Selected Grantee Publications
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- 25 results found
- Immunology
- K01
Stromal P53 Regulates Breast Cancer Development, the Immune Landscape, and Survival in an Oncogene-Specific Manner
Wu et al., Molecular Cancer Research. 2022.
https://www.doi.org/10.1158/1541-7786.MCR-21-0960
Loss of stromal p53 function drives tumor progression in breast cancer, but the exact mechanisms have been relatively unexplored. Using mouse models, researchers demonstrated that loss of cancer-associated fibroblast (CAF) p53 enhances carcinoma formation driven by oncogenic KRAS G12D, but not ERBB2, in mammary epithelia. These results corresponded with increased tumor cell proliferation and DNA damage, as well as decreased apoptosis, in the KRAS G12D model. Furthermore, a gene cluster associated with CAF p53 deficiency was found to associate negatively with survival in microarray and heat map analyses. These data indicate that stromal p53 loss promotes mammary tumorigenesis in an oncogene-specific manner, influences the tumor immune landscape, and ultimately affects patient survival. Supported by ORIP (K01OD026527) and NCI.
Antiretroviral Therapy Timing Impacts Latent Tuberculosis Infection Reactivation in a Tuberculosis/Simian Immunodeficiency Virus Coinfection Model
Sharan et al., Journal of Clinical Investigation. 2021.
https://pubmed.ncbi.nlm.nih.gov/34855621/
In the rhesus macaque model for Mycobacterium tuberculosis plus simian immunodeficiency virus (SIV) co-infection, chronic immune activation rather than depletion of CD4+ T cells correlates with reactivation of latent tuberculosis infection (LTBI). Researchers administered combined antiretroviral therapy (cART) at 2 weeks post-SIV co-infection to study whether restoration of CD4+ T cell immunity occurred more broadly, and whether this prevented LTBI compared to cART initiated at 4 weeks post-SIV. Earlier initiation of cART enhanced survival led to better control of viral replication and reduced immune activation in the periphery and lung vasculature, thereby reducing the rate of SIV-induced reactivation. Supported by ORIP (K01OD031898, P51OD011133, P51OD011132, S10OD028653) and NIAID.
Circulating Integrin α4β7+ CD4 T Cells Are Enriched for Proliferative Transcriptional Programs in HIV Infection
Lakshmanappa et al., Federation of European Biochemical Societies Letters. 2021.
https://doi.org/10.1002/1873-3468.14163
HIV preferentially infects α4β7+ CD4 T cells, forming latent reservoirs that contribute to HIV persistence, yet the properties of α4β7+ CD4 T cells are poorly understood. Investigating HIV-infected humans and SHIV-infected rhesus macaques, investigators demonstrated that α4β7+ CD4 T cells in blood are enriched for genes regulating cell cycle progression and cellular metabolism. In contrast, rectal α4β7+ CD4 T cells exhibited a core tissue-residency gene expression program. These features were conserved across primate species, suggesting that the tissue environment influences memory T-cell transcriptional networks. These findings provide an important foundation for understanding the role of α4β7 in HIV infection. Supported by ORIP (K01OD023034, R24OD010976) and NIAID.
Antibody-Based CCR5 Blockade Protects Macaques From Mucosal SHIV Transmission
Chang et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-23697-6
The efficacy of antiretroviral therapy (ART) as pre-exposure prophylaxis against HIV is hindered by incomplete patient adherence and ART-resistant variants. Researchers found that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges with a CCR5-tropic simian-human immunodeficiency virus (SHIVSF162P3). Biweekly injection of Leronlimab at 50 mg/kg provided complete protection from SHIV infection. Tissue biopsies from protected macaques post-challenge revealed complete CCR5 receptor occupancy and an absence of viral DNA. After Leronlimab washout, transfer of hematologic cells into naïve monkeys did not transmit infection, supporting the initiation of clinical trials. Supported by ORIP (P51OD011092, K01OD026561, P40OD028116) and NIAID.
Psychosocial Stress Alters the Immune Response and Results in Higher Viral Load During Acute SIV Infection in a Pigtailed Macaque Model of HIV
Guerrero-Martin et al., Journal of Infectious Diseases. 2021.
https://doi.org/10.1093/infdis/jiab252
Social distancing is an important countermeasure for a pandemic, but social isolation may also have adverse health outcomes in the context of infectious diseases, such as HIV. Researchers compared commonly measured parameters of HIV progression between singly and socially housed simian immunodeficiency virus (SIV)-infected pigtailed macaques. Throughout acute SIV infection, singly housed pigtailed macaques had a higher viral load in the plasma and cerebrospinal fluid and demonstrated greater CD4+ T cell declines and more CD4+ and CD8+ T cell activation compared to socially housed macaques. These findings suggest that psychosocial stress could augment the progression of HIV infection. Supported by ORIP (U42OD013117, P40OD013117, K01OD018244), NIAID, NINDS, and NIMH.