D D Ho

The Rockefeller University, New York, New York, United States

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Publications (331)3964.05 Total impact

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    ABSTRACT: Long-acting GSK1265744 (GSK744 LA) is a strand transfer inhibitor of the HIV/SIV (simian immunodeficiency virus) integrase and was shown to be an effective preexposure prophylaxis (PrEP) agent in a low-dose intrarectal SHIV (simian-human immunodeficiency virus) rhesus macaque challenge model. We examined the pharmacokinetics and efficacy of GSK744 LA as PrEP against repeat high-dose intravaginal SHIV challenge in female rhesus macaques treated with Depo-Provera (depot medroxyprogesterone acetate), which promotes viral transmission vaginally. When Depo-Provera-treated female rhesus macaques were dosed with GSK744 LA (50 mg/kg) monthly, systemic and tissue drug concentrations were lower than previously observed in male rhesus macaques. GSK744 concentrations were fivefold lower on average in cervical tissues than in rectal tissues. Eight female rhesus macaques were treated with GSK744 LA at week 0, and four female rhesus macaques served as controls. All animals received a high-dose challenge of SHIV162P3 at week 1. No infection was detected in GSK744 LA-treated rhesus macaques, whereas viremia was detected 1 to 2 weeks after SHIV challenge in all control animals. The GSK744 LA-treated rhesus macaques were given a second administration of drug at week 4 and further challenged at weeks 5 and 7. GSK744 LA treatment protected six of eight female rhesus macaques against three high-dose SHIV challenges, whereas all control animals became infected after the first challenge (P = 0.0003, log-rank test). These results support further clinical development of GSK744 LA for PrEP. Copyright © 2015, American Association for the Advancement of Science.
    Science translational medicine 01/2015; 7(270):270ra4. DOI:10.1126/scitranslmed.3010298 · 14.41 Impact Factor
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    ABSTRACT: Broadly cross-reactive neutralizing antibodies (bNabs) represent powerful tools to combat human immunodeficiency virus type 1 (HIV-1) infection. Here, we examined whether HIV-1-specific bNabs are capable of cross-neutralizing distantly related simian immunodeficiency viruses (SIVs) infecting central (Pan troglodytes troglodytes) (SIVcpzPtt) and eastern (Pan troglodytes schweinfurthii) (SIVcpzPts) chimpanzees (n = 11) as well as western gorillas (Gorilla gorilla gorilla) (SIVgor) (n = 1). We found that bNabs directed against the CD4 binding site (n = 10), peptidoglycans at the base of variable loop 3 (V3) (n = 5), and epitopes at the interface of surface (gp120) and membrane-bound (gp41) envelope glycoproteins (n = 5) failed to neutralize SIVcpz and SIVgor strains. In addition, apex V2-directed bNabs (n = 3) as well as llama-derived (heavy chain only) antibodies (n = 6) recognizing both the CD4 binding site and gp41 epitopes were either completely inactive or neutralized only a fraction of SIVcpzPtt strains. In contrast, one antibody targeting the membrane-proximal external region (MPER) of gp41 (10E8), functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Ig(mim2), CD4-218.3-E51, and CD4-218.3-E51-mim2), as well as mono- and bispecific anti-human CD4 (iMab and LM52) and CCR5 (PRO140, PRO140-10E8) receptor antibodies neutralized >90% of SIVcpz and SIVgor strains with low-nanomolar (0.13 to 8.4 nM) potency. Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5 and neutralized SIVcpz in chimpanzee CD4(+) T cells, with 50% inhibitory concentrations (IC50s) ranging from 3.6 to 40.5 nM. These findings provide new insight into the protective capacity of anti-HIV-1 bNabs and identify candidates for further development to combat SIVcpz infection. SIVcpz is widespread in wild-living chimpanzees and can cause AIDS-like immunopathology and clinical disease. HIV-1 infection of humans can be controlled by antiretroviral therapy; however, treatment of wild-living African apes with current drug regimens is not feasible. Nonetheless, it may be possible to curb the spread of SIVcpz in select ape communities using vectored immunoprophylaxis and/or therapy. Here, we show that antibodies and antibody-like inhibitors developed to combat HIV-1 infection in humans are capable of neutralizing genetically diverse SIVcpz and SIVgor strains with considerable breadth and potency, including in primary chimpanzee CD4(+) T cells. These reagents provide an important first step toward translating intervention strategies currently developed to treat and prevent AIDS in humans to SIV-infected apes. Copyright © 2015 Barbian et al.
