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152. A comparative immunological assessment of multiple clinical-stage adjuvants for the R21 malaria vaccine in nonhuman primates

Author

Arunachalam, Prabhu S., Ha, NaYoung, Dennison, S. Moses, Spreng, Rachel L., Seaton, Kelly E., Xiao, Peng, Feng, Yupeng, Zarnitsyna, Veronika I., Kazmin, Dmitri, Hu, Mengyun, Santagata, Jordan M., Xie, Xia, Rogers, Kenneth, Shirreff, Lisa M., Chottin, Claire, Spencer, Alexandra J., Dutta, Sheetij, Prieto, Katherine, Julien, Jean-Philippe, Tomai, Mark, Fox, Christopher B., Villinger, Francois, Hill, Adrian V. S., Tomaras, Georgia D., and Pulendran, Bali

Published
2024
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154. Simian Immunodeficiency Virus Susceptibility, Immunology, and Microbiome in the Female Genital Tract of Adolescent Versus Adult Pigtail Macaques.

Author

Berard, Alicia R., Miller, Charlene, Araínga, Mariluz, Broedlow, Courtney Ann, Noël-Romas, Laura, Schifanella, Luca, Hensley-McBain, Tiffany, Roederer, Alex, Driscoll, Connor B., Coronado, Ernesto, Manuzak, Jennifer, McKinnon, Lyle R., Villinger, Francois, Hope, Thomas J., Burgener, Adam D., and Klatt, Nichole R.

Abstract

In Sub-Saharan Africa, young women 15–24 years of age account for nearly 30% of all new HIV infections, however, biological and epidemiological factors underlying this disproportionate infection rate are unclear. In this study, we assessed biological contributors of SIV/HIV susceptibility in the female genital tract (FGT) using adolescent (n = 9) and adult (n = 10) pigtail macaques (PTMs) with weekly low-dose intravaginal challenges of SIV. Immunological variables were captured in vaginal tissue of PTMs by flow cytometry and cytokine assays. Vaginal biopsies were profiled by proteomic analysis. The vaginal microbiome was assessed by 16S rRNA sequencing. We were powered to detect a 2.2-fold increase in infection rates between age groups, however, we identified no significant differences in susceptibility. This model cannot capture epidemiological factors or may not best represent biological differences of HIV susceptibility. No immune cell subsets measured were significantly different between groups. Inflammatory marker MCP-1 was significantly higher (adj p = .02), and sCD40L trended higher (adj p = .06) in vaginal cytobrushes of adults. Proteomic analysis of vaginal biopsies showed no significant (adj p < .05) protein or pathway differences between groups. Vaginal microbiomes were not significantly different between groups. No differences were observed between age groups in this PTM model, however, these animals may not reflect biological factors contributing to HIV risk such as those found in their human counterparts. This model is therefore not appropriate to explore human adolescent differences in HIV risk. Young women remain a key population at risk for HIV infection, and there is still a need for comprehensive assessment and intervention strategies for epidemic control of this uniquely vulnerable population. [ABSTRACT FROM AUTHOR]

Published
2021
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155. Idiopathic chronic diarrhea associated with dysbiosis in a captive cynomolgus macaque ( Macaca fascicularis )

Author

Koo, Bon‐Sang, primary, Baek, Seung Ho, additional, Kim, Green, additional, Hwang, Eun‐ha, additional, Oh, Hanseul, additional, Son, Yeonghoon, additional, Lim, Kyung Seob, additional, Kang, Philyong, additional, Lee, Hwal‐Yong, additional, Jeong, Kang‐Jin, additional, Kim, Young‐Hyun, additional, Villinger, Francois, additional, and Hong, Jung‐Joo, additional

Published
2019
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158. Abstract 4972: Preclinical development of a first-in-class NKp30xBCMA NK cell engager for the treatment of multiple myeloma

Author

Draghi, Monia, primary, Schafer, Jamie L., additional, Nelson, Allison, additional, Frye, Zach, additional, Oliphant, Amanda, additional, Haserlat, Sara, additional, Lajoie, jason, additional, rogers, Kenneth, additional, Villinger, Francois, additional, Schmidt, Michael, additional, Tighe, Robert, additional, Bobrowicz, Piotr, additional, Watkins-Yoon, Jennifer, additional, and Schuetz, Thomas, additional

