Impact of HIV infection on colorectal cancer: Forty percent of patients who develop AIDS will develop cancer. With the advent of combined antiretroviral therapy (cART) patients with HIV are living longer. As the currently infected patient population ages, the inherent risk of developing cancer also increases. There have been numerous studies that have looked into the relative risk of developing AIDS and subsequently developing colon cancer. The results from these studies have been mixed with a number of studies pointing to AIDS being an increased risk factor while others showed no increased risk. Even with the conflicting reports, a pattern begins to emerge from patients who have AIDS and develop colon cancer. In one study, the average age of developing colon cancer in AIDS patients was 48 years old, as opposed to 60 years old in non-infected patients. Moreover, the stage of colon cancer diagnosed in AIDS patients is more advanced (III or IV) compared with HIV-negative individuals. This age difference in patients has been reported by multiple researchers, leading to further studies delving into the molecular mechanisms at play. A recent study utilized a humanized mouse model to ascertain the relationship between HIV and colon cancer. The group demonstrated that HIV was able to accelerate tumor outgrowth in the mouse model.

One of the key pathways that is modulated in colon cancer is the Wnt signaling pathway. It has been shown that β-catenin had higher levels of nuclear localization indicating an active Wnt/β-catenin pathway. In addition, studies have demonstrated a specific interaction between HIV encoded Nef and β-catenin. It was shown that Nef was able to bind β-catenin in its ligand binding site in a very similar fashion to E-cadherin. In order to determine whether patient HIV isolates had the same β-catenin binding motif, sequences were taken from Los Alamos National Laboratory (LANL) and measured on the amino acid level. For subtype B viruses, 92.7 percent of viruses had the β-catenin binding motif. While this study was performed in HEK-293T cells, there have been other studies looking at the Nef/β-catenin relationship in T cells. Similar to HEK-293T cells, Nef was also shown to bind β-catenin in T cells. Moreover, it has been shown that Nef was able to be secreted through exosomes by infected T cells and interact with gastrointestinal epithelial cells.

What has not been demonstrated is which gene products of the Wnt signaling pathway are specifically upregulated in the presence of Nef. A number of gene products from this pathway are involved in intestinal growth and migration. Understanding the molecular mechanisms behind how HIV is able to modulate the Wnt signaling pathway and the possibility of background mutations in critical cancer control genes is crucial to better understanding the link between HIV and cancer. Therefore, we are currently working to determine if HIV-encoded Nef is able to modulate the Wnt signaling pathway by interacting directly with β-catenin in T cells as well as cells of the colon and rectum causing a proinflammatory tumor microenvironment resulting in accelerated colon tumor outgrowth.

Impact of aging on HIV-1 replication, pathogenesis and immune activation profiles: Aging is a complicated process involving several intrinsic and extrinsic factors intricately linked together, including different systems of the human body. Common aging-related chronic conditions include diabetes, lipidemia, cardiovascular disease, immune dysregulation, changes in bone strength and density, and neurologic impairment, including dementia syndromes such as Alzheimer’s disease (AD) and vascular dementia. These diseases are progressive and often are treatable but not curable.

Often these diseases coexist within the aging population. Prevalence of these diseases is increased among HIV-1-infected patients, and current research suggests that this may be the result of premature aging associated with HIV-1 infection. Immunosenescence typically occurs in individuals greater than 70 years old. It is a general term used to describe an age-related decline in immune competence marked by alterations in the overall function of the immune system.

Immunosenescence is characterized by an increase in the number of terminally differentiated effector memory CD8+ T cells that are generally characterized by the inability to proliferate, the absence of CD28 expression, shortened telomeres, loss of telomerase activity and enhanced secretion of inflammatory cytokines. The number of naïve CD8+ T cells also tends to decrease. In addition, the CD4+/CD8+ T cell ratio decreases, overall T cell activation increases, T cell proliferation and thymic involution are reduced, and levels of many inflammatory mediators increase. Immunosenescent phenotypes are generally accelerated by the presence of chronic infections, with cytomegalovirus implicated most often in aging. With HAART therapy resulting in a chronic type of HIV-1 infection, in which patients with well-controlled disease potentially live several decades, immunosenescence is occurring in patients with controlled disease as well as in those with uncontrolled disease. The immunosenescence observed appears premature, occurring in younger HIV-1-infected patients than what occurs in the general population. The phenotype is similar to that observed in older, noninfected people.

