclusive CCR5 tropism, and gradual disease progression in infected RMs. Since no human AIDS vaccine recipient is likely to encounter an HIV-1 strain that exactly matches the immunogens, we immunized the RMs with recombinant Env proteins heterologous to the challenge virus. For induction of immune responses against Gag, Tat, and Nef, we explored a strategy of immunization with overlapping synthetic peptides (OSP). The immune responses against Gag and Tat were finally boosted with recombinant proteins. The vaccinees and a group of ten control animals were given five low-dose intrarectal (i.r.) challenges with SHIV-2873Nip. All controls and seven out of eight vaccinees became systemically infected; there was no significant difference in viremia levels of vaccinees vs. controls. Prevention of viremia was observed in one vaccinee which showed strong boosting of virus-specific cellular immunity during virus exposures. The protected animal showed no challenge virus-specific neutralizing antibodies in the TZM-bl or A3R5 cell-based assays and had low-level ADCC activity after the virus exposures. Microarray data strongly supported a role for cellular immunity in the protected animal. Our study represents a case of protection against heterologous tier 2 SHIV-C by vaccine-induced, virus-specific cellular immune responses., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
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- 2014
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6. Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV: outcome depends on IgG dose.
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Sholukh AM, Byrareddy SN, Shanmuganathan V, Hemashettar G, Lakhashe SK, Rasmussen RA, Watkins JD, Vyas HK, Thorat S, Brandstoetter T, Mukhtar MM, Yoon JK, Novembre FJ, Villinger F, Landucci G, Forthal DN, Ratcliffe S, Tuero I, Robert-Guroff M, Polonis VR, Bilska M, Montefiori DC, Johnson WE, Ertl HC, and Ruprecht RM
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- Acquired Immunodeficiency Syndrome virology, Animals, Disease Models, Animal, Macaca mulatta, Simian Immunodeficiency Virus immunology, Treatment Outcome, Acquired Immunodeficiency Syndrome prevention & control, Antibodies, Neutralizing administration & dosage, Cross Protection, HIV Antibodies administration & dosage, HIV-1 immunology, Immunization, Passive methods, Immunoglobulin G administration & dosage
- Abstract
Background: A key goal for HIV-1 envelope immunogen design is the induction of cross-reactive neutralizing antibodies (nAbs). As AIDS vaccine recipients will not be exposed to strains exactly matching any immunogens due to multiple HIV-1 quasispecies circulating in the human population worldwide, heterologous SHIV challenges are essential for realistic vaccine efficacy testing in primates. We assessed whether polyclonal IgG, isolated from rhesus monkeys (RMs) with high-titer nAbs (termed SHIVIG), could protect RMs against the R5-tropic tier-2 SHIV-2873Nip, which was heterologous to the viruses or HIV-1 envelopes that had elicited SHIVIG., Results: SHIVIG demonstrated binding to HIV Gag, Tat, and Env of different clades and competed with the broadly neutralizing antibodies b12, VRC01, 4E10, and 17b. SHIVIG neutralized tier 1 and tier 2 viruses, including SHIV-2873Nip. NK-cell depletion decreased the neutralizing activity of SHIVIG 20-fold in PBMC assays. Although SHIVIG neutralized SHIV-2873Nip in vitro, this polyclonal IgG preparation failed to prevent acquisition after repeated intrarectal low-dose virus challenges, but at a dose of 400 mg/kg, it significantly lowered peak viremia (P = 0.001). Unexpectedly, single-genome analysis revealed a higher number of transmitted variants at the low dose of 25 mg/kg, implying increased acquisition at low SHIVIG levels. In vitro, SHIVIG demonstrated complement-mediated Ab-dependent enhancement of infection (C'-ADE) at concentrations similar to those observed in plasmas of RMs treated with 25 mg/kg of SHIVIG., Conclusion: Our primate model data suggest a dual role for polyclonal anti-HIV-1 Abs depending on plasma levels upon virus encounter.