Published
2019
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159. Divergent HIV-1-Directed Immune Responses Generated by Systemic and Mucosal Immunization with Replicating Single-Cycle Adenoviruses in Rhesus Macaques

Author

Matchett, William E., primary, Anguiano-Zarate, Stephanie S., additional, Nehete, Pramod N., additional, Shelton, Kathryn, additional, Nehete, Bharti P., additional, Yang, Guojun, additional, Dorta-Estremera, Stephanie, additional, Barnette, Philip, additional, Xiao, Peng, additional, Byrareddy, Siddappa N., additional, Villinger, Francois, additional, Hessell, Ann J., additional, Haigwood, Nancy L., additional, Sastry, K. Jagannadha, additional, and Barry, Michael A., additional

Published
2019
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160. Delayed vaginal SHIV infection in VRC01 and anti-α4β7 treated rhesus macaques

Author

Calenda, Giulia, primary, Frank, Ines, additional, Arrode-Brusés, Géraldine, additional, Pegu, Amarendra, additional, Wang, Keyun, additional, Arthos, James, additional, Cicala, Claudia, additional, Rogers, Kenneth A., additional, Shirreff, Lisa, additional, Grasperge, Brooke, additional, Blanchard, James L., additional, Maldonado, Stephanie, additional, Roberts, Kevin, additional, Gettie, Agegnehu, additional, Villinger, Francois, additional, Fauci, Anthony S., additional, Mascola, John R., additional, and Martinelli, Elena, additional

Published
2019
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161. Development of rectal enema as microbicide (DREAM): Preclinical progressive selection of a tenofovir prodrug enema

Author

Hoang, Thuy, primary, Date, Abhijit A., additional, Ortiz, Jairo Ortiz, additional, Young, Ting-Wei, additional, Bensouda, Sabrine, additional, Xiao, Peng, additional, Marzinke, Mark, additional, Rohan, Lisa, additional, Fuchs, Edward J., additional, Hendrix, Craig, additional, Gumber, Sanjeev, additional, Villinger, Francois, additional, Cone, Richard A., additional, Hanes, Justin, additional, and Ensign, Laura M., additional

Published
2019
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163. Characterization of antibodies elicited by XMRV infection and development of immunoassays useful for epidemiologic studies

Author

Qiu Xiaoxing, Swanson Priscilla, Luk Ka-Cheung, Tu Bailin, Villinger Francois, Das Gupta Jaydip, Silverman Robert H, Klein Eric A, Devare Sushil, Schochetman Gerald, and Hackett John

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background Xenotropic Murine Leukemia Virus-related Virus (XMRV) is a human gammaretrovirus recently identified in prostate cancer tissue and in lymphocytes of patients with chronic fatigue syndrome. To establish the etiologic role of XMRV infection in human disease requires large scale epidemiologic studies. Development of assays to detect XMRV-specific antibodies would greatly facilitate such studies. However, the nature and kinetics of the antibody response to XMRV infection have yet to be determined. Results Three rhesus macaques were infected with XMRV to determine the dynamics of the antibody responses elicited by infection with XMRV. All macaques developed antibodies to XMRV during the second week of infection, and the predominant responses were to the envelope protein gp70, transmembrane protein p15E, and capsid protein p30. In general, antibody responses to gp70 and p15E appeared early with higher titers than to p30, especially in the early period of seroconversion. Antibodies to gp70, p15E and p30 persisted to 158 days and were substantially boosted by re-infection, thus, were identified as useful serologic markers. Three high-throughput prototype assays were developed using recombinant proteins to detect antibodies to these viral proteins. Both gp70 and p15E prototype assays demonstrated 100% sensitivity by detecting all Western blot (WB) positive serial bleeds from the XMRV-infected macaques and good specificity (99.5-99.9%) with blood donors. Seroconversion sensitivity and specificity of the p30 prototype assay were 92% and 99.4% respectively. Conclusions This study provides the first demonstration of seroconversion patterns elicited by XMRV infection. The nature and kinetics of antibody responses to XMRV in primates were fully characterized. Moreover, key serologic markers useful for detection of XMRV infection were identified. Three prototype immunoassays were developed to detect XMRV-specific antibodies. These assays demonstrated good sensitivity and specificity; thus, they will facilitate large scale epidemiologic studies of XMRV infection in humans.

