Introduction
Human immunodeficiency virus (HIV-1) is infamous for its devastating impact on the immune system, which leads to acquired immunodeficiency syndrome (AIDS). One of the lesser-known but equally serious complications associated with HIV-1 infection is an increased risk of various cancers, both AIDS-defining cancers (ADC), such as Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), and cervical cancer, and non-AIDS-defining cancers (NADC). This elevated cancer risk has long been attributed to the profound immune suppression caused by HIV-1. However, even with the advent of highly effective antiretroviral therapy (ART), which has significantly improved immune function and longevity among people living with HIV (PLWH), the incidence of both ADC and NADC remains elevated. This inconsistency raises the question: could HIV-1 itself, or its proteins, play a direct role in carcinogenesis independent of immune suppression?
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Mechanisms Beyond Immune Suppression
While immune suppression due to the depletion of CD4+ T-helper cells is a significant factor contributing to the higher incidence of cancer among PLWH, it is not the sole cause. ART, while capable of reducing viral load to undetectable levels and partially restoring immune function, does not completely ameliorate the immune dysregulation and chronic inflammation associated with HIV-1 infection. Persistent immune activation, driven by factors such as microbial translocation, co-infections, and residual viremia, continues to create an environment conducive to cancer development.
HIV-1 Protein-Mediated Oncogenesis
Experimental data have shown that HIV-1 virions and individual viral proteins can enter various cell types, including those not traditionally associated with HIV infection, such as epithelial cells. Five key HIV-1 proteins-envelope protein gp120, accessory protein Nef, matrix protein p17, transactivator of transcription Tat, and reverse transcriptase RT-are implicated in oxidative stress and oncogenesis. These proteins can be released from HIV-1-infected cells and affect bystander cells, potentially leading to the malignant transformation of normal epithelial cells.
Prevalence of Non-AIDS Defining Cancers
Liver Cancer
Liver cancer, particularly hepatocellular carcinoma (HCC), remains a major concern for PLWH. Co-infection with hepatitis B (HBV) and C viruses (HCV) accelerates liver disease progression and increases the likelihood of developing liver cancer. HIV-1 exacerbates liver damage by impairing immune responses, causing persistent immune activation, and generating oxidative stress. HIV-1 virions and proteins directly infect hepatic cells, activate hepatic stellate and Kupffer cells via TLR-4 signaling, and induce inflammation and fibrosis, thereby promoting HCC.
Fig. 1 The effect of HIV-1 on cells of the liver (Isaguliants M., et al. 2021).
Brain Cancer
PLWH are also at a higher risk for brain cancers, including primary central nervous system lymphomas (PCNSL) and glioblastomas (GBM). The incidence of these tumors, notably higher in PLWH compared to the general population, cannot solely be linked to immune suppression. HIV-1 directly infects and integrates into brain cells, disrupting their function and contributing to tumor development. This suggests HIV-1 has intrinsic tumorigenic properties independent of immune deficiency.
Squamous Cell Carcinomas
Squamous cell carcinomas, especially those related to high-risk human papillomaviruses (HR HPVs) such as cervical, anal, and oropharyngeal cancers, are prevalent among PLWH. While HIV-1-induced immune suppression facilitates the initial HPV infection and persistence, HIV-1 proteins further disrupt epithelial cell function without needing productive infection. This includes oxidative stress induction and epithelial-to-mesenchymal transition (EMT), facilitating malignant transformation.
Direct Carcinogenic Effects of HIV-1 Proteins
Cooperative Interactions with Other Oncogenic Viruses
The oncogenic potential of HIV-1 proteins is often amplified through interactions with other viruses. HIV-1 potentiates the carcinogenic effects of HBV, HCV, and HPV through various mechanisms. For instance, HIV-1 proteins such as Nef and gp120 can enhance the replication and expression of HBV and HCV viral genes, leading to increased liver damage and accelerated progression to HCC. Similarly, the interaction of HIV-1 proteins with HPV oncoproteins can facilitate the progression of HPV-induced neoplasia to invasive cancer.
Oxidative Stress
Oxidative stress is a central mechanism by which HIV-1 proteins contribute to carcinogenesis. HIV-1 infection and its proteins, including Tat, gp120, Nef, RT, and p17, induce the production of reactive oxygen species (ROS) in various cell types. This oxidative stress leads to DNA damage, genomic instability, and the activation of signaling pathways involved in cell proliferation and survival. The chronic inflammatory environment created by oxidative stress further promotes the malignant transformation of cells and the progression of existing tumors.
Individual Role of HIV-1 Proteins
Tat: Known for its ability to manipulate the cell cycle, Tat inhibits cell differentiation, blocks apoptosis, and promotes angiogenesis. It also interferes with DNA repair mechanisms, leading to genomic instability.
Gp120: This envelope protein induces EMT and promotes cell migration and survival through the TGF-beta and MAPK signaling pathways. It has been shown to enhance glycolysis, a hallmark of cancer cells, thereby supporting tumor growth and metastasis.
Nef: Nef modulates multiple signaling pathways, inhibits apoptosis, and enhances angiogenesis. It also interacts synergistically with other viral oncoproteins, such as KSHV K1, to promote tumorigenesis.
RT: Expression of RT induces EMT and increases the metastatic potential of cancer cells. It also contributes to oxidative stress and the upregulation of transcription factors involved in malignant transformation.
P17: This matrix protein promotes angiogenesis and lymphangiogenesis, contributing to the aggressive behavior of cancers. It also generates a pro-tumorigenic microenvironment by deregulating immune cell functions.
Oncogenic HIV-1 Proteins in the Extracellular Space
HIV-1 proteins can exert their oncogenic effects not only intracellularly but also in the extracellular space. Proteins like Tat, Nef, gp120, and p17 are released from infected cells and can be found in the plasma and tissue of PLWH. Their presence in the extracellular environment allows them to interact with and affect neighboring uninfected cells, perpetuating a cycle of chronic inflammation and immune activation. These extracellular proteins induce oxidative stress, modulate gene expression, and influence cell signaling pathways, contributing to the malignant transformation and propagation of cancer cells.
Conclusion
The persistence of high cancer rates among PLWH, even under successful ART, underscores the need to reevaluate the traditional understanding of HIV-1-associated carcinogenesis. While immune suppression and chronic inflammation are significant factors, the direct carcinogenic potential of HIV-1 proteins plays a crucial role. HIV-1 proteins such as Tat, Nef, gp120, RT, and p17 can induce oxidative stress, interfere with cell signaling, and modulate the tumor microenvironment in ways that promote cancer development and progression. Therefore, understanding the multifaceted mechanisms by which HIV-1 proteins contribute to carcinogenesis will be crucial for developing targeted therapies and preventive measures for PLWH.
References
- Isaguliants M., et al. Oncogenic effects of HIV-1 proteins, mechanisms behind. Cancers. 2021, 13(2): 305.
- Pellegrino M., et al. HIV-1 structural proteins or cell-signaling factors? That is the question! Current Issues in Molecular Biology. 2024, 46(6): 5100-5116.
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