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  • Review Article
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Antitumour effects of antiretroviral therapy

Nature Reviews Cancer volume 4, pages 861–875 (2004)Cite this article

Key Points

  • Infection with the human immunodeficincy virus (HIV) increases a patient's risk for developing certain types of cancers.

  • Immune hyperactivation, due to uncontrolled HIV replication, and immune deficiency have been shown to be the key factors in the initiation and progression of these cancers, particularly Kaposi's sarcoma and B-cell lymphomas, in HIV-infected patients.

  • Highly active antiretroviral therapy (HAART) reduces cancer risk and tumour burden in HIV-infected individuals.

  • The effects of these drugs cannot be entirely explained by their ability to suppress HIV replication and restore normal immune function — tumour development is not always correlated with a patient's viral load or level of immune reconstitution.

  • Direct antitumour effects of HAART could be related to specific actions of the protease inhibitors included in this therapeutic cocktail, such as ritonavir, saquinavir, indinavir and nelfinavir. These drugs have been shown to inhibit proliferation and induce apoptosis in cultured cancer cells, to block endothelial- and tumour-cell invasion, in vivo angiogenesis and tumour growth, as well as the inflammatory response.

  • The ability of these drugs to prevent tumour growth and progression might be mediated by their ability to inhibit proteasome function and the activity of matrix metalloproteinases.

  • As HAART has already been shown to be safe and effective for the treatment of patients with AIDS, these drugs might be exploited, alone or in combination with conventional cytotoxic therapy, for the treatment of non-HIV-infected patients with cancer.

Abstract

Infection by human immunodeficiency virus (HIV) is associated with an increased risk of certain tumours, particularly Kaposi's sarcoma, non-Hodgkin's lymphomas and cervical cancer. However, the incidence of these tumours in HIV-infected patients has decreased significantly since the widespread use of highly active antiretroviral therapy (HAART). This effect cannot be solely explained by the ability of these drugs to suppress HIV replication and thereby reconstitute the immune system. Recent studies have shown that inhibitors of the HIV aspartyl protease, which are widely used in HAART, have direct anti-angiogenic and antitumour effects that are unrelated to their antiviral activity. So these drugs might be used to treat cancer in patients who are not infected with HIV.

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Figure 1: Steps in tumour progression and metastasis affected by HIV-protease inhibitors.
Figure 2: Molecular targets of antiviral agents.

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Acknowledgements

We are grateful to H. Kleinman for helpful discussion and to Emanuela Vaccher for discussion on the potential clinical use of HIV-PIs in patients with cancer. We thank A. Carinci, S. Ceccarelli and F. M. Regini for editorial assistance. The work by the authors was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) and from the Italian Ministry of Health (Ricerca Finalizzata) to B. E.

Author information

Authors and Affiliations

  1. AIDS Division, Department of Infectious, Parasitic and Immune Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy

    Paolo Monini, Cecilia Sgadari, Elena Toschi, Giovanni Barillari & Barbara Ensoli

Authors
  1. Paolo Monini
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  2. Cecilia Sgadari
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  3. Elena Toschi
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  4. Giovanni Barillari
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  5. Barbara Ensoli
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Correspondence to Barbara Ensoli.

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Related links

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DATABASES

Entrez Gene

bFGF

COX2

ICAM1

IFNγ

IL-1β

IL-2

IL-2 receptor-α

IL-6

IL-8

MMP2

MMP3

MMP7

monocyte chemoattractant protein 3

MT1-MMP

selectin E

TNFα

TRAIL

transforming growth factor-β

VCAM1

VEGF

WAF1

National Cancer Institute

cervical cancer

non-Hodgkin's lymphomas

OMIM

Kaposi's sarcoma

FURTHER INFORMATION

European Organisation for Research and Treatment of Cancer

GenBank

HIV/AIDS Treatment Information Service

Medscape Druginfo

Southwest Oncology Group

Glossary

NAIVE AND MEMORY T-CELL REPERTOIRE

Mature T cells that have not yet encountered antigens are called naive T cells. Following antigen recognition, naive T cells become activated, proliferate and some differentiate into memory T cells. Both the naive and memory T-cell repertoires are progressively shrunk in HIV-infected patients.

EPIDERMODYSPLASIA VERRUCIFORMIS

A genetic disease characterized by increased susceptibility to human papillomaviruses.