Published
2010
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171. Heavy Elements Revealed in Jejunum of Simian Immunodeficiency Virus Infected Monkeys by Microparticle Induced X‐Ray Emission.

Author

Whitlow, Harry J., Deoli, Naresh T., de Vera, Armin, Morgan, Karen, and Villinger, Francois

Subjects
SIMIAN immunodeficiency virus, HEAVY elements, MACAQUES, SIMIAN viruses, JEJUNUM, X-rays, RHESUS monkeys
Abstract

Archived jejunum tissue block specimens from control and simian immunodeficiency virus‐infected rhesus macaques are characterized using particle‐induced X‐ray emission (PIXE) in a MeV ion microprobe with 2 MeV protons. The results show considerable variance in the concentration of some elements (Ti, Mn, and Fe) between viremic and control tissue. Ti, Mn, and Fe are present at levels 50‐fold lower in samples from viremic versus control monkeys, a difference markedly higher than previously reported for infections. Pb and Ti are observed particularly in the crypts of both viremic and control jejunum samples. This is likely to be caused by ingestion of paint fragments picked from the cages used to house the animals. [ABSTRACT FROM AUTHOR]

Published
2021
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174. Idiopathic chronic diarrhea associated with dysbiosis in a captive cynomolgus macaque (Macaca fascicularis).

Author

Koo, Bon‐Sang, Baek, Seung Ho, Kim, Green, Hwang, Eun‐ha, Oh, Hanseul, Son, Yeonghoon, Lim, Kyung Seob, Kang, Philyong, Lee, Hwal‐Yong, Jeong, Kang‐Jin, Kim, Young‐Hyun, Villinger, Francois, and Hong, Jung‐Joo

Subjects
KRA, MACAQUES, DIARRHEA, INFLAMMATORY bowel diseases
Abstract

Chronic inflammatory enteric diseases occur commonly in humans and animals, especially in captive bred macaques. However, information about the etiology of idiopathic chronic inflammatory diarrhea in cynomolgus monkeys is limited. In this paper, we reported the unusual case of idiopathic chronic diarrhea in a captive cynomolgus monkey based on microbial, imaging, and microbiome examinations. [ABSTRACT FROM AUTHOR]

Published
2020
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176. MAdCAM costimulation through Integrin-α4β7 promotes HIV replication

Author

Nawaz, Fatima, primary, Goes, Livia R., additional, Ray, Jocelyn C., additional, Olowojesiku, Ronke, additional, Sajani, Alia, additional, Ansari, Aftab A., additional, Perrone, Ian, additional, Hiatt, Joseph, additional, Van Ryk, Donald, additional, Wei, Danlan, additional, Waliszewski, Mia, additional, Soares, Marcelo A., additional, Jelicic, Katija, additional, Connors, Mark, additional, Migueles, Stephen A., additional, Martinelli, Elena, additional, Villinger, Francois, additional, Cicala, Claudia, additional, Fauci, Anthony S., additional, and Arthos, James, additional

Published
2018
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177. Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection

Author

Xiao, Peng, primary, Gumber, Sanjeev, additional, Marzinke, Mark A., additional, Date, Abhijit A., additional, Hoang, Thuy, additional, Hanes, Justin, additional, Ensign, Laura M., additional, Wang, Lin, additional, Rohan, Lisa, additional, Fuchs, Edward J., additional, Hendrix, Craig, additional, and Villinger, Francois, additional

Published
2018
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178. FDC:TFH Interactions within Cervical Lymph Nodes of SIV-Infected Rhesus Macaques

Author

Dave, Rajnish S., primary, Sharma, Ravi K., additional, Muir, Roshell R., additional, Haddad, Elias, additional, Gumber, Sanjeev, additional, Villinger, Francois, additional, Nehra, Artinder P., additional, Khan, Zafar K., additional, Wigdahl, Brian, additional, Ansari, Aftab A., additional, Byrareddy, Siddappa N., additional, and Jain, Pooja, additional