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- 2014
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7. Isolation of monoclonal antibodies with predetermined conformational epitope specificity.
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Sholukh AM, Mukhtar MM, Humbert M, Essono SS, Watkins JD, Vyas HK, Shanmuganathan V, Hemashettar G, Kahn M, Hu SL, Montefiori DC, Polonis VR, Schur PH, and Ruprecht RM
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- Animals, Antibodies, Monoclonal chemistry, Autoantigens chemistry, B-Lymphocytes immunology, Bacteriophages metabolism, Cell Line, Tumor, Cell Separation, Epitope Mapping methods, Flow Cytometry, HIV metabolism, Humans, Immunologic Techniques methods, Leukocytes, Mononuclear virology, Peptide Library, Peptides chemistry, Polymerase Chain Reaction methods, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus genetics, env Gene Products, Human Immunodeficiency Virus chemistry, Antibodies, Monoclonal isolation & purification, Epitopes chemistry
- Abstract
Existing technologies allow isolating antigen-specific monoclonal antibodies (mAbs) from B cells. We devised a direct approach to isolate mAbs with predetermined conformational epitope specificity, using epitope mimetics (mimotopes) that reflect the three-dimensional structure of given antigen subdomains. We performed differential biopanning using bacteriophages encoding random peptide libraries and polyclonal antibodies (Abs) that had been affinity-purified with either native or denatured antigen. This strategy yielded conformational mimotopes. We then generated mimotope-fluorescent protein fusions, which were used as baits to isolate single memory B cells from rhesus monkeys (RMs). To amplify RM immunoglobulin variable regions, we developed RM-specific PCR primers and generated chimeric simian-human mAbs with predicted epitope specificity. We established proof-of-concept of our strategy by isolating mAbs targeting the conformational V3 loop crown of HIV Env; the new mAbs cross-neutralized viruses of different clades. The novel technology allows isolating mAbs from RMs or other hosts given experimental immunogens or infectious agents.
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- 2012
- Full Text
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8. Prime-boost vaccination with heterologous live vectors encoding SIV gag and multimeric HIV-1 gp160 protein: efficacy against repeated mucosal R5 clade C SHIV challenges.
- Author
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Lakhashe SK, Velu V, Sciaranghella G, Siddappa NB, Dipasquale JM, Hemashettar G, Yoon JK, Rasmussen RA, Yang F, Lee SJ, Montefiori DC, Novembre FJ, Villinger F, Amara RR, Kahn M, Hu SL, Li S, Li Z, Frankel FR, Robert-Guroff M, Johnson WE, Lieberman J, and Ruprecht RM
- Subjects
- Adenoviridae genetics, Animals, Antibodies, Neutralizing blood, Antigens, Viral genetics, Antigens, Viral immunology, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Enzyme-Linked Immunospot Assay, Gene Products, gag administration & dosage, HIV Envelope Protein gp160 administration & dosage, HIV Infections prevention & control, HIV-1 immunology, Immunity, Mucosal, Immunization, Secondary, Interferon-gamma analysis, Listeria monocytogenes genetics, Macaca mulatta immunology, Macaca mulatta virology, Simian Immunodeficiency Virus immunology, Vaccination, Viral Load, Viremia immunology, tat Gene Products, Human Immunodeficiency Virus administration & dosage, Adenoviridae immunology, Gene Products, gag immunology, HIV Envelope Protein gp160 immunology, Listeria monocytogenes immunology, tat Gene Products, Human Immunodeficiency Virus immunology
- Abstract
We sought to induce primate immunodeficiency virus-specific cellular and neutralizing antibody (nAb) responses in rhesus macaques (RM) through a bimodal vaccine approach. RM were immunized intragastrically (i.g.) with the live-attenuated Listeria monocytogenes (Lm) vector Lmdd-BdopSIVgag encoding SIVmac239 gag. SIV Gag-specific cellular responses were boosted by intranasal and intratracheal administration of replication-competent adenovirus (Ad5hr-SIVgag) encoding the same gag. To broaden antiviral immunity, the RM were immunized with multimeric HIV clade C (HIV-C) gp160 and HIV Tat. SIV Gag-specific cellular immune responses and HIV-1 nAb developed in some RM. The animals were challenged intrarectally with five low doses of R5 SHIV-1157ipEL-p, encoding a heterologous HIV-C Env (22.1% divergent to the Env immunogen). All five controls became viremic. One out of ten vaccinees was completely protected and another had low peak viremia. Sera from the completely and partially protected RM neutralized the challenge virus > 90%; these RM also had strong SIV Gag-specific proliferation of CD8⁺ T cells. Peak and area under the curve of plasma viremia (during acute phase) among vaccinees was lower than for controls, but did not attain significance. The completely protected RM showed persistently low numbers of the α4β7-expressing CD4⁺ T cells; the latter have been implicated as preferential virus targets in vivo. Thus, vaccine-induced immune responses and relatively lower numbers of potential target cells were associated with protection., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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9. Schistosoma mansoni enhances host susceptibility to mucosal but not intravenous challenge by R5 Clade C SHIV.
