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Rockville, MD, United States

Lugli E.,National Institute of Allergy and Infectious Diseases | Mueller Y.M.,Drexel University | Lewis M.G.,BIOQUAL Inc. | Villinger F.,Emory University | And 3 more authors.
Blood | Year: 2011

Human immunodeficiency virus (HIV) infection is characterized by a progressive loss of memory CD4+ T cells in multiple tissues, especially at mucosal surfaces where most of these cells reside. Although antiretroviral therapy (ART) suppresses viral replication and promotes the recovery of peripheral CD4+ T cells, HIV-infected patients fail to fully reconstitute the CD4+ T-cell pool at mucosal sites. IL-15 has been shown to preferentially expand memory-phenotype T cells and promote their migration to nonlymphoid tissues. Here we examined IL-15 treatment in combination with highly active ART in chronically SIV-infected rhesus macaques and found that IL-15 delayed viral suppression and failed to enhance ART-induced total and antigen-specific CD4+ T-cell reconstitution at mucosal and lymphoid sites. IL-15 was able to induce the transient proliferation of SIV-specific, CMV-specific, and total memory CD8+ T cells, but not of SIV-specific or total CD4+ T cells. Moreover, upon treatment interruption, macaques receiving combined IL-15+ART lost CD4+ T cells faster than those receiving ART alone. These results suggest that the combination of IL-15 with highly active ART is not more efficient than ART alone in promoting CD4+ T-cell recovery in HIV-infected individuals and may accelerate CD4+ T-cell loss after treatment interruption. © 2011 by The American Society of Hematology. Source

Tebas P.,University of Pennsylvania | Frank I.,University of Pennsylvania | Lewis M.,BIOQUAL Inc. | Quinn J.,University of Pennsylvania | And 7 more authors.
AIDS | Year: 2010

Objective: To evaluate the safety and immunogenicity of the H1N1 2009 vaccine in HIV-positive individuals. Design: A single-arm study. Setting: Clinic at the Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA. Participants: HIV-infected adults with an indication for H1N1 vaccination. Intervention: Single intramuscular 15 μg dose of the monovalent, unadjuvanted, inactivated, split virus H1N1 vaccine. Main outcomes: Immunogenicity, safety and tolerability. Results: A total of 120 participants were enrolled, 71% men, 68% African-American, with median age of 46 years. All of them but one were on antiretroviral treatment, with a median current CD4 cell counts of 502 cells/μl, and a nadir CD4 cell counts of 132 cells/μl. The HIV RNA level was below 400 copies/ml in 92% of participants. All participants completed the 3 weeks of follow-up. Thirty of the 120 (25%) participants had antibody hemagglutination-inhibition assay titers equal or greater than 1: 40 at baseline. Among participants without evidence of previous exposure, only 61% develop protective titers by week 3 of the study. Nonresponders had lower current and nadir CD4 cell counts than responders. Only four of nine participants with detectable HIV viral load at baseline developed protective antibody titers. Age and race were not predictors of the response to the vaccine. The vaccine was well tolerated. Conclusion: These results suggest that only 60% of well controlled HIV-infected individuals without preexisting immunity to H1N1 develop protective antibody titers after immunization. Alternative vaccines, dosing, adjuvants or schedule strategies are needed to achieve effective immunization of this vulnerable population. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Purcell R.H.,U.S. National Institutes of Health | Engle R.E.,U.S. National Institutes of Health | Kabrane-Lazizi Y.,U.S. National Institutes of Health | Nguyen H.T.,U.S. National Institutes of Health | And 4 more authors.
Emerging Infectious Diseases | Year: 2011

The role of rats in human hepatitis E virus (HEV) infections remains controversial. A genetically distinct HEV was recently isolated from rats in Germany, and its genome was sequenced. We have isolated a genetically similar HEV from urban rats in Los Angeles, California, USA, and characterized its ability to infect laboratory rats and nonhuman primates. Two strains of HEV were isolated from serum samples of 134 wild rats that had a seroprevalence of antibodies against HEV of ≈80%. Virus was transmissible to seronegative Sprague-Dawley rats, but transmission was spotty and magnitude and duration of infection were not robust. Viremia was higher in nude rats. Serologic analysis and reverse transcription PCR were comparably sensitive in detecting infection. The sequence of the Los Angeles virus was virtually identical to that of isolates from Germany. Rat HEV was not transmissible to rhesus monkeys, suggesting that it is not a source of human infection. Source

Barouch D.H.,Beth Israel Deaconess Medical Center | Barouch D.H.,Massachusetts Institute of Technology | Whitney J.B.,Beth Israel Deaconess Medical Center | Moldt B.,Scripps Research Institute | And 25 more authors.
Nature | Year: 2013

Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans. © 2013 Macmillan Publishers Limited. All rights reserved. Source

Rao S.S.,National Institute of Allergy and Infectious Diseases | Kong W.-P.,National Institute of Allergy and Infectious Diseases | Wei C.-J.,National Institute of Allergy and Infectious Diseases | Van Hoeven N.,Centers for Disease Control and Prevention | And 5 more authors.
PLoS ONE | Year: 2010

Efforts to develop a broadly protective vaccine against the highly pathogenic avian influenza A (HPAI) H5N1 virus have focused on highly conserved influenza gene products. The viral nucleoprotein (NP) and ion channel matrix protein (M2) are highly conserved among different strains and various influenza A subtypes. Here, we investigate the relative efficacy of NP and M2 compared to HA in protecting against HPAI H5N1 virus. In mice, previous studies have shown that vaccination with NP and M2 in recombinant DNA and/or adenovirus vectors or with adjuvants confers protection against lethal challenge in the absence of HA. However, we find that the protective efficacy of NP and M2 diminishes as the virulence and dose of the challenge virus are increased. To explore this question in a model relevant to human disease, ferrets were immunized with DNA/rAd5 vaccines encoding NP, M2, HA, NP+M2 or HA+NP+M2. Only HA or HA+NP+M2 vaccination conferred protection against a stringent virus challenge. Therefore, while gene-based vaccination with NP and M2 may provide moderate levels of protection against low challenge doses, it is insufficient to confer protective immunity against high challenge doses of H5N1 in ferrets. These immunogens may require combinatorial vaccination with HA, which confers protection even against very high doses of lethal viral challenge. Source

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