Browsing by Author "Blair, Lily"

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    ItemOpen Access
    Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques.
    (PLoS Pathog, 2015-08) Santra, Sampa; Tomaras, Georgia D; Warrier, Ranjit; Nicely, Nathan I; Liao, Hua-Xin; Pollara, Justin; Liu, Pinghuang; Alam, S Munir; Zhang, Ruijun; Cocklin, Sarah L; Shen, Xiaoying; Duffy, Ryan; Xia, Shi-Mao; Schutte, Robert J; Pemble Iv, Charles W; Dennison, S Moses; Li, Hui; Chao, Andrew; Vidnovic, Kora; Evans, Abbey; Klein, Katja; Kumar, Amit; Robinson, James; Landucci, Gary; Forthal, Donald N; Montefiori, David C; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Rerks-Ngarm, Supachai; Robb, Merlin L; Michael, Nelson L; Kim, Jerome H; Soderberg, Kelly A; Giorgi, Elena E; Blair, Lily; Korber, Bette T; Moog, Christiane; Shattock, Robin J; Letvin, Norman L; Schmitz, Joern E; Moody, MA; Gao, Feng; Ferrari, Guido; Shaw, George M; Haynes, Barton F
    HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.
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    ItemOpen Access
    Microbial Cell-Free DNA Identifies Etiology of Bloodstream Infections, Persists Longer Than Conventional Blood Cultures, and its Duration of Detection is Associated with Metastatic Infection in Patients with Staphylococcus aureus and Gram-Negative Bacteremia.
    (Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021-08-30) Eichenberger, Emily M; de Vries, Christiaan R; Ruffin, Felicia; Sharma-Kuinkel, Batu; Park, Lawrence; Hong, David; Scott, Erick R; Blair, Lily; Degner, Nicholas; Hollemon, Desiree H; Blauwkamp, Timothy A; Ho, Carine; Seng, Hon; Shah, Pratik; Wanda, Lisa; Fowler, Vance G; Ahmed, Asim A

    Background

    Microbial cell-free DNA (mcfDNA) sequencing of plasma can identify presence of a pathogen in a host. This study evaluated the duration of pathogen detection by mcfDNA sequencing vs. conventional blood culture in patients with bacteremia.

    Methods

    Blood samples from patients with culture-confirmed bloodstream infection were collected within 24 hours of the index positive blood culture and 48 to 72 hours thereafter. mcfDNA was extracted from plasma and next-generation sequencing (NGS) applied. Reads were aligned against a curated pathogen database. Statistical significance was defined with Bonferroni adjustment for multiple comparisons (p < 0.0033).

    Results

    A total of 175 patients with Staphylococcus aureus bacteremia (SAB; n=66), Gram-negative bacteremia (GNB; n=74), or non-infected controls (n=35) were enrolled. The overall sensitivity of mcfDNA sequencing compared to index blood culture was 89.3% (125/140) and the specificity was 74.3%. Among patients with bacteremia, pathogen specific mcfDNA remained detectable for significantly longer than conventional blood cultures (median 15 days vs. 2 days; p<0.0001). Each additional day of mcfDNA detection significantly increased the odds of metastatic infection (Odds Ratio [OR]: 2.89; 95% Confidence Interval [CI]: 1.53-5.46; p=0.0011).

    Conclusions

    Pathogen mcfDNA identified the bacterial etiology of bloodstream infection for a significantly longer interval than conventional cultures, and its duration of detection was associated with increased risk for metastatic infection. mcfDNA could play a role in the diagnosis of partially treated endovascular infections.