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Siddappa NB, Hemashettar G, Shanmuganathan V, Semenya AA, Sweeney ED, Paul KS, Lee SJ, Secor WE, and Ruprecht RM
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- Administration, Rectal, Animals, Disease Susceptibility, Eggs, Feces parasitology, Female, Host-Pathogen Interactions immunology, Immunity, Mucosal, Injections, Intravenous, Interleukin-4 blood, Macaca mulatta, Schistosomiasis mansoni parasitology, Schistosomiasis mansoni virology, Simian Acquired Immunodeficiency Syndrome parasitology, Simian Acquired Immunodeficiency Syndrome virology, Statistics, Nonparametric, Viral Load, Viremia immunology, Viremia parasitology, Viremia virology, Virus Replication, Schistosoma mansoni immunology, Schistosomiasis mansoni immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology
- Abstract
Background: The high prevalence of HIV-1/AIDS in areas endemic for schistosomiasis and other helminthic infections has led to the hypothesis that parasites increase host susceptibility to immunodeficiency virus infection. We previously showed that rhesus macaques (RM) with active schistosomiasis were significantly more likely to become systemically infected after intrarectal (i.r.) exposure to an R5-tropic clade C simian-human immunodeficiency virus (SHIV-C) than were parasite-free controls. However, we could not address whether this was due to systemic or mucosal effects. If systemic immunoactivation resulted in increased susceptibility to SHIV-C acquisition, a similarly large difference in host susceptibility would be seen after intravenous (i.v.) SHIV-C challenge. Conversely, if increased host susceptibility was due to parasite-induced immunoactivation at the mucosal level, i.v. SHIV-C challenge would not result in significant differences between parasitized and parasite-free monkeys., Methods and Findings: We enrolled two groups of RM and infected one group with Schistosoma mansoni; the other group was left parasite-free. Both groups were challenged i.v. with decreasing doses of SHIV-C. No statistically significant differences in 50% animal infectious doses (AID(50)) or peak viremia were seen between the two groups. These data strongly contrast the earlier i.r. SHIV-C challenge (using the same virus stock) in the presence/absence of parasites, where we noted a 17-fold difference in AID(50) and one log higher peak viremia in parasitized monkeys (P<0.001 for both). The lack of significant differences after the i.v. challenge implies that the increased host susceptibility is predominantly due to parasite-mediated mucosal upregulation of virus replication and spread, rather than systemic effects., Conclusions: The major impact of schistosome-induced increased host susceptibility is at the mucosal level. Given that >90% of all new HIV-1 infections worldwide are acquired through mucosal contact, parasitic infections that inflame mucosae may play an important role in the spread of HIV-1.
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- 2011
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10. Development of a tier 1 R5 clade C simian-human immunodeficiency virus as a tool to test neutralizing antibody-based immunoprophylaxis.
