The AIDS and Cancer Specimen Resource (ACSR): HIV malignancy specimens and data available at no cost

Using in vitro and in vivo studies, Ayers et al. (2018) identified mast cells (MCs) as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV, and as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesion microenvironment [6]. Importantly, the study identifies MC antagonists as a promising novel therapeutic approach for KS [6].

Byakwaga et al. (2021) examined the activation of mast cells (MC) in a cross-sectional study of untreated PWH in a cohort in Uganda with or without KS [9]. The study found a dose-response relationship between plasma IgE levels and the presence and severity of KS, and that therapies targeting IgE-mediated MC activation might be a new treatment approach [9].

A study by Toptan et al. (2018) showed that both the Epstein-Barr virus (EBV) and the Kaposi sarcoma herpes virus (KSHV) express circular RNAs (circRNAs) in tumors and cell lines infected with both viruses, which is a novel significant finding [10]. Until this study, it was not known whether human DNA viruses express circRNAs. Understanding the function of tumor virus circRNAs, which are unique biomarkers, may contribute to the knowledge about how these viruses cause cancer [10].

A study by Abere et al. (2020) showed that for one KSHV region, the PAN/K7.3 locus, broadly and bidirectionally generated circRNA levels that paralleled corresponding linear RNA levels, while another KSHV circRNA (circ-vIRF4) showed expression that differed from that of the corresponding linear RNA. The study also showed that all KSHV circRNAs are incorporated into KSHV virions and are potentially expressed as immediate early products in newly infected cells [11].

Thakker et al. (2018), for the first time, demonstrated epidermal growth factor-like domain (EGFL7) to be an important angiogenic molecule secreted and upregulated during KSHV infection that could be exploited for blocking KSHV associated malignancies in conjugation with other anti-angiogenic therapies [12].

Lee et al. (2018) showed that lymphangiogenic pathways are involved in KSHV infection and progression to KSHV-associated pathogenesis. This study reported for the first time that viral interferon regulatory factor 3 (vIRF3) is detected in over 40% of KS lesions and functioning as a proangiogenic factor, inducing hyper sprouting formation and abnormal growth of lymphatic endothelial cells in a histone deacetylase 5 (HDAC5) dependent manner, which is a signal-response regulator for vascular homeostasis [13].

Cavallin et al. (2018) showed that KSHV lytic replication as well as the KSHV-oncogene vGPCR activates PDGFRA signaling through upregulation of its ligands PDGFA/B, and that blocking of PDGFRA signaling is anti-tumorigenic indicating that stable inhibition of PDFGR-signaling has potential for KS treatment [14].

A study by Kumar et al. (2019) demonstrated that KSHV infection induced the E3 ligase HACE1 protein to regulate KSHV-induced oxidative stress by promoting the activation of Nrf2 and nuclear translocation. Absence of HACE1 resulted in increased ROS, which facilitates virus entry, cellular death and reduced nuclear Nrf2, antioxidant, and viral gene expression. Taken together, these studies suggest that HACE1 can be a potential target to induce cell death of KSHV-infected cells [15].

Valiya Veettila et al. (2020) identified neuronal and neuroendocrine gene (NE) proteins characteristic of NE tumors that are upregulated in KSHV infected patient tissues, and which potentially may provide an avenue to escape host immune surveillance when expressed at immunologically privileged sites such as at the interface of neurons and endothelial cells. These newly identified NE gene products potentially could serve as biomarkers and therapeutic targets for KSHV infected cells [16].

A study by Naipauer et al. (2020) revealed that CpG hypo-methylation of oncogenic and differentiation pathway predominantly promotes KSHV in vivo tumorigenesis, occurs and selects for pre-existing host mutations that allow the KSHV oncovirus to express oncogenic lytic genes by creating permissive environment for viral-induced innate immunity and inflammation, which provides a selective advantage in vivo conducive to tumorigenesis. The results of this study point out the mutagenic potential of KSHV indicating the existence of KSHV-induced oncogenic host mutations in KS lesions that could be selected upon treatment and impact AIDS-KS therapies [17].

Members of the ACSR, together with collaborators at the UPMC Hillman Cancer Center and School of Medicine in Pittsburgh reviewed the status of the bacteria-virus interactions in Kaposi’s sarcoma-associated herpesvirus (KSHV) infection and KSHV-driven cancers [18]. Due to immunosuppression, patients with KSHV are at an increased risk for bacterial infections. In addition, infection with distinct opportunistic bacterial species have been associated with increased cell proliferation and tumorigenesis in KSHV-induced cancers through activation of pro-survival and -mitogenic cell signaling pathways. Moreover, among patients coinfected by HIV and KSHV, patients with KS have distinct oral microbiota compared to non-KS patients elucidating the various mechanisms in which bacteria affect KSHV-associated pathogenesis, will help identify therapeutic targets for KSHV infection and KSHV-related cancers [18].

A person with HIV is 10 to 20 times more likely to develop aggressive non-Hodgkin lymphoma (NHL) despite HAART and 5 to 26 times more likely to develop Hodgkin lymphoma, a non-AIDS defining neoplasm, than a person without HIV infection [19]. The clinical outcome in patients with HIV-NHL has improved, approaching that of the general population when standard-dose chemotherapy paradigms are used in conjunction with HAART [20, 21]. HIV-NHLs make up the majority of lymphoma diagnoses and represent a diverse set of malignancies. The most common HIV-NHL is diffuse large B cell lymphoma (DLBCL), which is 17-fold more likely to occur. Its clinical course is more aggressive and often presents at advanced stages in HIV infected patients as compared to HIV-negative patients. However, the molecular pathology driving the aggressive nature of DLBCL is still poorly understood. The following studies supported by specimens and data from the ACSR are shedding some light on AIDS-defined non-Hodgkin lymphoma and were made with the support of the ACSR.

