The recently completed HIV prevention trials network study 052 is a landmark collaboration demonstrating that HIV transmission in discordant couples can be dramatically reduced by treating the infected individual with antiretroviral therapy (ART). However, the cellular and virological events that occur in the female reproductive tract (FRT) during ART that result in such a drastic decrease in transmission were not studied and remain unknown. Here, we implemented an in vivo model of ART in BM/liver/thymus (BLT) humanized mice in order to better understand the ability of ART to prevent secondary HIV transmission. We demonstrated that the entire FRT of BLT mice is reconstituted with human CD4+ cells that are shed into cervicovaginal secretions (CVS). A high percentage of the CD4+ T cells in the FRT and CVS expressed CCR5 and therefore are potential HIV target cells. Infection with HIV increased the numbers of CD4+ and CD8+ T cells in CVS of BLT mice. Furthermore, HIV was present in CVS during infection. Finally, we evaluated the effect of ART on HIV levels in the FRT and CVS and demonstrated that ART can efficiently suppress cell-free HIV-RNA in CVS, despite residual levels of HIV-RNA+ cells in both the FRT and CVS.
Rikke Olesen, Michael D. Swanson, Martina Kovarova, Tomonori Nochi, Morgan Chateau, Jenna B. Honeycutt, Julie M. Long, Paul W. Denton, Michael G. Hudgens, Amy Richardson, Martin Tolstrup, Lars Østergaard, Angela Wahl, J. Victor Garcia
Melanoma prognosis is dictated by tumor-infiltrating lymphocytes, the migratory and functional behavior of which is guided by chemokine or cytokine gradients. Here, we retrospectively analyzed the expression patterns of 9 homing receptors (CCR/CXCR) in naive and memory CD4+ and CD8+ T lymphocytes in 57 patients with metastatic melanoma (MMel) with various sites of metastases to evaluate whether T cell CCR/CXCR expression correlates with intratumoral accumulation, metastatic progression, and/or overall survival (OS). Homing receptor expression on lymphocytes strongly correlated with MMel dissemination. Loss of CCR6 or CXCR3, but not cutaneous lymphocyte antigen (CLA), on circulating T cell subsets was associated with skin or lymph node metastases, loss of CXCR4, CXCR5, and CCR9 corresponded with lung involvement, and a rise in CCR10 or CD103 was associated with widespread dissemination. High frequencies of CD8
Nicolas Jacquelot, David P. Enot, Caroline Flament, Nadège Vimond, Carolin Blattner, Jonathan M. Pitt, Takahiro Yamazaki, María Paula Roberti, Romain Daillère, Marie Vétizou, Vichnou Poirier-Colame, Michaëla Semeraro, Anne Caignard, Craig L. Slingluff Jr., Federica Sallusto, Sylvie Rusakiewicz, Benjamin Weide, Aurélien Marabelle, Holbrook Kohrt, Stéphane Dalle, Andréa Cavalcanti, Guido Kroemer, Anna Maria Di Giacomo, Michele Maio, Phillip Wong, Jianda Yuan, Jedd Wolchok, Viktor Umansky, Alexander Eggermont, Laurence Zitvogel
Raymond P. Najjar, Jamie M. Zeitzer
The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor
Shao-Qing Kuang, Olga Medina-Martinez, Dong-chuan Guo, Limin Gong, Ellen S. Regalado, Corey L. Reynolds, Catherine Boileau, Guillaume Jondeau, Siddharth K. Prakash, Callie S. Kwartler, Lawrence Yang Zhu, Andrew M. Peters, Xue-Yan Duan, National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) Investigators, National Heart, Lung, and Blood Institute (NHLBI) Grand Opportunity (GO) Exome Sequencing Project (ESP), Michael J. Bamshad, Jay Shendure, Debbie A. Nickerson, Regie L. Santos-Cortez, Xiurong Dong, Suzanne M. Leal, Mark W. Majesky, Eric C. Swindell, Milan Jamrich, Dianna M. Milewicz
T regulatory cells (Tregs) control immune homeostasis by preventing inappropriate responses to self and nonharmful foreign antigens. Tregs use multiple mechanisms to control immune responses, all of which require these cells to be near their targets of suppression; however, it is not known how Treg-to-target proximity is controlled. Here, we found that Tregs attract CD4+ and CD8+ T cells by producing chemokines. Specifically, Tregs produced both CCL3 and CCL4 in response to stimulation, and production of these chemokines was critical for migration of target T cells, as Tregs from
Scott J. Patterson, Anne M. Pesenacker, Adele Y. Wang, Jana Gillies, Majid Mojibian, Kim Morishita, Rusung Tan, Timothy J. Kieffer, C. Bruce Verchere, Constadina Panagiotopoulos, Megan K. Levings
Selenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome–encoded, transfer RNA (tRNA[Ser]Sec). Here, we have identified a human tRNA[Ser]Sec mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a marked reduction in expression of stress-related, but not housekeeping, selenoproteins. Evaluation of primary cells from the homozygous proband and a heterozygous parent indicated that the observed deficit in stress-related selenoprotein production is likely mediated by reduced expression and diminished 2′-O-methylribosylation at uridine 34 in mutant tRNA[Ser]Sec. Moreover, this methylribosylation defect was restored by cellular complementation with normal tRNA[Ser]Sec. This study identifies a tRNA mutation that selectively impairs synthesis of stress-related selenoproteins and demonstrates the importance of tRNA modification for normal selenoprotein synthesis.
Erik Schoenmakers, Bradley Carlson, Maura Agostini, Carla Moran, Odelia Rajanayagam, Elena Bochukova, Ryuta Tobe, Rachel Peat, Evelien Gevers, Francesco Muntoni, Pascale Guicheney, Nadia Schoenmakers, Sadaf Farooqi, Greta Lyons, Dolph Hatfield, Krishna Chatterjee
This month’s cover image shows a liver tumor nodule following injection of colorectal cancer cells depleted of PKLR (liver and red blood cell pyruvate kinase), with staining for tumor cells (luciferase, green), apoptotic cells (cleaved caspase-3, red), and nuclei (DAPI, blue). On page 681, Nguyen et al. demonstrate that liver metastases of colorectal cancer are driven by pyruvate kinase isozyme expression.
JCI This Month is a digest of the research, reviews, and other features published each month.
The development of combination antiretroviral therapy (ART) in the mid-1990s initially raised hopes that HIV was a curable disease; however, further studies revealed that the virus persists, even in patients with undetectable levels of HIV in their plasma. Resting CD4+ T cells harbor stably integrated viral genomes that can produce infectious virus following T cell activation. Importantly, treatment interruption leads to a rapid recrudescence of infection from this latent reservoir, usually within 2 to 3 weeks. Several distinct areas of HIV research are now focused on the development of strategies to precent the latent reservoir from replicating or to eliminate it entirely. Reviews in this series detail progress in our understanding of the molecular and cellular mechanisms of viral latency, efforts to accurately assess the size and composition of the latent viral reservoir, the characterization and development of HIV-targeted broadly neutralizing antibodies and cytolytic T lymphocytes, as well as animal models for the study of HIV latency and therapeutic strategies.