    mBio 01/2015; 6(2). DOI:10.1128/mBio.00296-15 · 6.88 Impact Factor
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    AIDS Research and Human Retroviruses 10/2014; 30 Suppl 1:A224. DOI:10.1089/aid.2014.5490.abstract · 2.46 Impact Factor
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    ABSTRACT: Recombinant Mycobacterium bovis bacillus Calmette-Guèrin (rBCG) has been explored as a vector for vaccines against HIV because of its ability to induce long lasting humoral and cell mediated immune responses. To maximize the potential for rBCG vaccines to induce effective immunity against HIV, various strategies are being employed to improve its ability to prime CD8 + T cells, which play an important role in the control of HIV infections. In this study we adopted a previously described approach of incorporating glycolipids that activate CD1d-restricted natural killer T (NKT) cells to enhance priming of CD8 + T cells by rBCG strains expressing an SIV Gag antigen (rBCG-SIV gag). We found that the incorporation of the synthetic NKT activating glycolipid a-galactosylceramide (a-GC) into rBCG-SIV gag significantly enhanced CD8 + T cell responses against an immunodominant Gag epitope, compared to responses primed by unmodified rBCG-SIV gag. The abilities of structural analogues of a-GC to enhance CD8 + T cell responses to rBCG were compared in both wild type and partially humanized mice that express human CD1d molecules in place of mouse CD1d. These studies identified an a-GC analogue known as 7DW8-5, which has previously been used successfully as an adjuvant in non-human primates, as a promising compound for enhancing immunogenicity of antigens delivered by rBCG.vectors. Our findings support the incorporation of synthetic glycolipid activators of NKT cells as a novel approach to enhance the immunogenicity of rBCG-vectored antigens for induction of CD8 + T cell responses. The glycolipid adjuvant 7DW8-5 may be a promising candidate for advancing to non-human primate and human clinical studies for the development of HIV vaccines based on rBCG vectors.
    PLoS ONE 09/2014; 9(9). DOI:10.1371/journal.pone.0108383 · 3.53 Impact Factor
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    ABSTRACT: Extending our previous analyses to the most recently described broadly neutralizing monoclonal antibodies (bNAbs) we confirm a drift of HIV-1 clade B variants over two decades toward higher resistance to bNAbs targeting almost all the identified gp120 neutralizing epitopes. In contrast, the sensitivity to bNAbs targeting the gp41 MPER remained stable, suggesting a selective pressure on gp120 preferentially. Despite this evolution, selected combinations of bNAbs remain capable to neutralize efficiently most of the circulating variants.
    Journal of Virology 09/2014; 88(23). DOI:10.1128/JVI.02083-14 · 4.65 Impact Factor
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    ABSTRACT: While broadly neutralizing monoclonal antibodies (bNAbs) have always been considered potential therapeutic options for the prophylactic and treatment of HIV infection, their lack of breadth against all HIV variants has been one of the limiting factors. To provide sufficient neutralization breadth and potency against diverse viruses, including neutralization escape variants, strategies to combine different bNAbs have been explored recently. We rationally designed and engineered a novel bispecific HIV-1 neutralizing antibody (bibNAb), iMabm36, for high potency and breadth against HIV. iMabm36 is composed of the anti-CD4 Ab ibalizumab (iMab) linked to two copies of the single-domain Ab m36 which targets a highly conserved CD4-induced epitope. iMabm36 neutralizes a majority of a large, multi-clade panel of pseudoviruses (96%, n=118) at an IC50 concentration of less than 10 µg/mL, with 83% neutralized at an IC50 concentration of less than 0.1µg/ml. In addition, iMabm36 neutralizes six replication-competent transmitted-founder viruses to 100% inhibition at a concentration of less than 0.1µg/ml in a PBMC-based neutralizing assay. Mechanistically, improved antiviral activity of iMabm36 is dependent on both CD4 binding activity of iMab component and CD4i binding activity of the m36 component. After characterizing viral resistance to iMabm36 neutralization was due to mutations residing in the bridging sheet of gp120, an optimized m36 variant was engineered that, when fused to iMab, improved antiviral activity significantly. Together inter-dependency of this dual mechanism of action enables iMabm36 to potently inhibit HIV-1 entry. These results demonstrate that mechanistic-based design of bibNAbs could generate potential preventive and therapeutic candidates for HIV/AIDS.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 05/2014; DOI:10.1097/QAI.0000000000000218 · 4.39 Impact Factor
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    ABSTRACT: GSK1265744 (GSK744) is an integrase strand-transfer inhibitor that has been formulated as a long-acting (LA) injectable suitable for monthly to quarterly clinical administration. GSK744 LA was administered at two time points 4 weeks apart beginning 1 week before virus administration, and macaques were challenged weekly for 8 weeks. GSK744 LA, at plasma concentrations achievable with quarterly injections in humans, protected all animals against repeated low-dose challenges. In a second experiment, macaques were given GSK744 LA 1 week before virus administration and challenged repeatedly until infection occurred. Protection decreased over time and correlated with the plasma drug levels. With a quarterly dosing schedule in humans, our results suggest that GSK744 LA could potentially decrease adherence problems associated with daily preexposure prophylaxis (PrEP).