Published
2017
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180. Inhibition of HIV-1 infectivity by zinc-ejecting aromatic C-nitroso compounds

Author

Rice, William G., Schaeffer, Catherine A., Harten, Brad, Villinger, Francois, South, Terri L., Summers, Michael F., Henderson, Louis E., Bess, Julian W., Jr., Arthur, Larry O., McDougall, J. Steven, Orloff, Sherry L., Mendeleyev, Jerome, and Kun, Ernest

Subjects
HIV infection -- Drug therapy, AIDS (Disease) -- Drug therapy, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Two C-nitroso aromatic compounds hinder the ability of the HIV-1 virus to infect human lymphocytes. The two compounds are 3-nitrosobenzamide and 6-nitroso-1,2-benzopyrone. The compounds also eject zinc from HIV-1 virions which are intact and from nucleocapsid zinc fingers of HIV-1 which are isolated. This suggests a new kind of drug therapy for the AIDS disease by attacking the zinc fingers of the retrovirus.

Published
1993

181. Induction of Th1 biased Tfh (Tfh1 cells) in lymphoid tissues during chronic SIV infection defines functionally distinct germinal center Tfh cells

Author

Velu, Vijayakumar, Mylvaganam, Geetha Hanna, Gangadhara, Sailaja, Hong, Jung Joo, Iyer, Smita S., Gumber, Sanjeev, Ibegbu, Chris C., Villinger, Francois, and Amara, Rama Rao

Subjects
Receptors, CCR6, Receptors, CXCR5, B-Lymphocytes, Receptors, CCR4, Receptors, CXCR3, Lymphoid Tissue, Interleukins, CD40 Ligand, Simian Acquired Immunodeficiency Syndrome, hemic and immune systems, chemical and pharmacologic phenomena, T-Lymphocytes, Helper-Inducer, Th1 Cells, Germinal Center, Macaca mulatta, Article, stomatognathic diseases, Interferon-gamma, stomatognathic system, Hypergammaglobulinemia, Immunoglobulin G, Animals, Female, Simian Immunodeficiency Virus
Abstract

Chronic HIV infection is associated with accumulation of germinal center (GC) T follicular helper (Tfh) cells in the lymphoid tissue. The GC Tfh cells can be heterogeneous based on the expression of chemokine receptors associated with T helper lineages, such as CXCR3 (Th1), CCR4 (Th2), and CCR6 (Th17). However, the heterogeneous nature of GC Tfh cells in the lymphoid tissue and its association with viral persistence and Ab production during chronic SIV/HIV infection are not known. To address this, we characterized the expression of CXCR3, CCR4, and CCR6 on GC Tfh cells in lymph nodes following SIVmac251 infection in rhesus macaques. In SIV-naive rhesus macaques, only a small fraction of GC Tfh cells expressed CXCR3, CCR4, and CCR6. However, during chronic SIV infection, the majority of GC Tfh cells expressed CXCR3, whereas the proportion of CCR4(+) cells did not change, and CCR6(+) cells decreased. CXCR3(+), but not CXCR3(-), GC Tfh cells produced IFN-γ (Th1 cytokine) and IL-21 (Tfh cytokine), whereas both subsets expressed CD40L following stimulation. Immunohistochemistry analysis demonstrated an accumulation of CD4(+)IFN-γ(+) T cells within the hyperplastic follicles during chronic SIV infection. CXCR3(+) GC Tfh cells also expressed higher levels of ICOS, CCR5, and α4β7 and contained more copies of SIV DNA compared with CXCR3(-) GC Tfh cells. However, CXCR3(+) and CXCR3(-) GC Tfh cells delivered help to B cells in vitro for production of IgG. These data demonstrate that chronic SIV infection promotes expansion of Th1-biased GC Tfh cells, which are phenotypically and functionally distinct from conventional GC Tfh cells and contribute to hypergammaglobulinemia and viral reservoirs.

