Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Meghan Rothenberger is active.

Publication


Featured researches published by Meghan Rothenberger.


Proceedings of the National Academy of Sciences of the United States of America | 2014

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

Courtney V. Fletcher; Kathryn Staskus; Stephen W. Wietgrefe; Meghan Rothenberger; Cavan Reilly; Jeffrey G. Chipman; Greg J. Beilman; Alexander Khoruts; Ann Thorkelson; Thomas E. Schmidt; Jodi Anderson; Katherine E. Perkey; Mario Stevenson; Alan S. Perelson; Ashley T. Haase; Timothy W. Schacker

Significance We show that HIV continues to replicate in the lymphatic tissues of some individuals taking antiretroviral regimens considered fully suppressive, based on undetectable viral loads in peripheral blood, and that one mechanism for persistent replication in lymphatic tissues is the lower concentrations of the antiretroviral drugs in those tissues compared with peripheral blood. These findings are significant because they provide a rationale and framework for testing the efficacy of new agents and combinations of drugs that will fully suppress replication in lymphatic tissues. More suppressive regimens could improve immune reconstitution, as well as provide the effective regimens needed for functional cure and eradication of infection. Antiretroviral therapy can reduce HIV-1 to undetectable levels in peripheral blood, but the effectiveness of treatment in suppressing replication in lymphoid tissue reservoirs has not been determined. Here we show in lymph node samples obtained before and during 6 mo of treatment that the tissue concentrations of five of the most frequently used antiretroviral drugs are much lower than in peripheral blood. These lower concentrations correlated with continued virus replication measured by the slower decay or increases in the follicular dendritic cell network pool of virions and with detection of viral RNA in productively infected cells. The evidence of persistent replication associated with apparently suboptimal drug concentrations argues for development and evaluation of novel therapeutic strategies that will fully suppress viral replication in lymphatic tissues. These strategies could avert the long-term clinical consequences of chronic immune activation driven directly or indirectly by low-level viral replication to thereby improve immune reconstitution.


PLOS Pathogens | 2013

Challenges in Detecting HIV Persistence during Potentially Curative Interventions: A Study of the Berlin Patient

Steven A. Yukl; Eli Boritz; Michael P. Busch; Christopher Bentsen; Tae Wook Chun; Evelyn E. Eisele; Ashley T. Haase; Ya Chi Ho; Gero Hütter; J. Shawn Justement; Sheila M. Keating; Tzong Hae Lee; Peilin Li; Danielle Murray; Sarah Palmer; Christopher D. Pilcher; Satish K. Pillai; Richard W. Price; Meghan Rothenberger; Timothy W. Schacker; Janet D. Siliciano; Robert F. Siliciano; Elizabeth Sinclair; Matt C. Strain; Joseph K. Wong; Douglas D. Richman; Steven G. Deeks

There is intense interest in developing curative interventions for HIV. How such a cure will be quantified and defined is not known. We applied a series of measurements of HIV persistence to the study of an HIV-infected adult who has exhibited evidence of cure after allogeneic hematopoietic stem cell transplant from a homozygous CCR5Δ32 donor. Samples from blood, spinal fluid, lymph node, and gut were analyzed in multiple laboratories using different approaches. No HIV DNA or RNA was detected in peripheral blood mononuclear cells (PBMC), spinal fluid, lymph node, or terminal ileum, and no replication-competent virus could be cultured from PBMCs. However, HIV RNA was detected in plasma (2 laboratories) and HIV DNA was detected in the rectum (1 laboratory) at levels considerably lower than those expected in ART-suppressed patients. It was not possible to obtain sequence data from plasma or gut, while an X4 sequence from PBMC did not match the pre-transplant sequence. HIV antibody levels were readily detectable but declined over time; T cell responses were largely absent. The occasional, low-level PCR signals raise the possibility that some HIV nucleic acid might persist, although they could also be false positives. Since HIV levels in well-treated individuals are near the limits of detection of current assays, more sensitive assays need to be developed and validated. The absence of recrudescent HIV replication and waning HIV-specific immune responses five years after withdrawal of treatment provide proof of a clinical cure.


