University of Pittsburgh Cancer Institute (UPCI)

AIDS-related and Immune Deficiency-related Malignancies (ARM)

Kaposi's sarcomaAIDS-related cancers are now the most common malignancies in sub-Saharan Africa. Human immunodeficiency virus (HIV) itself is classified as an infectious carcinogen by WHO International Agency for Research on Cancer (IARC), primarily due to its capacity to increase risk for opportunistic cancers. CVP ARM members are investigating the mechanisms for HIV-related immunodeficiency and pathogenesis. In addition, research within this theme examines multiple tumor types that arise in the setting of immune deficiency, such as Kaposi's sarcoma (KS), post-transplant lymphoproliferative disorder (PTLD) and human papilloma virus (HPV)-induced anal carcinoma. These studies involve analyses of critical immune cell populations, mechanisms for infection, epidemiology and molecular epidemiology of tumor viral infections, and clinical treatment and prevention of tumor virus disease in immunocompromised populations.

Selected Publications

  • Long acting (LA) injectable antiretroviral agents are being evaluated as a potential strategy for pre-exposure prophylaxis of HIV infection. In a collaborative study, it was determined that single dose administration of TMC278 LA was safe and well tolerated with dose-dependent plasma pharmacokinetic exposure. Exposure to TMC278 LA was associated with significant suppression of viral replication in rectal tissue (p<0.0001) that persisted for up to four months. This is the first study to demonstrate prolonged suppression of explant viral replication following systemic antiretroviral exposure. (McGowan et. al., AIDS Res Hum Retroviruses. 2014 Oct;30 Suppl 1:A71.)
  • Primary effusion lymphoma (PEL), associated with the latent infection by Kaposi's sarcoma associated herpesvirus (KSHV), constitutively expresses interferon-regulatory factor 4 (IRF4). IRF4 differentially regulates expression of cellular interferon-stimulated genes (ISGs) and viral genes. Using inducible IRF4 knockdown, it was demonstrated that IRF4 silencing results in enhanced transcription of KSHV replication transactivator RTA. As a result, viral transcription is increased, leading to virus reactivation. These results indicate that IRF4 helps to maintain the balance between latency and KSHV reactivation in PEL cells. (Forero et. al., Virology. 2014 Jun;458-459:4-10.)
  • HIV/HCV co-infection provides a model to determine the role of immunity on HCV transmission and evolution. Results from a recent study in HIV-infected subjects with a wide range of CD4 cell count suggest that HCV transmission and evolution may not be influenced by host CD4 cell count at the time of infection. (Shen et. al., Virology. 2014 Jan 20;449:339-49.)
  • Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection, but direct evidence for this is lacking. Recent findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic simian immunodeficiency virus (SIV) infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings, therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology. (Kader et. al., PLoS Pathog. 2013;9(7):e1003530.)

Members

Section Leader: Ross Cranston, MD

Ayyavoo, Velpandi, PhD
Infectious Diseases & Microbiology
Moore, Patrick, MD, MPH
Microbiology and Molecular Genetics
Barratt-Boyes, Simon, PhD, BVSc
Infectious Diseases & Microbiology
Pantanowitz, Liron, MD
Pathology
Chang, Yuan, MD
Pathology
Reinhart, Todd, ScD
Infectious Diseases & Microbiology
Cranston, Ross, MD
Medicine
Rinaldo, Charles, PhD
Pathology
Gupta, Phalguni, PhD
Infectious Diseases & Microbiology
Wiley, Clayton, MD, PhD
Pathology