    Science 03/2014; 343(6175). DOI:10.1126/science.1248707 · 31.48 Impact Factor
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    ABSTRACT: To combat the possibility of a zoonotic H5N1 pandemic in a timely fashion, it is necessary to develop a vaccine that would confer protection against homologous and heterologous human H5N1 influenza viruses. Using a replicating modified vaccinia virus Tian Tan strain (MVTT) as a vaccine vector, we constructed MVTTHA-QH and MVTTHA-AH, which expresses the H5 gene of a goose-derived Qinghai strain A/Bar-headed Goose/Qinghai/1/2005 or human-derived Anhui Strain A/Anhui/1/2005. The immunogenicity profiles of both vaccine candidates were evaluated. Vaccination with MVTTHA-QH induced a significant level of neutralizing antibodies (Nabs) against a homologous strain and a wide range of H5N1 pseudoviruses (clades 1, 2.1, 2.2, 2.3.2, and 2.3.4). Neutralization tests (NT) and Haemagglutination inhibition (HI) antibodies inhibit the live autologous virus as well as a homologous A/Xingjiang/1/2006 and a heterologous A/Vietnam/1194/2004, representing two human isolates from clade 2.2 and clade 1, respectively. Importantly, mice vaccinated with intranasal MVTTHA-QH were completely protected from challenge with lethal dosages of A/Bar-headed Goose/Qinghai/1/2005 and the A/Viet Nam/1194/2004, respectively, but not control mice that received a mock MVTTS vaccine. However, MVTTHA-AH induced much lower levels of NT against its autologous strain. Our results suggest that it is feasible to use the H5 gene from A/Bar-headed Goose/Qinghai/1/2005 to construct an effective vaccine, when using MVTT as a vector, to prevent infections against homologous and genetically divergent human H5N1 influenza viruses.
    PLoS ONE 12/2013; 8(12):e83274. DOI:10.1371/journal.pone.0083274 · 3.53 Impact Factor
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    ABSTRACT: A key strategy to a successful vaccine against malaria is to identify and develop new adjuvants that can enhance T-cell responses and improve protective immunity. Upon co-administration with a rodent malaria vaccine in mice, 7DW8-5, a recently identified novel analog of α-galactosylceramide (α-GalCer), enhances the level of malaria-specific protective immune responses more strongly than the parent compound. In this study, we sought to determine whether 7DW8-5 could provide a similar potent adjuvant effect on a candidate human malaria vaccine in the more relevant non-human primate (NHP) model, prior to committing to clinical development. The candidate human malaria vaccine, AdPfCA (NMRC-M3V-Ad-PfCA), consists of two non-replicating recombinant adenoviral (Ad) vectors, one expressing the circumsporozoite protein (CSP) and another expressing the apical membrane antigen-1 (AMA1) of Plasmodium falciparum. In several phase 1 clinical trials, AdPfCA was well tolerated and demonstrated immunogenicity for both humoral and cell-mediated responses. In the study described herein, 25 rhesus macaques received prime and boost intramuscular (IM) immunizations of AdPfCA alone or with an ascending dose of 7DW8-5. Our results indicate that 7DW8-5 is safe and well-tolerated and provides a significant enhancement (up to 9-fold) in malaria-specific CD8+ T-cell responses after both priming and boosting phases, supporting further clinical development.