Proceedings of the National Academy of Sciences of the United States of America | 2015

Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption

Meghan Rothenberger; Brandon F. Keele; Stephen W. Wietgrefe; Courtney V. Fletcher; Gregory J. Beilman; Jeffrey G. Chipman; Alexander Khoruts; Jacob D. Estes; Jodi Anderson; Samuel P. Callisto; Thomas E. Schmidt; Ann Thorkelson; Cavan Reilly; Katherine E. Perkey; Thomas Reimann; Netanya S. Utay; Krystelle Nganou Makamdop; Mario Stevenson; Ashley T. Haase; Timothy W. Schacker

Significance Antiretroviral therapy (ART) effectively suppresses HIV replication; however, treatment cannot be stopped, because latently infected CD4+ T cells will rekindle infection. As one estimate of the size of the pool of latently infected cells that must be purged for cure, we asked whether recrudescent infection is the result of reactivation from one or a larger number latently infected cells. We briefly stopped ART in fully suppressed patients to see how widespread new infections were in the lymphoid tissues (LTs) and how diverse rebounding/founder viruses were in peripheral blood. Recrudescent infection was detectable in multiple different LTs, and the population was genetically diverse, consistent with reactivation from a larger number of cells. These findings underscore the challenges facing strategies to eradicate HIV infection. Antiretroviral therapy (ART) suppresses HIV replication in most individuals but cannot eradicate latently infected cells established before ART was initiated. Thus, infection rebounds when treatment is interrupted by reactivation of virus production from this reservoir. Currently, one or a few latently infected resting memory CD4 T cells are thought be the principal source of recrudescent infection, but this estimate is based on peripheral blood rather than lymphoid tissues (LTs), the principal sites of virus production and persistence before initiating ART. We, therefore, examined lymph node (LN) and gut-associated lymphoid tissue (GALT) biopsies from fully suppressed subjects, interrupted therapy, monitored plasma viral load (pVL), and repeated biopsies on 12 individuals as soon as pVL became detectable. Isolated HIV RNA-positive (vRNA+) cells were detected by in situ hybridization in LTs obtained before interruption in several patients. After interruption, multiple foci of vRNA+ cells were detected in 6 of 12 individuals as soon as pVL was measureable and in some subjects, in more than one anatomic site. Minimal estimates of the number of rebounding/founder (R/F) variants were determined by single-gene amplification and sequencing of viral RNA or DNA from peripheral blood mononuclear cells and plasma obtained at or just before viral recrudescence. Sequence analysis revealed a large number of R/F viruses representing recrudescent viremia from multiple sources. Together, these findings are consistent with the origins of recrudescent infection by reactivation from many latently infected cells at multiple sites. The inferred large pool of cells and sites to rekindle recrudescent infection highlights the challenges in eradicating HIV.


PLOS ONE | 2015

Glycerol Monolaurate Microbicide Protection against Repeat High-Dose SIV Vaginal Challenge

Ashley T. Haase; Eva G. Rakasz; Nancy Schultz-Darken; Karla R. Nephew; Kimberly L. Weisgrau; Cavan Reilly; Qingsheng Li; Peter J. Southern; Meghan Rothenberger; Marnie L. Peterson; Patrick M. Schlievert

Measures to prevent sexual mucosal transmission are critically needed, particularly to prevent transmission to young women at high risk in the microepidemics in South Africa that disproportionally contribute to the continued pandemic. To that end, microbicides containing anti-retroviral (ARV) agents have been shown to prevent transmission, but with efficacy limited both by adherence and pre-existing innate immune and inflammatory conditions in the female reproductive tract (FRT). Glycerol monolaurate (GML) has been proposed as a microbicide component to enhance efficacy by blocking these transmission-facilitating innate immune response to vaginal exposure. We show here in an especially rigorous test of protection in the SIV-rhesus macaque model of HIV-1 transmission to women, that GML used daily and before vaginal challenge protects against repeat high doses of SIV by criteria that include virological and immunological assays to detect occult infection. We also provide evidence for indirect mechanisms of action in GML-mediated protection. Developing a sustained formulation for GML delivery could contribute an independent, complementary protective component to an ARV-containing microbicide.