Published
2016

184. Pharmacokinetics and Preliminary Safety of Pod-Intravaginal Rings Delivering the Monoclonal Antibody VRC01-N for HIV Prophylaxis in a Macaque Model

Author

Zhao, Chunxia, primary, Gunawardana, Manjula, additional, Villinger, Francois, additional, Baum, Marc M., additional, Remedios-Chan, Mariana, additional, Moench, Thomas R., additional, Zeitlin, Larry, additional, Whaley, Kevin J., additional, Bohorov, Ognian, additional, Smith, Thomas J., additional, Anderson, Deborah J., additional, and Moss, John A., additional

Published
2017
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185. Simian Immunodeficiency Virus Targeting of CXCR3 + CD4 + T Cells in Secondary Lymphoid Organs Is Associated with Robust CXCL10 Expression in Monocyte/Macrophage Subsets

Author

Fujino, Masayuki, primary, Sato, Hirotaka, additional, Okamura, Tomotaka, additional, Uda, Akihiko, additional, Takeda, Satoshi, additional, Ahmed, Nursarat, additional, Shichino, Shigeyuki, additional, Shiino, Teiichiro, additional, Saito, Yohei, additional, Watanabe, Satoru, additional, Sugimoto, Chie, additional, Kuroda, Marcelo J., additional, Ato, Manabu, additional, Nagai, Yoshiyuki, additional, Izumo, Shuji, additional, Matsushima, Kouji, additional, Miyazawa, Masaaki, additional, Ansari, Aftab A., additional, Villinger, Francois, additional, and Mori, Kazuyasu, additional

Published
2017
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187. Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques

Author

Kasturi, Sudhir Pai, primary, Kozlowski, Pamela A., additional, Nakaya, Helder I., additional, Burger, Matheus C., additional, Russo, Pedro, additional, Pham, Mathew, additional, Kovalenkov, Yevgeniy, additional, Silveira, Eduardo L. V., additional, Havenar-Daughton, Colin, additional, Burton, Samantha L., additional, Kilgore, Katie M., additional, Johnson, Mathew J., additional, Nabi, Rafiq, additional, Legere, Traci, additional, Sher, Zarpheen Jinnah, additional, Chen, Xuemin, additional, Amara, Rama R., additional, Hunter, Eric, additional, Bosinger, Steven E., additional, Spearman, Paul, additional, Crotty, Shane, additional, Villinger, Francois, additional, Derdeyn, Cynthia A., additional, Wrammert, Jens, additional, and Pulendran, Bali, additional

Published
2017
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189. In vivo blockade of the PD-1 pathway using soluble rPD-1-Fc enhances CD4+ and CD8+ T cell responses but has limited clinical benefit

Author

Amancha, Praveen K., Hong, Jung Joo, Rogers, Kenneth, Ansari, Aftab A., and Villinger, Francois

Subjects
CD4-Positive T-Lymphocytes, Programmed Cell Death 1 Receptor, Drug Evaluation, Preclinical, Organophosphonates, Simian Acquired Immunodeficiency Syndrome, Apoptosis, CD8-Positive T-Lymphocytes, Article, Animals, Emtricitabine, Viremia, Tenofovir, Immunity, Cellular, Lymphokines, Zalcitabine, Adenine, Histocompatibility Antigens Class I, Antibodies, Monoclonal, Combined Modality Therapy, Macaca mulatta, Recombinant Proteins, Immunoglobulin Fc Fragments, Anti-Retroviral Agents, Solubility, RNA, Viral, Simian Immunodeficiency Virus, Immunotherapy
Abstract

The programmed cell death-1 (PD-1)/programmed cell death ligand-1 pathway has been shown to limit cell-mediated effector functions during chronic viral infections impeding clearance of pathogens. As a strategy to reverse this exhaustion and increase T cell polyfunctionality, PD-1 ligands were blocked in vivo using a recombinant macaque PD-1 fused to a macaque Ig-Fc (rPD-1-Fc) in SIVmac239-infected rhesus macaques during the early chronic phase of infection, either alone or in combination with antiretroviral therapy. In vitro blockade showed improvement of Ag-specific CD4(+) and CD8(+) T cells from monkeys chronically infected with SIV. Of note, a prolonged 5-d blockade in culture was beneficial for both gag-specific CD4(+) and CD8(+) T cells based on proliferation and dual cytokine production. Although the in vivo administration of rPD-1-Fc induced enhanced SIV-specific CD4 and CD8 T cell proliferation both in the blood and gut, it failed to alter plasma viremia. However, rPD-1-Fc administration in the context of antiretroviral therapy interruption induced a significant delay of viral load rebound. In addition, rPD-1-Fc administration in MamuA*001(+) monkeys led to both an increase in the frequencies and Ki67 expression of GagCM9(+) CD8(+) T cells in the blood and rectal mucosa and polyfunctionality of GagCM9(+) CD8(+) T cells in blood. In conclusion, however, our data suggest that PD-1/programmed cell death ligand-1 blockade using soluble rPD-1-Fc instead of anti-PD-1 mAb, although effective in rescuing the effector function of SIV-specific CD4(+) and CD8(+) T cells during the early chronic phase of infection, has limited clinical benefit.