    PLoS ONE 10/2013; 8(10):e78407. DOI:10.1371/journal.pone.0078407 · 3.53 Impact Factor
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    ABSTRACT: Ibalizumab is a humanized monoclonal antibody that binds human CD4-a key receptor for HIV-and blocks HIV-1 infection. However, HIV-1 strains with mutations resulting in loss of an N-linked glycan from the V5 loop of the envelope glycoprotein gp120 are resistant to ibalizumab. Previous structural analysis suggests that this glycan fills a void between the gp120 V5 loop and the ibalizumab light chain, perhaps causing steric hindrance that disrupts viral entry. If this void contributes to HIV-1 resistance to ibalizumab, we reasoned that 'refilling' it by engineering an N-linked glycan into the ibalizumab light chain at a position spatially proximal to gp120 V5 may restore susceptibility to ibalizumab. Indeed, one such ibalizumab variant neutralized 100% of 118 diverse HIV-1 strains tested in vitro, including 10 strains resistant to parental ibalizumab. These findings demonstrate that the strategic placement of a glycan in the variable region of a monoclonal antibody can substantially enhance its activity.
    Nature Biotechnology 10/2013; 31(11). DOI:10.1038/nbt.2677 · 39.08 Impact Factor
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    ABSTRACT: In the absence of an effective HIV-1 vaccine, passive immunization using broadly neutralizing Abs or Ab-like molecules could provide an alternative to the daily administration of oral antiretroviral agents that has recently shown promise as preexposure prophylaxis. Currently, no single broadly neutralizing Ab (bNAb) or combination of bNAbs neutralizes all HIV-1 strains at practically achievable concentrations in vivo. To address this problem, we created bispecific Abs that combine the HIV-1 inhibitory activity of ibalizumab (iMab), a humanized mAb directed to domain 2 of human CD4, with that of anti-gp120 bNAbs. These bispecific bNAbs (BibNAbs) exploit iMab's potent anti-HIV-1 activity and demonstrated clinical efficacy and safety to anchor and thereby concentrate a second broadly neutralizing agent at the site of viral entry. Two BibNabs, PG9-iMab and PG16-iMab, exhibit exceptional breadth and potency, neutralizing 100% of the 118 viruses tested at low picomolar concentrations, including viruses resistant to both parental mAbs. The enhanced potency of these BibNAbs was entirely dependent on CD4 anchoring, not on membrane anchoring per se, and required optimal Ab geometry and linker length. We propose that iMab-based BibNAbs, such as PG9-iMab and PG16-iMab, are promising candidates for passive immunization to prevent HIV-1 infection.
    Proceedings of the National Academy of Sciences 07/2013; DOI:10.1073/pnas.1304985110 · 9.81 Impact Factor
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    ABSTRACT: Clostridium difficile is a spore-forming bacillus that produces toxin-mediated enteric disease. C. difficile expresses two major virulence factors, toxin A (TcdA) and toxin B (TcdB). Human and animal studies demonstrate a clear association between humoral immunity to these toxins and protection against C. difficile infection (CDI). The receptor binding-domains (RBD) of TcdA and TcdB are known to be immunogenic. Here, we tested the immunadjuvantative properties of Salmonella enterica serovar Typhimurium flagellin (FliC) subunit D1 as an innate immune agonist expressed as a recombinant fusion vaccine targeting the RBDs of TcdA and TcdB in mice. Intraperitoneally immunized mice developed prominent anti- TcdA and anti- TcdB immunoglobulin G in serum. The protective efficacy of the recombinant vaccines, with or without an adjuvant, was tested in a mouse model of CDI that closely represents the human disease. Following intraperitoneal immunization and oral challenge with C. difficile VPI 10463, C57BL/6 mice were able to mount a protective immune response that prevented diarrhea and death compared to control mice equivalent to two doses of toxoid A and toxoid B vaccine adjuvanted with alum when compared to control mice (P<.001). These results provide evidence that a recombinant protein-based vaccine targeting the RBDs of the C.difficile toxins adjuvanted with S.typhimurium flagellin can induce rapid, high level protection in a mouse model of CDI when challenged with the homologous strain from which the vaccine antigens were derived, and warrants further preclinical testing against clinically relevant C. difficile strains in the mouse and hamster models of CDI.