Journal of Clinical Investigation | 2018

Lymphoid tissue fibrosis is associated with impaired vaccine responses

Cissy Kityo; Krystelle Nganou Makamdop; Meghan Rothenberger; Jeffrey G. Chipman; Torfi Hoskuldsson; Gregory J. Beilman; Bartosz Grzywacz; Peter Mugyenyi; Francis Ssali; Rama Akondy; Jodi Anderson; Thomas E. Schmidt; Thomas Reimann; Samuel P. Callisto; Jordan Schoephoerster; Jared Schuster; Proscovia Muloma; Patrick Ssengendo; Eirini Moysi; Constantinos Petrovas; Ray Lanciotti; Lin Zhang; Maria T. Arévalo; Benigno Rodriguez; Ted M. Ross; Lydie Trautmann; Rafick-Pierre Sekaly; Michael M. Lederman; Richard A. Koup; Rafi Ahmed

&NA; Vaccine responses vary by geographic location. We have previously described how HIV‐associated inflammation leads to fibrosis of secondary lymph nodes (LNs) and T cell depletion. We hypothesized that other infections may cause LN inflammation and fibrosis, in a process similar to that seen in HIV infection, which may lead to T cell depletion and affect vaccine responses. We studied LNs of individuals from Kampala, Uganda, before and after yellow fever vaccination (YFV) and found fibrosis in LNs that was similar to that seen in HIV infection. We found blunted antibody responses to YFV that correlated to the amount of LN fibrosis and loss of T cells, including T follicular helper cells. These data suggest that LN fibrosis is not limited to HIV infection and may be associated with impaired immunologic responses to vaccines. This may have an impact on vaccine development, especially for infectious diseases prevalent in the developing world.


Open Forum Infectious Diseases | 2018

Transplantation of CCR5∆32 Homozygous Umbilical Cord Blood in a Child With Acute Lymphoblastic Leukemia and Perinatally Acquired HIV Infection

Meghan Rothenberger; John E. Wagner; Ashley T. Haase; Douglas D. Richman; Bartosz Grzywacz; Matthew C. Strain; Steven M. Lada; Jacob D. Estes; Courtney V. Fletcher; Anthony T. Podany; Jodi Anderson; Thomas E. Schmidt; Steve Wietgrefe; Timothy W. Schacker; Michael R. Verneris

Abstract Background Allogeneic hematopoietic cell transplantation (allo-HCT) in a CCR5∆32 homozygous donor resulted in HIV cure. Understanding how allo-HCT impacts the HIV reservoir will inform cure strategies. Methods A 12-year-old with perinatally acquired, CCR5-tropic HIV and acute lymphoblastic leukemia underwent myeloablative conditioning and umbilical cord blood (UCB) transplantation from a CCR5∆32 homozygous donor. Peripheral blood mononuclear cells (PBMCs) and the rectum were sampled pre- and post-transplant. The brain, lung, lymph node (LN), stomach, duodenum, ileum, and colon were sampled 73 days after transplantation (day +73), when the patient died from graft-vs-host disease. Droplet digital polymerase chain reaction (ddPCR) and in situ hybridization (ISH) were used detect the HIV reservoir in tissues. CCR5 and CD3 expression in the LN was assessed using immunohistochemistry (IHC). Results HIV DNA (vDNA) was detected in PBMCs by ddPCR pretransplant but not post-transplant. vDNA was detected by ISH in the rectum at days –8 and +22, and in the LN, colon, lung, and brain day +73. vDNA was also detected in the lung by ddPCR. IHC revealed CCR5+CD3+ cells in the LN postmortem. Conclusions HIV was detected in multiple tissues 73 days after CCR5∆32 homozygous UCB allo-HCT despite myeloablative conditioning and complete donor marrow engraftment. These results highlight the importance of analyzing tissue during HIV cure interventions and inform the choice of assay used to detect HIV in tissue reservoirs.


Surgical Infections | 2015

Inguinal Lymph Node and Anorectal Mucosal Biopsies for Human Immunodeficiency Virus Research Protocols in an Emerging Nation: Patient Outcomes and Lessons Learned

Meghan Rothenberger; C. Kityo Mutuluuza; Francis Ssali; Jake S. Jasurda; Thomas E. Schmidt; Timothy W. Schacker; Gregory J. Beilman; Jeffrey G. Chipman