Published
2013

190. Sustained virologic control in SIV + macaques after antiretroviral and α 4 β 7 antibody therapy

Author

Byrareddy, Siddappa N., primary, Arthos, James, additional, Cicala, Claudia, additional, Villinger, Francois, additional, Ortiz, Kristina T., additional, Little, Dawn, additional, Sidell, Neil, additional, Kane, Maureen A., additional, Yu, Jianshi, additional, Jones, Jace W., additional, Santangelo, Philip J., additional, Zurla, Chiara, additional, McKinnon, Lyle R., additional, Arnold, Kelly B., additional, Woody, Caroline E., additional, Walter, Lutz, additional, Roos, Christian, additional, Noll, Angela, additional, Van Ryk, Donald, additional, Jelicic, Katija, additional, Cimbro, Raffaello, additional, Gumber, Sanjeev, additional, Reid, Michelle D., additional, Adsay, Volkan, additional, Amancha, Praveen K., additional, Mayne, Ann E., additional, Parslow, Tristram G., additional, Fauci, Anthony S., additional, and Ansari, Aftab A., additional

Published
2016
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195. 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015).

Author

Pate, Kelly Metcalf, Pate, Kelly Metcalf, Pohlmeyer, Chris, Walker-Sperling, Victoria, Foote, Jeremy, Najarro, Kevin, Cryer, Catherine, Salgado, Maria, Gama, Lucio, Engle, Elizabeth, Shirk, Erin, Queen, Suzanne, Chioma, Stanley, Vermillion, Meghan, Bullock, Brandon, Li, Ming, Lyons, Claire, Adams, Robert, Zink, Chris, Clements, Janice, Mankowski, Joseph, Blankson, Joel, Micci, Luca, Ryan, Emily, Fromentin, Rémi, Benne, Clarisse, Chomont, Nicolas, Lifson, Jeffrey, Paiardini, Mirko, Lee, Sulggi, Fromentin, Remi, Silicano, Robert, Silicano, Janet, Richman, Douglas, O'Doherty, Una, Palmer, Sarah, Burbelo, Peter, Deeks, Steven, Ghneim, Khader, Ahlers, Jeff, Fourati, Slim, Shive, Carey, Cameron, Mark, Mukerjee, Pranab, Ghannoum, Mahmoud, Rodriguez, Benigno, Lederman, Michael, Sekaly, Rafick, Frange, Pierre, Faye, Albert, Avettand-Fenoel, Veronique, Bellaton, Erainna, Deschamps, Diane, Angin, Mathieu, Caillat-Zucman, Sophie, Peytavin, Gilles, Le Chenadec, Jerome, Warszawski, Josiane, Rouzioux, Christine, Saez-Cirion, Asier, Chang, Christina, Cameron, Paul, Elliott, Julian, Perelson, Alan, Roche, Michael, Dantanarayana, Ashanti, Solomon, Ajantha, Naranbhai, Vivek, Tenakoon, Surekha, Hoh, Rebecca, McMahon, James, Sikaris, Ken, Hartogensis, Wendy, Bacchetti, Peter, Hecht, Frederick, Deeks, Steve, Lewin, Sharon, Byrareddy, Siddappa, Arthos, James, Cicala, Claudia, Reimann, Keith, Parslow, Tristram, Santangelo, Philip, Villinger, Francois, Fauci, Anthony, Ansari, Aftab, George, Michael, Weiser, Barbara, Burger, Harold, Lewy, Tyler, Anastos, Kathryn, Asmuth, David, Somsouk, Ma, Hunt, Peter, Min, Zhong, Miller, Christopher, Li, Xiao Dong, Hinkle, John, Pate, Kelly Metcalf, Pate, Kelly Metcalf, Pohlmeyer, Chris, Walker-Sperling, Victoria, Foote, Jeremy, Najarro, Kevin, Cryer, Catherine, Salgado, Maria, Gama, Lucio, Engle, Elizabeth, Shirk, Erin, Queen, Suzanne, Chioma, Stanley, Vermillion, Meghan, Bullock, Brandon, Li, Ming, Lyons, Claire, Adams, Robert, Zink, Chris, Clements, Janice, Mankowski, Joseph, Blankson, Joel, Micci, Luca, Ryan, Emily, Fromentin, Rémi, Benne, Clarisse, Chomont, Nicolas, Lifson, Jeffrey, Paiardini, Mirko, Lee, Sulggi, Fromentin, Remi, Silicano, Robert, Silicano, Janet, Richman, Douglas, O'Doherty, Una, Palmer, Sarah, Burbelo, Peter, Deeks, Steven, Ghneim, Khader, Ahlers, Jeff, Fourati, Slim, Shive, Carey, Cameron, Mark, Mukerjee, Pranab, Ghannoum, Mahmoud, Rodriguez, Benigno, Lederman, Michael, Sekaly, Rafick, Frange, Pierre, Faye, Albert, Avettand-Fenoel, Veronique, Bellaton, Erainna, Deschamps, Diane, Angin, Mathieu, Caillat-Zucman, Sophie, Peytavin, Gilles, Le Chenadec, Jerome, Warszawski, Josiane, Rouzioux, Christine, Saez-Cirion, Asier, Chang, Christina, Cameron, Paul, Elliott, Julian, Perelson, Alan, Roche, Michael, Dantanarayana, Ashanti, Solomon, Ajantha, Naranbhai, Vivek, Tenakoon, Surekha, Hoh, Rebecca, McMahon, James, Sikaris, Ken, Hartogensis, Wendy, Bacchetti, Peter, Hecht, Frederick, Deeks, Steve, Lewin, Sharon, Byrareddy, Siddappa, Arthos, James, Cicala, Claudia, Reimann, Keith, Parslow, Tristram, Santangelo, Philip, Villinger, Francois, Fauci, Anthony, Ansari, Aftab, George, Michael, Weiser, Barbara, Burger, Harold, Lewy, Tyler, Anastos, Kathryn, Asmuth, David, Somsouk, Ma, Hunt, Peter, Min, Zhong, Miller, Christopher, Li, Xiao Dong, and Hinkle, John

Published
2015

196. Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: complete protection of rhesus monkeys from mucosal SHIV challenge.

Author

Sholukh, Anton M, Sholukh, Anton M, Watkins, Jennifer D, Vyas, Hemant K, Gupta, Sandeep, Lakhashe, Samir K, Thorat, Swati, Zhou, Mingkui, Hemashettar, Girish, Bachler, Barbara C, Forthal, Donald N, Villinger, Francois, Sattentau, Quentin J, Weiss, Robin A, Agatic, Gloria, Corti, Davide, Lanzavecchia, Antonio, Heeney, Jonathan L, Ruprecht, Ruth M, Sholukh, Anton M, Sholukh, Anton M, Watkins, Jennifer D, Vyas, Hemant K, Gupta, Sandeep, Lakhashe, Samir K, Thorat, Swati, Zhou, Mingkui, Hemashettar, Girish, Bachler, Barbara C, Forthal, Donald N, Villinger, Francois, Sattentau, Quentin J, Weiss, Robin A, Agatic, Gloria, Corti, Davide, Lanzavecchia, Antonio, Heeney, Jonathan L, and Ruprecht, Ruth M

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.