    Infection and immunity 04/2013; DOI:10.1128/IAI.01074-12 · 4.16 Impact Factor
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    ABSTRACT: OBJECTIVES:: Passive immunization for the prevention of HIV-1 infection is currently being reenergized. The anti-CD4 monoclonal antibody ibalizumab has demonstrated safety and efficacy in Phase 1 and 2 clinical trials for treatment of HIV-1 infection and is undergoing a Phase 1 clinical trial in HIV-1 uninfected individuals for prevention. Here, we sought to assess ibalizumab's antiviral breadth and potency and identify determinants of natural, pre-existing resistance. METHODS:: Ibalizumab's breadth and potency was assessed against a large, clinically relevant panel of HIV-1 pseudoviruses (n=116) commonly used to assess vaccine candidates. Determinants of resistance were assessed by sequence analysis. RESULTS:: Ibalizumab neutralized 92% and 66% of viruses as defined by 50% and 80% inhibition, respectively. Median in vitro neutralization potency by IC50 was 0.03 µg/mL, substantially lower than the broadly neutralizing mAbs, PG9 or VRC01. The dominant determinant of resistance was the absence of a potential N-linked glycosylation site (PNGS) at the V5 N-terminus (p<0.001), with the V2 loop length possibly influencing the degree of resistance afforded by the absence of the V5 N-terminal PNGS (p=0.001). Other significant independent correlates of resistance included PNGS at position 386 and the side chain length of residue 375. Ibalizumab exhibited complementary resistance to VRC01 (p=0.006) and sCD4 (p<0.001), in part mediated by the V5 PNGS. CONCLUSIONS:: Ibalizumab's breadth and potency compared favorably to broadly neutralizing anti-HIV-1 monoclonal antibodies, supporting the clinical development of ibalizumab, alone or in combination, for HIV-1 prevention.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 09/2012; 62(1). DOI:10.1097/QAI.0b013e3182732746 · 4.39 Impact Factor
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    ABSTRACT: Recently, more clinical trials are being conducted in Africa and Asia, therefore, background morbidity in the respective populations is of interest. Between 2000 and 2007, the International AIDS Vaccine Initiative sponsored 19 Phase 1 or 2A preventive HIV vaccine trials in the US, Europe, Sub-Saharan Africa and India, enrolling 900 healthy HIV-1 uninfected volunteers. To assess background morbidity as reflected by unsolicited adverse events (AEs), unrelated to study vaccine, reported in clinical trials from four continents. All but three clinical trials were double-blind, randomized, and placebo-controlled. Study procedures and data collection methods were standardized. The frequency and severity of AEs reported during the first year of the trials were analyzed. To avoid confounding by vaccine-related events, solicited reactogenicity and other AEs occurring within 28 d after any vaccination were excluded. In total, 2134 AEs were reported by 76% of all participants; 73% of all events were mild. The rate of AEs did not differ between placebo and vaccine recipients. Overall, the percentage of participants with any AE was higher in Africa (83%) compared with Europe (71%), US (74%) and India (65%), while the percentage of participants with AEs of moderate or greater severity was similar in all regions except India. In all regions, the most frequently reported AEs were infectious diseases, followed by gastrointestinal disorders. Despite some regional differences, in these healthy participants selected for low risk of HIV infection, background morbidity posed no obstacle to clinical trial conduct and interpretation. Data from controlled clinical trials of preventive interventions can offer valuable insights into the health of the eligible population.
    Human Vaccines & Immunotherapeutics 05/2012; 8(5):630-8. DOI:10.4161/hv.19454 · 3.64 Impact Factor
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    ABSTRACT: Using murine IgG subclass molecules (IgG1 or IgG2a) synthetically fused to HIV-1 or influenza test antigens, we explored the potential for IgG Fc scaffolds to augment immunogenicity. Each antigen (Ag) was grafted onto a hinge-Fc scaffold containing all critical residues necessary for interaction with effector cells, thus retaining effector functions of the native IgG subclass. We hypothesized that the differential affinity of FcγRs for specific IgG subclasses would influence the magnitude of immune responses elicited by immunization with an Ag-IgG Fc fusion vaccine. We demonstrate here that the antigen-specific humoral response elicited by Ag-IgG2a fusion vaccines is at least tenfold greater than that elicited by native antigen, that this response is superior to that elicited by Ag-IgG1, and that the augmented antigen-specific humoral response elicited is Fcγ receptor-dependent.