Studies suggest that premature aging phenotypes in both the CD8+ and CD4+ T cell compartments predict faster clinical disease progression. HIV-1-associated immunosenescence may thus contribute to long-term continued immunodeficiency as well as to premature aging-associated diseases in infected patients.
Current research in the laboratory is investigating the potential that viral and host genetic factors alter susceptibility to accelerated HIV-associated aging events and negatively impact neurocognitive outcomes. This work will draw a molecular portrayal of aging of HIV+ patients utilizing unique longitudinal peripheral blood samples in conjunction with a comprehensive neurocognitive protocol from the Drexel HIV/AIDS Genetic Analysis Cohort divided into two groups: adult (age 30-45) and aged (age 50-65) as well as samples from the National NeuroAIDS Tissue Consortium (NNTC), derived from brain tissue in the absence or presence of minor or major neurocognitive impairment (NCI). This study utilizes molecular and systems biology approaches along with detailed immunological assessments to generate an overall picture of important pathways in HIV-1 pathogenesis and to determine how age affects these pathways, particularly those relevant to viral transcription and immune activation.

A second line of research in our laboratory focuses on HIV-1 and hepatitis C virus (HCV) coinfection in an aging population. A large number of HIV-1-infected individuals are coinfected with other viral and nonviral pathogens, including HCV, which alone currently infects approximately 170 million individuals worldwide. Both HIV-1 and HCV share similar modes of transmission, and as such approximately 30 percent of HIV-1-infected patients are coinfected with HCV, suggesting that there are greater than 10 million coinfected individuals globally. Studies have demonstrated that the normal pathogenesis of HCV infection is significantly impacted by infection with HIV-1, with coinfected individuals possessing higher HCV viral loads, and more rapid progression to serious liver disease, including cirrhosis and hepatocellular carcinoma. Additionally, it has been demonstrated that the efficacy of HCV therapy is decreased in HIV/HCV coinfected individuals. In a similar manner to HIV monoinfected patients, HIV/HCV coinfected patients have been shown to be increasing in age as therapies are getting more successful at extending the lifespan of infected individuals. However, mortality associated with liver disease still remains high in HIV-infected patients. In addition to direct liver effects caused by both HIV and HCV, coinfected patients are at increased risk of cardiovascular disease, stroke, diabetes mellitus and other comorbidities typically associated with aging.

Given these observations, the overall aim of the proposed studies in our laboratory is determining whether HIV/HCV coinfection synergistically enhances the effects of age by accelerating immune system activation. These studies utilize molecular and cellular biology approaches to generate an overall picture of important pathways in HIV/HCV pathogenesis and to determine how age affects these pathways, and the potential relevance of coinfection to aging. Currently, we are quantifying and comparing immune activation profiles with gene expression profiles of adult and aged patients with respect to HIV/HCV coinfection to ascertain the effects that coinfection has with regard to chronic immune activation within aged patients. These studies are developing and utilizing unique HIV/HCV coinfected patient cohorts to determine the impact of age on human gene expression, immune activation and development of neurocognitive impairment. These studies will impact research on HIV/HCV/age by identifying new targets and strategies for anti-HIV-1 therapeutics and by minimizing the impact of both age and HCV on HIV-1 disease.

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Selected Publications

“Bifunctional Chimera That Coordinately Targets Human Immunodeficiency Virus 1 (HIV-1) Envelope gp120 and Host Cell CCR5 Co-receptor at the Virus-Cell Interface”
Rashad A, Song LR, Holmes A, Acharya K, Zhang S, Wang ZL, Gary E, Xie X, Pirrone V, Kutzler M, Long YQ, and I Chaiken
Journal of Medicinal Chemistry, in press, 2018

“Defining the molecular mechanisms of HIV-1 Tat secretion: PtdIns(4,5)P2 at the epicenter”
Mele AR, Marino J, Chen K, Pirrone V, Janetopoulos C, Wigdahl B, Klase Z, and MR Nonnemacher
Traffic, in press, 2018

“Human Immunodeficiency Virus (HIV) Infection and Cancer”
*Loarca L, *Fraietta JA, Pirrone V, Szep Z, and B Wigdahl (eds)
InTech Open, Rijeka, Croatia, ISBN 978-953-51-2961-5, 2017
*These authors contributed equally to this work.

“Mitochondrial haplogroup influences motor function in long-term HIV-1-infected individuals”
Azar A, Devlin K, Mell J, Giovannetti T, Pirrone V, Nonnemacher MR, Passic S, Kercher K, Williams J, Jacobson J, Wigdahl B, Dampier W, Libon DJ, and C Sell
PloSOne, 11(10): e0163772, 2016

“Coinfection with Hepatitis C Virus among HIV-1-Infected Individuals Increases Proinflammatory Cytokines and HIV-1 Disease Severity”
Parikh N, Dampier W, Passic SR, Zhong W, Blakey B, Aiamkitsumrit B, Pirrone V, Nonnemacher MR, Szep Z, Jacobson JM, and B Wigdahl
MOJ Immunology, 4(1): 00115, 2016

“Specific amino acids in HIV-1 Vpr are significantly associated with changes in patient neurocognitive status”
Dampier W, Antell GC, Aiamkitsumrit B, Nonnemacher M R., Jacobson J M., Pirrone V, Zhong W, Kercher K, Passic S, Williams JW, James A, Devlin KN, Giovanetti T, Libon DJ, Szep Z, Wigdahl B, and FC Krebs
Journal of Neurovirology, 23(1): 113-124, 2016

“Prolonged Morphine Exposure Induces Increased Firm Adhesion in an In Vitro Model of the Blood–Brain Barrier”
Strazza M, Pirrone V, Wigdahl B, Dampier W, Lin W, Feng R, Maubert ME, Weksler B, Romero IA, Pierre-Olivier C, and MR Nonnemacher
International Journal of Molecular Sciences, 17(6). pii: E916, 2016

“Optimization of the in vitro co-culture of the hCMEC/D3 brain microvascular endothelial cell line and primary human peripheral blood mononuclear cells for functional studies”
Strazza M, Pirrone V, Wigdahl B, and MR Nonnemacher
Journal of Neuroscience Methods, 269: 39-45, 2016

“Utilization of HIV‑1 envelope V3 to identify X4‑ and R5‑specific Tat and LTR sequence signatures”
Antell GC, Dampier W, Aiamkitsumrit B, Nonnemacher MR, Jacobson JM, Pirrone V, Zhong W, Kercher K, Passic S, Williams JW, Schwartz G, Hershberg U, Krebs FC, and B Wigdahl
Retrovirology, 13: 32, 2016

“HIV-1 genetic variation resulting in the development of new quasispecies continues to be encountered in the peripheral blood of well-suppressed patients”
Dampier W, Nonnemacher M R., Mell J, Earl J, Ehrlich G, Pirrone V, Aiamkitsumrit B, Zhong W, Kercher K, Passic S, Williams J, Jacobson JM, and B Wigdahl
PloSONE, 11(5): e0155382, 2016

“HIV-1 LTR single nucleotide polymorphisms (SNPs) are diagnostic of clinical disease parameters”
*Nonnemacher MR, *Pirrone V, Feng R, Moldover B, Passic S, Williams JW, Aiamkitsumrit B, Dampier W, Wojno A, Kilareski E, Blakey B, Ku J, Shah S, Sullivan NT, Jacobson JM, and B Wigdahl
PloSOne, 11(4): e0150835, 2016
*Authors contributed equally

“HIV-1 Latency and Eradication: Past, Present and Future”
Datta PK, Kaminski R, Hu W, Pirrone V, Sullivan NT, Nonnemacher MR, Dampier W, Wigdahl B, and K Khalili
Current HIV Research, Epub ahead of print, 2016

“Interaction between Tat and Drugs of Abuse during HIV-1 Infection and Central Nervous System Disease”
Maubert M, Pirrone V, Rivera NT, Wigdahl B, and MR Nonnemacher
Frontiers in Microbiology, 6:1512, 2016

“Biomarkers of HIV Susceptibility and Disease Progression”
Pirrone V, Mell J, Janto B, and B Wigdahl
Ebiomedicine, 1(2-3):99-100, 2014

"Impact of age on markers of HIV-1 disease"
Pirrone V, Libon DJ, Sell C, Lerner CA, Nonnemacher MR, and B Wigdahl
Future Virology, 9(1):81-101, 2013