BACKGROUND Lymph nodes and gut-associated lymphatic tissue are important reservoirs of the human immunodeficiency virus (HIV). Little is known about these reservoirs in different geographic populations. We report the surgical outcomes of excisional lymph node and anorectal mucosal biopsies performed internationally and describe the lessons learned. METHODS Patients were recruited through the Joint Clinical Research Center (JCRC) in Kampala, Uganda, where procedures were performed. Studies were approved by the Institutional Review Boards of the JCRC and the University of Minnesota. Instruments and supplies were shipped to Uganda and prepared onsite. Drugs and skin preparations were purchased locally. Lymph nodes were removed through 1-3 cm incisions with ligatures on lymphovascular pedicles. Incisions were closed with subcuticular sutures and epidermal tape. Two to four pieces of anorectal mucosa were obtained through anoscopes using biopsy forceps. RESULTS One hundred thirty-eight lymph node biopsies and 98 anorectal mucosal biopsies were performed on 71 patients. Forty-one patients were HIV-positive. Many patients had multiple procedures. Two minor complications resulted: One hematoma and one lymphocele. Despite the cost of travel and lodging, cost per biopsy was lower in Uganda compared with the United States. CONCLUSION Invasive clinical research can be performed with minimal morbidity in emerging nations with outcomes similar to those found in the United States, but with lower cost.


Journal of General Internal Medicine | 2018

Herpes Vegetans: an Unusual and Acyclovir-Resistant Form of HSV

Sanna D. Ronkainen; Meghan Rothenberger

A 44-year-old man with longstanding AIDS, non-adherent to antiretrovirals (ARVs) and opportunistic infection prophylaxis, presented with 2 months of painful groin nodules. Examination revealed firm, exophytic nodules with purulent drainage from the groin to the base of the penis. Testing for gonorrhea, chlamydia and syphilis was negative. Biopsy revealed ulceration with underlying granulation tissue with chronic inflammatory infiltrate including plasma cells, lymphocytes, eosinophils, and histiocytes. T-cell gene rearrangement was negative, and stains/cultures for acid-fast bacilli, fungi, and bacteria were unrevealing. Viral culture was positive for herpes simplex virus (HSV) resistant to acyclovir (Fig. 1). Herpes vegetans is an atypical presentation of HSV seen in the setting of immunodeficiency, most commonly AIDS. Differential diagnosis of ulcerated genital nodules in immunocompromised patients includes condyloma acuminata, condyloma lata, verrucous carcinoma, pemphigus vegetans, or a deep fungal or mycobacterial infection. Biopsy for histology and culture is necessary for workup of this differential, as superficial viral cultures of nodules are often negative. Interestingly, in the setting of verrucous or vegetative presentation of HSV, acyclovir resistance is often present. Treatment of acyclovirresistant HSVusually consists of intravenous administration of foscarnet, though alternatives include topical trifluridine, cidofovir, or imiquimod, or intralesional cidofovir. This patient was successfully treated with foscarnet.


Journal of Pharmaceutical Sciences | 2017

Evaluation of Vaginal Drug Levels and Safety of a Locally Administered Glycerol Monolaurate Cream in Rhesus Macaques

Ameya R. Kirtane; Meghan Rothenberger; Abby Frieberg; Karla R. Nephew; Nancy Schultz-Darken; Thomas E. Schmidt; Thomas Reimann; Ashley T. Haase; Jayanth Panyam

The human immunodeficiency virus epidemic affects millions of people worldwide. As women are more vulnerable to infection, female-controlled interventions can help control the spread of the disease significantly. Glycerol monolaurate (GML), an inexpensive and safe compound, has been shown to protect against simian immunodeficiency virus infection when applied vaginally. However, on account of its low aqueous solubility, fabrication of high-dose formulations of GML has proven difficult. We describe the development of a vaginal cream that could be loaded with up to 35% GML. Vaginal drug levels and safety of 3 formulations containing increasing concentrations of GML (5%w/w, 15%w/w, and 35%w/w) were tested in rhesus macaques after vaginal administration. GML concentration in the vaginal tissue increased as the drug concentration in the cream increased, with 35% GML cream resulting in tissue concentration of ∼0.5 mg/g, albeit with high interindividual variability. Compared with the vehicle control, none of the GML creams had any significant effect on the vaginal flora and cytokine (macrophage inflammatory protein 3α and interleukin 8) levels, suggesting that high-dose GML formulations do not induce local adverse effects. In summary, we describe the development of a highly loaded vaginal cream of GML, and vaginal drug levels and safety after local administration in macaques.


BMC Infectious Diseases | 2014

Fungemia due to Lachancea fermentati: a case report.

Anne Marie Leuck; Meghan Rothenberger; Jaime S. Green

Collaboration


Dive into the Meghan Rothenberger's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Cavan Reilly

University of Minnesota

View shared research outputs
Top Co-Authors

Avatar

Courtney V. Fletcher

University of Nebraska Medical Center

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge