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Kensington, MD, United States

Bialuk I.,U.S. National Cancer Institute | Bialuk I.,Medical University of Bialystok | Whitney S.,Advanced BioScience Laboratories | Andresen V.,U.S. National Cancer Institute | And 14 more authors.
Vaccine | Year: 2011

The role of antibodies directed against the hyper variable envelope region V1 of human immunodeficiency virus type 1 (HIV-1), has not been thoroughly studied. We show that a vaccine able to elicit strain-specific non-neutralizing antibodies to this region of gp120 is associated with control of highly pathogenic chimeric SHIV 89.6P replication in rhesus macaques. The vaccinated animal that had the highest titers of antibodies to the amino terminus portion of V1, prior to challenge, had secondary antibody responses that mediated cell killing by antibody-dependent cellular cytotoxicity (ADCC), as early as 2 weeks after infection and inhibited viral replication by antibody-dependent cell-mediated virus inhibition (ADCVI), by 4 weeks after infection. There was a significant inverse correlation between virus level and binding antibody titers to the envelope protein, (R = -0.83, p = 0.015), and ADCVI (R = -0.84 p = 0.044). Genotyping of plasma virus demonstrated in vivo selection of three SHIV 89.6P variants with changes in potential N-linked glycosylation sites in V1. We found a significant inverse correlation between virus levels and titers of antibodies that mediated ADCVI against all the identified V1 virus variants. A significant inverse correlation was also found between neutralizing antibody titers to SHIV89.6 and virus levels (R = -0.72 p = 0.0050). However, passive inoculation of purified immunoglobulin from animal M316, the macaque that best controlled virus, to a naïve macaque, resulted in a low serum neutralizing antibodies and low ADCVI activity that failed to protect from SHIV 89.6P challenge. Collectively, while our data suggest that anti-envelope antibodies with neutralizing and non-neutralizing Fc(R-dependent activities may be important in the control of SHIV replication, they also demonstrate that low levels of these antibodies alone are not sufficient to protect from infection. Source

Lagenaur L.A.,U.S. National Institutes of Health | Lagenaur L.A.,Osel, Inc. | Sanders-Beer B.E.,Bioqual | Brichacek B.,U.S. National Institutes of Health | And 7 more authors.
Mucosal Immunology | Year: 2011

Most human immunodeficiency virus (HIV) transmissions in women occur through the cervicovaginal mucosa, which is coated by a bacterial biofilm including Lactobacillus. This commensal bacterium has a role in maintaining a healthy mucosa and can be genetically engineered to produce antiviral peptides. Here, we report a 63% reduction in transmission of a chimeric simian/HIV (SHIV SF162P3) after repeated vaginal challenges of macaques treated with Lactobacillus jensenii expressing the HIV-1 entry inhibitor cyanovirin-N. Furthermore, peak viral loads in colonized macaques with breakthrough infection were reduced sixfold. Colonization and prolonged antiviral protein secretion by the genetically engineered lactobacilli did not cause any increase in proinflammatory markers. These findings lay the foundation for an accessible and durable approach to reduce heterosexual transmission of HIV in women, which is coitally independent, inexpensive, and enhances the natural protective effects of the vaginal microflora. Source

Gordon S.N.,NCI Inc | Cecchinato V.,NCI Inc | Andresen V.,NCI Inc | Heraud J.-M.,World Health Organization | And 15 more authors.
Journal of Infectious Diseases | Year: 2011

The licensed smallpox vaccine, ACAM2000, is a cell culture derivative of Dryvax. Both ACAM2000 and Dryvax are administered by skin scarification and can cause progressive vaccinia, with skin lesions that disseminate to distal sites. We have investigated the immunologic basis of the containment of vaccinia in the skin with the goal to identify safer vaccines for smallpox. Macaques were depleted systemically of T or B cells and vaccinated with either Dryvax or an attenuated vaccinia vaccine, LC16m8. B cell depletion did not affect the size of skin lesions induced by either vaccine. However, while depletion of both CD4+ and CD8+ T cells had no adverse effects on LC16m8-vaccinated animals, it caused progressive vaccinia in macaques immunized with Dryvax. As both Dryvax and LC16m8 vaccines protect healthy macaques from a lethal monkeypox intravenous challenge, our data identify LC16m8 as a safer and effective alternative to ACAM2000 and Dryvax vaccines for immunocompromised individuals. Source

Fouts T.R.,Profectus Biosciences, Inc. | Bagley K.,Profectus Biosciences, Inc. | Prado I.J.,Profectus Biosciences, Inc. | Bobb K.L.,Profectus Biosciences, Inc. | And 18 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

A guiding principle for HIV vaccine design has been that cellular and humoral immunity work together to provide the strongest degree of efficacy. However, three efficacy trials of Ad5-vectored HIV vaccines showed no protection. Transmission was increased in two of the trials, suggesting that this vaccine strategy elicited CD4+ T-cell responses that provide more targets for infection, attenuating protection or increasing transmission. The degree to which this problem extends to other HIV vaccine candidates is not known. Here, we show that a gp120-CD4 chimeric subunit protein vaccine (full-length single chain) elicits heterologous protection against simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) acquisition in three independent rhesus macaque repeated low-dose rectal challenge studies with SHIV162P3 or SIVmac251. Protection against acquisition was observed with multiple formulations and challenges. In each study, protection correlated with antibody-dependent cellular cytotoxicity specific for CD4-induced epitopes, provided that the concurrent antivaccine T-cell responses were minimal. Protection was lost in instances when T-cell responses were high or when the requisite antibody titers had declined. Our studies suggest that balance between a protective antibody response and antigen-specific T-cell activation is the critical element to vaccine-mediated protection against HIV. Achieving and sustaining such a balance, while enhancing antibody durability, is the major challenge for HIV vaccine development, regardless of the immunogen or vaccine formulation. Source

Menon V.,Advanced BioScience Laboratories | Sneha Priya R.,Indian Institute of Technology Madras | Labranche C.,Duke University | Montefiori D.,Duke University | And 3 more authors.
Journal of Medical Primatology | Year: 2015

Background: Recent preclinical studies have demonstrated the use of properly folded trimeric HIV-1 envelope proteins as immunogen for eliciting protecting immune response in macaques. Methods: Trimeric gp145 protein of Indian clade C HIV-1 (93IN101) was characterized for antigenicity by evaluating its binding to sCD4, and several monoclonal antibodies to HIV-1 by bio-layer interferometry. Ten macaques were immunized four times with purified gp145 in adjuplex adjuvant, and serum antibodies were characterized for binding to gp145 and neutralization. Immunized macaques were subjected to weekly low-dose vaginal challenge with SHIV1157-ipEL-p for 8 weeks. Results: Env protein elicited strong antibody response in macaques. Following challenge, seven of ten immunized macaques resisted challenge, while six of eight control animals were infected. Conclusions: Env proteins from a clade C Indian isolate can elicit protective immune response and therefore may be a candidate for inclusion in a multiclade-based HIV-1 vaccine. © 2015 John Wiley & Sons A/S. Source

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