A retrospective study examined the transcriptional, genomic and protein expression differences between HIV(+) and HIV(-) germinal center B-cell (GCB) diffuse large B cell lymphoma (DLBCL) cases using digital gene expression analysis, array comparative genomic hybridization (CGH) and immunohistochemistry (IHC) [22]. The results show that genes associated with cell cycle progression, DNA replication and DNA damage repair are significantly upregulated in HIV(+) GCB-DLBCL compared to HIV(-) tumors. In contrast, genes associated with cell cycle inhibition and apoptosis regulating Bcl2 proteins were significantly decreased and have less copy number variations as HIV (-) tumors, as determined by array CGH data, indicating enhanced genomic stability in (HIV (+) tumors. In summary, this study shows that HIV(+) GBC-DLBCL is distinct from HIV(-) GBC-DLBCL in its molecular profile. In addition as compared to the HIV (-) tumor, the study revealed an overexpression of TRFC/CD71 mRNA, an iron uptake mediator and positive regulator of T- and B cell proliferation, in HIV (+) GCB DLBCL tumors resulting in a loss of both adaptive and innate immune signaling, as well as alterations in receptor signaling [22].

Using the Lymph2Cx diagnostic assay for Cell of Origin (COO) typing transcriptional differences between HIV (+) and HIV (-) GCB-DLBCL, Maguire et al. (2019) examined 40 cases [23]. Reduced BCL2, a negative prognostic DLBCL marker, was observed in HIV (+) DLBCL suggesting a reduced dependence on the pro-survival effects of BCL2 and a switch to a mechanism that prevents cycle inhibition and induction of apoptosis in HIV (+) GBC-DLBCL [23].

Further insights into lymphomagenesis in HIV positive people comes from a retrospective study of HIV (+) and HIV (-) DLBCL formalin-fixed paraffin-embedded patient tissues assessing expression of activation-induced cytidine deaminase (AID) levels, known to be upregulated in non-neoplastic B-cells in vitro, by Shponka et al. (2020) [24]. The study showed higher AID and DC-SIGN receptor expression levels in HIV (+) DLBCL compared to HIV (-) DLBCL suggesting involvement of both AID and potentially the DC-SIGN receptor-signaling pathway in HIV related pathogenesis of lymphoma [24].

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, with a variable response to chemotherapy depending on, and not limited to, cell of origin, double/triple hit, or MYC/BCL-2 co-expression status. Similar to DLBCL, AIDS-related DLBCL (ARL) with non-germinal center histology or MYC expression reports poorer response to treatment. In the immunocompetent population with DLBCL, CD30 positivity defines a histology with improved survival, however, the characteristics and outcomes of ARL treated HIV (+) tumors expressing CD30 are not well studied.

Chaudry et al. ((2021) assessing 135 ARL patients showed that 30% expressed CD30 [25]. The CD30 positive cases were mostly a non-germinal center phenotype and had a strong correlation with EBV. No differences in survival were identified in this study, possibly due to the small numbers of patients assessed with survival data [25].

This is an important finding since CD30 is the target for Brentuximab vedotin (BV, ADCETRIS®), an antibody-drug conjugate (ADC) consisting of an anti-CD30 monoclonal antibody covalently linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) by a protease-cleavable linker [26‐28]. Brentuximab vedotin is currently approved for classical Hodgkin lymphoma (CHL), anaplastic large cell lymphoma (ALCL) (another lymphoma where malignant cells uniformly express CD30), as well as CD30-expressing peripheral T-cell lymphomas and mycosis fungoides (MF) [ADCETRIS prescribing information]. The efficacy of Brentuximab vedotin (BV, ADCETRIS®) in ARL patients with DLBCL needs be examined in clinical trials.

Wong et al. (2019) found the kinase Tyro3 upregulated in different NHL subtypes and in primary effusion lymphoma (PEL) cell lines and exudates by using multiplexed inhibitor bead-mass spectrometry (MIB/MS) [29]. Tyro3 plays a pivotal role in cell survival in PEL, a viral lymphoma associated with Kaposi’s sarcoma-associated herpesvirus (KSHV). They also developed an inhibitor against Tyro3 named UNC3810A, which hindered cell growth in PEL, but not in other NHL subtypes where Tyro3 was not highly expressed. This indicates that Tyro3 is a potential therapeutic target [29].

Although T cell NHLs are rare in people living with HIV, the existing data suggest a very poor prognosis with a median OS of 5–12 months [30]. HIV1 infection increases the risk of cancer, immunodeficiency, and co-infection with oncogenic viruses, such as EPS, KSHV and human papilloma virus, can cause clonal expansions of T cells in vivo. Mellors et al. (2021) showed that HIV-1 proviruses integrated in the first introns of signal transducer and activator of transcription 3 (STAT3) and lymphocyte-specific protein tyrosine kinase (LCK) can play a significant role in the development of T cell lymphomas [31]. The development of these cancers appears to be a multistep process involving additional nonviral mutations, which could help explain why T cell lymphomas are rare in persons with HIV-1 infection [31].

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV+) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. Gagliardi et al. (2020) characterized 118 tumors from Ugandan patients, of whom 72 were HIV+, and performed extended mutation analysis on an additional 89 tumors [32]. The study detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were found to be correlated with upregulation of nearby genes and endogenous retroviruses [32].