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Siddappa NB, Hemashettar G, Wong YL, Lakhashe S, Rasmussen RA, Watkins JD, Novembre FJ, Villinger F, Else JG, Montefiori DC, and Ruprecht RM
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- AIDS Vaccines genetics, Animals, Antibodies, Neutralizing immunology, CD4-Positive T-Lymphocytes immunology, Disease Models, Animal, Genes, env, HIV-1 genetics, Macaca mulatta immunology, Phylogeny, Reverse Transcriptase Polymerase Chain Reaction, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus genetics, AIDS Vaccines immunology, HIV-1 immunology, Macaca mulatta virology, Simian Immunodeficiency Virus immunology
- Abstract
Background: While some recently transmitted HIV clade C (HIV-C) strains exhibited tier 1 neutralization phenotypes, most were tier 2 strains (J Virol 2010; 84:1439). Because induction of neutralizing antibodies (nAbs) through vaccination against tier 2 viruses has proven difficult, we have generated a tier 1, clade C simian-human immunodeficiency virus (SHIV-C) to permit efficacy testing of candidate AIDS vaccines against tier 1 viruses., Methods: SHIV-1157ipEL was created by swapping env of a late-stage virus with that of a tier 1, early form., Results: After adaptation to rhesus macaques (RM), passaged SHIV-1157ipEL-p replicated vigorously in vitro and in vivo while maintaining R5 tropism. The virus was reproducibly transmissible intrarectally. Phylogenetically, SHIV-1157ipEL-p Env clustered with HIV-C sequences. All RM chronically infected with SHIV-1157ipEL-p developed high nAb titers against autologous as well as heterologous tier 1 strains., Conclusions: SHIV-1157ipEL-p was reproducibly transmitted in RM, induced cross-clade nAbs, and represents a tool to evaluate anti-HIV-C nAb responses in primates., (© 2010 John Wiley & Sons A/S.)
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- 2011
- Full Text
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11. An anti-HIV-1 V3 loop antibody fully protects cross-clade and elicits T-cell immunity in macaques mucosally challenged with an R5 clade C SHIV.
- Author
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Watkins JD, Siddappa NB, Lakhashe SK, Humbert M, Sholukh A, Hemashettar G, Wong YL, Yoon JK, Wang W, Novembre FJ, Villinger F, Ibegbu C, Patel K, Corti D, Agatic G, Vanzetta F, Bianchi S, Heeney JL, Sallusto F, Lanzavecchia A, and Ruprecht RM
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cell Proliferation, Enzyme-Linked Immunosorbent Assay, Lymphocytes cytology, Lymphocytes immunology, Macaca, Macaca mulatta, RNA, Viral genetics, Antibodies, Monoclonal immunology, HIV Antibodies immunology, T-Lymphocytes immunology
- Abstract
Neutralizing antibodies have been shown to protect macaques against SHIV challenge. However, genetically diverse HIV-1 clades have evolved, and a key question left unanswered is whether neutralizing antibodies can confer cross-clade protection in vivo. The novel human monoclonal antibody HGN194 was isolated from an individual infected with an HIV-1 clade AG recombinant circulating recombinant form (CRF). HGN194 targets an epitope in the third hypervariable loop (V3) of HIV-1 gp120 and neutralizes a range of relatively neutralization-sensitive and resistant viruses. We evaluated the potential of HGN194 to protect infant rhesus monkeys against a SHIV encoding a primary CCR5-tropic HIV-1 clade C envelope. After high-dose mucosal challenge, all untreated controls became highly viremic while all HGN194-treated animals (50 mg/kg) were completely protected. When HGN194 was given at 1 mg/kg, one out of two monkeys remained aviremic, whereas the other had delayed, lower peak viremia. Interestingly, all protected monkeys given high-dose HGN194 developed Gag-specific proliferative responses of both CD4+ and CD8+ T cells. To test whether generation of the latter involved cryptic infection, we ablated CD8+ cells after HGN194 clearance. No viremia was detected in any protected monkeys, thus ruling out virus reservoirs. Thus, induction of CD8 T-cell immunity may have resulted from transient "Hit and Run" infection or cross priming via Ag-Ab-mediated cross-presentation. Together, our data identified the HGN194 epitope as protective and provide proof-of-concept that this anti-V3 loop mAb can prevent infection with sterilizing immunity after challenge with virus of a different clade, implying that V3 is a potential vaccine target.
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- 2011
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12. Vaccination against heterologous R5 clade C SHIV: prevention of infection and correlates of protection.
- Author
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Lakhashe SK, Wang W, Siddappa NB, Hemashettar G, Polacino P, Hu SL, Villinger F, Else JG, Novembre FJ, Yoon JK, Lee SJ, Montefiori DC, Ruprecht RM, and Rasmussen RA
- Subjects
- Animals, Fusion Proteins, gag-pol immunology, HIV Envelope Protein gp160 immunology, HIV Infections immunology, Humans, Infant, Macaca mulatta, Vaccines, Synthetic immunology, Viremia prevention & control, tat Gene Products, Human Immunodeficiency Virus immunology, HIV Infections prevention & control, HIV-1 immunology, Simian Immunodeficiency Virus immunology, Vaccination methods, Viral Vaccines immunology
- Abstract
A safe, efficacious vaccine is required to stop the AIDS pandemic. Disappointing results from the STEP trial implied a need to include humoral anti-HIV-1 responses, a notion supported by RV144 trial data even though correlates of protection are unknown. We vaccinated rhesus macaques with recombinant simian immunodeficiency virus (SIV) Gag-Pol particles, HIV-1 Tat and trimeric clade C (HIV-C) gp160, which induced cross-neutralizing antibodies (nAbs) and robust cellular immune responses. After five low-dose mucosal challenges with a simian-human immunodeficiency virus (SHIV) that encoded a heterologous R5 HIV-C envelope (22.1% divergence from the gp160 immunogen), 94% of controls became viremic, whereas one third of vaccinees remained virus-free. Upon high-dose SHIV rechallenge, all controls became infected, whereas some vaccinees remained aviremic. Peak viremia was inversely correlated with both cellular immunity (p<0.001) and cross-nAb titers (p<0.001). These data simultaneously linked cellular as well as humoral immune responses with the degree of protection for the first time.
- Published
- 2011
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13. UV-induced association of the CSB remodeling protein with chromatin requires ATP-dependent relief of N-terminal autorepression.
- Author
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Lake RJ, Geyko A, Hemashettar G, Zhao Y, and Fan HY
- Subjects
- Adenosine Triphosphatases physiology, Chromatin Assembly and Disassembly physiology, Chromatin Assembly and Disassembly radiation effects, Cockayne Syndrome genetics, DNA Helicases genetics, DNA Helicases metabolism, DNA Repair Enzymes genetics, DNA Repair Enzymes metabolism, Humans, Models, Genetic, Poly-ADP-Ribose Binding Proteins, Adenosine Triphosphate metabolism, Chromatin metabolism, DNA Helicases physiology, DNA Repair Enzymes physiology, Ultraviolet Rays
- Abstract
The ATP-dependent chromatin remodeler CSB is essential for transcription-coupled DNA repair, and mutations in CSB lead to Cockayne syndrome. Here, we examined the recruitment of CSB to chromatin after ultraviolet (UV) irradiation and uncovered a regulatory mechanism that ensures the specific association of this remodeler with chromatin. We demonstrate that ATP hydrolysis by CSB is essential for stable CSB-chromatin association after UV irradiation and that defects in this association underlie some forms of Cockayne syndrome. We also show that the N-terminal region of CSB negatively regulates chromatin association during normal cell growth. Of interest, in the absence of the negative regulatory region, ATP hydrolysis becomes dispensable for chromatin association, indicating that CSB uses energy from ATP hydrolysis to overcome the inhibitory effect imposed by its N-terminal region. Together, our results suggest that the recruitment of CSB to lesion-stalled transcription is an ATP-dependent process and involves a gross conformational change of CSB., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
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