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

  • In addition to their enhanced IL-12p70 producing capacity, human dendritic cells (DC) matured in the presence of inflammatory mediators of type 1 immunity are uniquely programmed to form networks of tunneling nanotube-like structures in response to CD40L-expressing Th cells or rCD40L. This immunologic process of DC reticulation facilitates intercellular trafficking of endosome-associated vesicles and Ag, but also pathogens such HIV-1, and is regulated by the opposing roles of IFN-γ and IL-4. The initiation of DC reticulation represents a novel helper function of CD40L and a superior mechanism of intercellular communication possessed by type 1 polarized DC, as well as a target for exploitation by pathogens to enhance direct cell-to-cell spread. (Zaccard et al., J Immunol. 2015 Feb 1;194(3):1047-56.)
  • Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are human DNA tumor viruses that express nuclear antigens [latency-associated nuclear antigen 1 (LANA1) and Epstein-Barr nuclear antigen 1 (EBNA1)] necessary to maintain and replicate the viral genome. We report here that both LANA1 and EBNA1 undergo highly efficient +1/-2 programmed ribosomal frameshifting to generate previously undescribed alternative reading frame (ARF) proteins in their repeat regions. Repeat sequence recoding has not been described previously for human DNA viruses. (Kwun et al., Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):E4342-9.)
  • Peptides representing autologous variants of major histocompatibility complex (MHC) class I-restricted epitopes from HIV-1 Gag and Env were used as antigens in gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) and polyfunctional cytokine assays. Here we show that dendritic cells (DC) enhanced T cell reactivity at all stages of disease progression but specifically restored T cell reactivity after combination antiretroviral therapy (cART) to early infection levels. Type 1 cytokine secretion was also enhanced by DC and was most apparent late post-cART. We additionally show that DC reveal polyfunctional T cell responses after many years of treatment, when potential immunotherapies would be implemented. These data underscore the potential efficacy of DC immunotherapy that aims to awaken a dormant, autologous, HIV-1-specific CD8+ T cell response. (Smith et al., J Virol. 2014 Sep 1;88(17):9976-90.)
  • Using newly developed measures for intracellular detection of lytic cycle proteins and expression of cytokines and chemokines, we show that human herpesvirus 8 (HHV-8; Kaposi's sarcoma [KS]-associated herpesvirus) targets a range of naive B cell, IgM memory B cell, and plasma cell-like populations for infection and induction of interleukin-6, tumor necrosis factor alpha, macrophage inhibitory protein 1α, macrophage inhibitory protein 1β, and interleukin-8 in vitro and in the blood of HHV-8/HIV-1-coinfected subjects with KS. These B cell lineage subsets that support HHV-8 infection are highly polyfunctional, producing combinations of 2 to 5 of these cytokines and chemokines, with greater numbers in the blood of subjects with KS than in those without KS. (Knowlton et al., MBio. 2014 Sep 2;5(5):e01277-14.)


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
Chang, Yuan, MD
Reinhart, Todd, ScD
Infectious Diseases & Microbiology
Cranston, Ross, MD
Rinaldo, Charles, PhD
Gupta, Phalguni, PhD
Infectious Diseases & Microbiology
Wiley, Clayton, MD, PhD