    Vaccine 11/2011; 30(1):42-50. DOI:10.1016/j.vaccine.2011.10.056 · 3.49 Impact Factor
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    ABSTRACT: Passive transfer of broadly neutralizing HIV antibodies can prevent infection, which suggests that vaccines that elicit such antibodies would be protective. Thus far, however, few broadly neutralizing HIV antibodies that occur naturally have been characterized. To determine whether these antibodies are part of a larger group of related molecules, we cloned 576 new HIV antibodies from four unrelated individuals. All four individuals produced expanded clones of potent broadly neutralizing CD4-binding-site antibodies that mimic binding to CD4. Despite extensive hypermutation, the new antibodies shared a consensus sequence of 68 immunoglobulin H (IgH) chain amino acids and arise independently from two related IgH genes. Comparison of the crystal structure of one of the antibodies to the broadly neutralizing antibody VRC01 revealed conservation of the contacts to the HIV spike.
    Science 08/2011; 333(6049):1633-7. DOI:10.1126/science.1207227 · 31.48 Impact Factor
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    ABSTRACT: DC-SIGN, a C-type lection expressed on dendritic cells, enhances HIV-1 infection in cis and in trans. HIV-1 circulating recombinant form (CRF) 07_BC viruses have been the predominant strain found among injection drug users in southern China and Taiwan. The goal of this study was to map the DC-SIGN-interactive domain on the gp120 of CRF07_BC. Pseudotyped viruses containing single (N233Q, N275Q, N330Q, N351Q, N355Q, N381Q, and N387Q), double (N233Q + N275Q, N233Q + N351Q, N275Q + N351Q), or triple (N233Q + N275Q + N351Q) N-glycan mutant gp120 were generated. Capture assays showed that the DC-SIGN-binding capacity of pseudoviruses with N275Q or N351Q decreased significantly. Rabbit antisera against synthetic peptides covering the N275 (R72 antiserum) or N351 (R77 antiserum) region blocked the interaction between wild-type gp120 and DC-SIGN in the capture assay. Furthermore, pseudotype viruses containing gp120 from five different CRF07_BC isolates were generated and R72 and R77 antisera blocked their interactions with DC-SIGN (80% for R72 and 40% for R77, respectively) in the capture assays. In conclusion, the N275 and N351 glycan sites on the CRF07_BC gp120 play an important role in mediating the interaction between gp120 and DC-SIGN. This information is valuable for developing both therapeutic and preventive agents for HIV-1 infection.
    AIDS research and human retroviruses 08/2011; 27(8):831-9. DOI:10.1089/AID.2010.0215 · 2.46 Impact Factor
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    ABSTRACT: DNA-based vaccines have been safe but weakly immunogenic in humans to date. We sought to determine the safety, tolerability, and immunogenicity of ADVAX, a multigenic HIV-1 DNA vaccine candidate, injected intramuscularly by in vivo electroporation (EP) in a Phase-1, double-blind, randomized placebo-controlled trial in healthy volunteers. Eight volunteers each received 0.2 mg, 1 mg, or 4 mg ADVAX or saline placebo via EP, or 4 mg ADVAX via standard intramuscular injection at weeks 0 and 8. A third vaccination was administered to eleven volunteers at week 36. EP was safe, well-tolerated and considered acceptable for a prophylactic vaccine. EP delivery of ADVAX increased the magnitude of HIV-1-specific cell mediated immunity by up to 70-fold over IM injection, as measured by gamma interferon ELISpot. The number of antigens to which the response was detected improved with EP and increasing dosage. Intracellular cytokine staining analysis of ELISpot responders revealed both CD4+ and CD8+ T cell responses, with co-secretion of multiple cytokines. This is the first demonstration in healthy volunteers that EP is safe, tolerable, and effective in improving the magnitude, breadth and durability of cellular immune responses to a DNA vaccine candidate. ClinicalTrials.gov NCT00545987.
