Abstract
HIV-induced immune suppression results in the high prevalence of HIV/AIDS-associated malignancies including Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer. HIV-infected people are also at an increased risk of “non-AIDS-defining” malignancies not directly linked to immune suppression but associated with viral infections. Their incidence is increasing despite successful antiretroviral therapy. The mechanism behind this phenomenon remains unclear. Here, we obtained daughter clones of murine mammary gland adenocarcinoma 4T1luc2 cells expressing consensus reverse transcriptase of HIV-1 subtype A FSU_A strain (RT_A) with and without primary mutations of drug resistance. In in vitro tests, mutations of resistance to nucleoside inhibitors K65R/M184V reduced the polymerase, and to nonnucleoside inhibitors K103N/G190S, the RNase H activities of RT_A. Expression of these RT_A variants in 4T1luc2 cells led to increased production of the reactive oxygen species (ROS), lipid peroxidation, enhanced cell motility in the wound healing assay, and upregulation of expression of Vimentin and Twist. These properties, particularly, the expression of Twist, correlated with the levels of expression RT_A and/or the production of ROS. When implanted into syngeneic BALB/C mice, 4T1luc2 cells expressing nonmutated RT_A demonstrated enhanced rate of tumor growth and increased metastatic activity, dependent on the level of expression of RT_A and Twist. No enhancement was observed for the clones expressing mutated RT_A variants. Plausible mechanisms are discussed involving differential interactions of mutated and nonmutated RTs with its cellular partners involved in the regulation of ROS. This study establishes links between the expression of HIV-1 RT, production of ROS, induction of EMT, and enhanced propagation of RT-expressing tumor cells. Such scenario can be proposed as one of the mechanisms of HIV-induced/enhanced carcinogenesis not associated with immune suppression.
Highlights
HIV-induced depletion of CD4+ T-helper cells determines high prevalence of HIV/AIDS-associated malignancies, including Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer
HIVinfected people have increased risks for the forms of cancer not directly associated with the immune suppression, such as lung cancer, liver cancer caused by infections with hepatitis B and hepatitis C viruses, and anogenital and oropharyngeal cancer associated with human papillomavirus (HPV) infections [1]
We have previously found that the transient expression of HIV-1 reverse transcriptase (RT) in the mammalian cells induces the production of Reactive Oxygen Species (ROS), oxidative stress, and oxidative stress response [26, 27]
Summary
HIV-induced depletion of CD4+ T-helper cells determines high prevalence of HIV/AIDS-associated malignancies, including Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer. Blocks apoptosis, increases cell migration/motility, and accelerates tumor formation [19]. In tumor cells, it induces a significant reduction in the expression of cell cycle inhibitors of transcription and an increase in the levels of proliferation markers [21] and stimulates growth of tumor cells [22]. It induces a significant reduction in the expression of cell cycle inhibitors of transcription and an increase in the levels of proliferation markers [21] and stimulates growth of tumor cells [22] Both structural and regulatory HIV-1 proteins demonstrate direct carcinogenic effects and/or promote the effects of known carcinogens
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