Cancer and HIV: The Molecular Mechanisms of the Deadly Duo

Abstract

The immune deficiency associated with human immunodeficiency virus (HIV) infection causes a distinct increased risk of developing certain cancer types. Kaposi sarcoma (KS), invasive cervical cancer and non-Hodgkin's lymphoma (NHL) are the prominent malignancies that manifest as a result of opportunistic viral infections in patients with advanced HIV infection. Despite the implementation of antiretroviral therapy (ART), the prevalence of these acquired immunodeficiency syndrome (AIDS)-defining malignancies (ADMs) remains high in developing countries. In contrast, developed countries have experienced a steady decline in the occurrence of these cancer types. However, there has been an increased mortality rate attributed to non-ADMs. Here, we provide a review of the molecular mechanisms that are responsible for the development of ADMs and non-ADMs which occur in HIV-infected individuals. It is evident that ART alone is not sufficient to fully mitigate the potential for ADMs and non-ADMs in HIV-infected individuals. To enhance the diagnosis and treatment of both HIV and malignancies, a thorough comprehension of the mechanisms driving the development of such cancers is imperative.

Keywords: AIDS-defining malignancy; HIV/AIDS; Kaposi sarcoma; antiretroviral therapy (ART); cancer; invasive cervical cancer; non-AIDS-defining malignancy; non-Hodgkin’s lymphoma; viral load.

Figure 1

The various complex interactions between HHV-8 and HIV that lead to the formation of KS lesions. These include the production of inflammatory cytokines and growth factors by HHV-8. The lesion in turn produces FGF-2. The involvement of LANA leads to the inhibition of p53 and activation of signaling pathways. HIV in combination with HHV-8 causes bcl-2-mediated inhibition of p53. HIV Tat-1-1 protein acts a transcription factor to promote angiogenesis, growth and inhibition of apoptosis in addition to promoting viral replication.

Figure 2

The continual exposure of the immune system to constantly changing HIV antigens and the resultant inflammatory stress has been implicated in the accelerated aging of the immune system, which is usually only seen at the end of a healthy individual’s lifetime. This enhanced “inflammaging” leads to the depletion of the naïve T-cell population and the accumulation of differentiated and anergic T-cells. These essentially ineffective HIV-targeting T-cells have a reduced capacity to proliferate and are susceptible to activation-induced apoptosis. These changes render the immune system ineffective in eliciting a strong immune response towards new antigens that might arise, compromising the immune surveillance and eradication of new cancerous cells. This includes chronic HIV-induced inflammation. Various inflammatory mediators produced during HIV infection, such as ROS and RNS, contribute to carcinogenesis by modifying the growth and survival of normal cells or triggering the proliferation of cells with tumorigenic potential.