    PLoS ONE 05/2011; 6(5):e19252. DOI:10.1371/journal.pone.0019252 · 3.53 Impact Factor
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    ABSTRACT: The central role of dendritic cell (DC) in mounting an immune response to a novel antigen is now well established. We sought to demonstrate the use of a particular vaccine strategy based on directing HIV-1 Gag proteins to DCs in conjunction with an activation signal. CD40L was expressed on the surface of virus-like particles (VLPs) to target HIV-1 Gag antigens to the CD40 receptor on DCs, whereas CD40L-CD40 interaction would also result in cellular activation. Multiple CD40L VLP constructs were made and evaluated in vitro and in vivo. Indeed, one VLP that expressed CD40L to the highest level showed greatest capacity to activate DCs in vitro. Correspondingly, this CD40L-VLP also proved to be most immunogenic in mice in raising both humoral and cellular responses to HIV-1 Gag. Confirmatory studies were performed to demonstrate the increased immunogenicity of CD40L-VLP is no longer observed when tested in CD40-/- mice. Our findings lend support to the belief that vaccine strategies that both target and activate DCs could yield a superior immune response.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2011; 56(5):393-400. DOI:10.1097/QAI.0b013e31820b844e · 4.39 Impact Factor
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    ABSTRACT: The rapid genetic drift of influenza virus hemagglutinin is an obstacle to vaccine efficacy. Previously, we found that the consensus hemagglutinin DNA vaccine (pCHA5) can only elicit moderate neutralization activities toward the H5N1 clade 2.1 and clade 2.3 viruses. Two approaches were thus taken to improve the protection broadness of CHA5. The first one was to include certain surface amino acids that are characteristic of clade 2.3 viruses to improve the protection profiles. When we immunized mice with CHA5 harboring individual mutations, the antibodies elicited by CHA5 containing P157S elicited higher neutralizing activity against the clade 2.3 viruses. Likewise, the viruses pseudotyped with hemagglutinin containing 157S became more susceptible to neutralization. The second approach was to update the consensus sequence with more recent H5N1 strains, generating a second-generation DNA vaccine pCHA5II. We showed that pCHA5II was able to elicit higher cross-neutralization activities against all H5N1 viruses. Comparison of the neutralization profiles of CHA5 and CHA5II, and the animal challenge studies, revealed that CHA5II induced the broadest protection profile. We concluded that CHA5II combined with electroporation delivery is a promising strategy to induce antibodies with broad cross-reactivities against divergent H5N1 influenza viruses.
    Proceedings of the National Academy of Sciences 02/2011; 108(9):3510-5. DOI:10.1073/pnas.1019744108 · 9.81 Impact Factor

Publication Stats

45k Citations
3,964.05 Total Impact Points

Institutions

  • 1997–2015
    • The Rockefeller University
      • Aaron Diamond AIDS Research Center (ADARC)
      New York, New York, United States
    • The Scripps Research Institute
      La Jolla, California, United States
    • State University of New York Downstate Medical Center
      • Department of Microbiology and Immunology
      Brooklyn, New York, United States
    • Centers for Disease Control and Prevention
      Атланта, Michigan, United States
  • 2011
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1991–2011
    • CUNY Graduate Center
      New York, New York, United States
    • Houston Zoo
      Houston, Texas, United States
  • 2008
    • Academia Sinica
      • Genomics Research Center
      Taipei, Taipei, Taiwan
  • 2007
    • Wuhan Institute Of Virology
      Wu-han-shih, Hubei, China
  • 2004
    • Columbia University
      • Division of Infectious Diseases
      New York, New York, United States
    • Queen Mary Hospital
      Hong Kong, Hong Kong
  • 1995–2004
    • Los Alamos National Laboratory
      • Theoretical Division
      Los Alamos, NM, United States
    • Nicosia General Hospital
      Lefkoşa, Lefkosia, Cyprus
    • Santa Fe Institute
      Santa Fe, New Mexico, United States
  • 2003
    • Weill Cornell Medical College
      • Department of Medicine
      New York City, New York, United States
    • Abbott Laboratories
      • Abbott Laboratories
      North Chicago, Illinois, United States
  • 2002
    • American Society of Hematology
      San Francisco, California, United States
  • 1998
    • Walter Reed Army Institute of Research
      Silver Spring, Maryland, United States
    • New York State
      New York City, New York, United States
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 1996
    • NCI-Frederick
      Фредерик, Maryland, United States
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands
  • 1991–1993
    • University of California, Los Angeles
      • • Division of Infectious Diseases
      • • Department of Medicine
      Los Ángeles, California, United States
  • 1992
    • New York Medical College
      New York, New York, United States
  • 1986–1991
    • Cedars-Sinai Medical Center
      • • Cedars Sinai Medical Center
      • • Department of Medicine
      • • Division of Infectious Diseases
      Los Angeles, CA, United States
  • 1989
    • University of Hawaiʻi at Mānoa
      • Department of Pediatrics
      Honolulu, HI, United States
  • 1986–1988
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1986–1987
    • Massachusetts General Hospital
      • • Pediatric Infectious Disease Unit
      • • Department of Neurology
      Boston, Massachusetts, United States