Published
2015

197. SIV/SHIV Infection Triggers Vascular Inflammation, Diminished Expression of Krüppel-like Factor 2 and Endothelial Dysfunction

Author

Panigrahi, Soumya, primary, Freeman, Michael L., additional, Funderburg, Nicholas T., additional, Mudd, Joseph C., additional, Younes, Souheil A., additional, Sieg, Scott F., additional, Zidar, David A., additional, Paiardini, Mirko, additional, Villinger, Francois, additional, Calabrese, Leonard H., additional, Ransohoff, Richard M., additional, Jain, Mukesh K., additional, and Lederman, Michael M., additional

Published
2015
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198. Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques

Author

Micci, Luca, primary, Ryan, Emily S., additional, Fromentin, Rémi, additional, Bosinger, Steven E., additional, Harper, Justin L., additional, He, Tianyu, additional, Paganini, Sara, additional, Easley, Kirk A., additional, Chahroudi, Ann, additional, Benne, Clarisse, additional, Gumber, Sanjeev, additional, McGary, Colleen S., additional, Rogers, Kenneth A., additional, Deleage, Claire, additional, Lucero, Carissa, additional, Byrareddy, Siddappa N., additional, Apetrei, Cristian, additional, Estes, Jacob D., additional, Lifson, Jeffrey D., additional, Piatak, Michael, additional, Chomont, Nicolas, additional, Villinger, Francois, additional, Silvestri, Guido, additional, Brenchley, Jason M., additional, and Paiardini, Mirko, additional

Published
2015
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199. MAdCAM costimulation through Integrin-α4β7 promotes HIV replication.

Author

Nawaz, Fatima, Goes, Livia R., Ray, Jocelyn C., Olowojesiku, Ronke, Sajani, Alia, Ansari, Aftab A., Perrone, Ian, Hiatt, Joseph, Van Ryk, Donald, Wei, Danlan, Waliszewski, Mia, Soares, Marcelo A., Jelicic, Katija, Connors, Mark, Migueles, Stephen A., Martinelli, Elena, Villinger, Francois, Cicala, Claudia, Fauci, Anthony S., and Arthos, James

Published
2018
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200. Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α4β7.

Author

Lertjuthaporn, Sakaorat, Cicala, Claudia, Van Ryk, Donald, Liu, Matthew, Yolitz, Jason, Wei, Danlan, Nawaz, Fatima, Doyle, Allison, Horowitch, Brooke, Park, Chung, Lu, Shan, Lou, Yang, Wang, Shixia, Pan, Ruimin, Jiang, Xunqing, Villinger, Francois, Byrareddy, Siddappa N., Santangelo, Philip J., Morris, Lynn, and Wibmer, Constantinos Kurt

Subjects
PATHOGENIC microorganisms, RECOMBINANT proteins, PEPTIDES, PROTEINS, VACCINES
Abstract

The GI tract is preferentially targeted during acute/early HIV-1 infection. Consequent damage to the gut plays a central role in HIV pathogenesis. The basis for preferential targeting of gut tissues is not well defined. Recombinant proteins and synthetic peptides derived from HIV and SIV gp120 bind directly to integrin α4β7, a gut-homing receptor. Using both cell-surface expressed α4β7 and a soluble α4β7 heterodimer we demonstrate that its specific affinity for gp120 is similar to its affinity for MAdCAM (its natural ligand). The gp120 V2 domain preferentially engages extended forms of α4β7 in a cation -sensitive manner and is inhibited by soluble MAdCAM. Thus, V2 mimics MAdCAM in the way that it binds to α4β7, providing HIV a potential mechanism to discriminate between functionally distinct subsets of lymphocytes, including those with gut-homing potential. Furthermore, α4β7 antagonists developed for the treatment of inflammatory bowel diseases, block V2 binding to α4β7. A 15-amino acid V2 -derived peptide is sufficient to mediate binding to α4β7. It includes the canonical LDV/I α4β7 binding site, a cryptic epitope that lies 7–9 amino acids amino terminal to the LDV/I, and residues K169 and I181. These two residues were identified in a sieve analysis of the RV144 vaccine trial as sites of vaccine -mediated immune pressure. HIV and SIV V2 mAbs elicited by both vaccination and infection that recognize this peptide block V2-α4β7 interactions. These mAbs recognize conformations absent from the β- barrel presented in a stabilized HIV SOSIP gp120/41 trimer. The mimicry of MAdCAM-α4β7 interactions by V2 may influence early events in HIV infection, particularly the rapid seeding of gut tissues, and supports the view that HIV replication in gut tissue is a central feature of HIV pathogenesis. [ABSTRACT FROM AUTHOR]

Published
2018
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