MULTICENTRIC CASTLEMAN'S DISEASE

Lymphoproliferative disorder characterized by reactive lymph nodes with expanded germinal centres and B-cell proliferation. In HIV-infected individuals, the plasma-cell variant is the predominant form, which, in this setting, is invariably infected by KSHV.

HODGKIN'S DISEASE

A heterogeneous lymphoma entity originating from germinal-centre or post-germinal-centre B cells. The classical form has a post-germinal-centre phenotype and is the predominant form in HIV-infected individuals.

MATRIX METALLOPROTEINASES (MMPS)

Enzymes that degrade the extracellular matrix and are required for tumour-cell invasion of basement membranes and migration in interstitial tissue. MMPs are involved in angiogenesis, wound healing, tumour invasion, inflammation and all processes requiring tissue remodelling.

HELPER T CELLS

T lymphocytes that express the surface molecules CD3 and CD4, and recognize antigen peptides presented by MCH-class-II molecules. Following antigen recognition, these cells produce cytokines that activate B-cells, macrophages and granulocytes, and that induce differentiation of cytotoxic T lymphocytes into effector cells.

IMMUNOBLASTIC LYMPHOMA

A subtype of NHLs that belongs to the group of the diffused large-cell lymphomas, accounting for about 25% of HIV-associated lymphomas. It is associated with EBV infection and expression of LMP1.

PRIMARY-NERVOUS-SYSTEM LYMPHOMA

A NHL subtype, usually with immunoblastic features, that arises in the central nervous system. This subtype is invariably associated with EBV infection, and expresses the viral oncoprotein LMP1.

CENTROBLASTIC DIFFUSE LARGE-CELL LYMPHOMA

A systemic subtype of NHL belonging to the group of the diffused large-cell lymphomas, accounting for about 10% of HIV-associated lymphomas. About 30% of these lymphomas are infected with EBV but do not express the viral oncoprotein LMP1.

BURKITT'S LYMPHOMA

A systemic subtype of NHL that accounts for about 30% of HIV-associated lymphomas. It is characterized by c-MYC alteration due to chromosomal translocation, and by p53 inactivation. About 30% of cases are associated with EBV infection, and tumour cells do not express the viral oncoprotein LMP1.

HIV-1 Tat PROTEIN

A viral regulatory protein that induces expression of viral genes.

TH1-TYPE PRO-INFLAMMATORY CYTOKINES

Cytokines produced by helper T cells of the TH1 subset. These cytokines activate T cells and macrophages, and stimulate cell-mediated immunity. Most of these cytokines also have inflammatory activity, activate vessels and recruit immune cells at sites of tissue damage.

CLASSIC, AFRICAN AND POST-TRANSPLANT KAPOSI'S SARCOMA

Three epidemiological forms of the disease that share the same histopathological traits as HIV-associated Kaposi's sarcoma (AIDS-KS), although they are less aggressive, and are not associated with HIV infection. The classic form is prevalent in elderly people of Mediterranean origin, the African form is endemic in central Africa, and post-transplant Kaposi's sarcoma occurs in transplant patients receiving immune-suppressive therapy.

T-CELL PRIMING

Occurs following the first encounter of naive T cells with antigenic peptides on antigen-presenting cells, and results in the induction of a primary immune response.

CYTOTOXIC T LYMPHOCYTES

T cells that express the surface molecules CD3 and CD8, and recognize antigen peptides presented by MCH-class-I molecules. Following antigen recognition and stimulation by T helper cells, activation of these cells allows them to kill cancer cells and cells infected with intracellular pathogens such as viruses.

IMMUNOPROTEASOME

A form of proteasome that is present in professional antigen-presenting cells and is induced in other cell types by inflammation. The immunoproteasome produces epitope peptides for presentation to cytotoxic T cells.

PROFESSIONAL ANTIGEN-PRESENTING CELLS

Cells that internalize and process antigens for presentation to immune cells by MHC-class-I and -II molecules. Include macrophages, B cells and dendritic cells.

OSTEOPAENIA AND OSTEOPOROSIS

Bone undergoes continuous remodelling through resorption and formation of the calcified matrix. Osteopaenia (bone thinning) and osteoporosis (bone softening) are characterized by bone demineralization, leading to low bone mineral density or content.

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Monini, P., Sgadari, C., Toschi, E. et al. Antitumour effects of antiretroviral therapy. Nat Rev Cancer 4, 861–875 (2004). https://doi.org/10.1038/nrc1479

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