Novel mechanism of HIV-1 driven carcinogenicity affecting epithelial cells

Maria Isaguliants (Issagouliantis), Juris Jansons, Dzeina Mezale, Dace Skrastina, Ekaterina Bayurova, Darya Avdoshina, Alla Kondrashova

Research output: Contribution to conferenceAbstractpeer-review

Abstract

HIV-1 infected people are characterized by high prevalence of cancers affecting epithelial cells despite successful antiretroviral treatment. We hypothesize that this is due to the direct carcinogenic properties of HIV-1 Tat, Nef, gp120, p17 and reverse transcriptase (HIVRT). This study aimed at characterizing carcinogenicity of HIVRT. DNA encoding HIVRT, rat telomerase reverse transcriptase and its telomerase domain (rtTERT) were synthesized and cloned into lentiviral vector (Addgene). Resulting lentiviruses were used to transduce murine mammary gland adenocarcinoma 4T1luc2 cells (Caliper) generating subclones expressing rtTERT (n=8) and HIVRT (n=2). RtTERT and HIVRT genomic inserts were quantified by ddPCR. Subclones were ectopically implanted into BALB/c mice; tumor growth was monitored by in vivo, and metastatic activity, by ex vivo bioluminescent imaging (Spectrum, PerkinElmer). Mouse organs were formalin-fixed, paraffin-embedded, sectioned, hematoxylin–eosin-stained, and examined by light microscopy with computer-assisted morphometry using specialized NIS-Elements (Nikon). Data was analyzed using nonparametrical statistics (Statistica AXA 11). 4T1luc2 cells expressing HIVRT and rtTERT were obtained. Expression of HIVRT led to increased production of ROS, lipid peroxidation, enhanced cell motility, and overexpression of Twist mRNA, dependent on the levels of HIVRT expression. Implanted into syngeneic BALB/C mice, HIVRT-expressing cells caused enhanced, and rtTERT-expressing, reduced tumor growth and metastasis formation compared to parental cells (p<0.05). Activities of rtTERT-expressing cells inversely and of HIVRT-expressing cells directly correlated with the number of respective genomic inserts, and for HIVRT were proportional to HIVRT expression and levels of ROS (p<0.05). We present a novel mechanism of HIV-associated malignant transformation of epithelial cells by HIVRT, analogous to the effects exerted by HIV-1 proteins Tat, gp120, Nef and p17. HIV-1 RT as other carcinogenic HIV-1 proteins triggers malignant transformation of normal epithelial cells, causes propagation of precancerous and cancer cells and thus promotes HIV-1 associated carcinogenesis aggravated by HBV, HCV, EBV and HPV-coinfections. Acknowledgements: LZP-2018/2-0308, RFBR 20-04-01034.
Original languageEnglish
Pages254
Publication statusPublished - 24 Mar 2021
EventRSU Research week 2021: Knowledge for Use in Practice - Rīga, Latvia
Duration: 24 Mar 202126 Mar 2021
https://rw2021.rsu.lv/conferences/knowledge-use-practice

Conference

ConferenceRSU Research week 2021: Knowledge for Use in Practice
Abbreviated titleRW2021
Country/TerritoryLatvia
CityRīga
Period24/03/2126/03/21
Internet address

Field of Science

  • 3.3 Health sciences

Publication Type

  • 3.4. Other publications in conference proceedings (including local)

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