HIV-1, Cancer and Splicing: The Triangle

BOSTON - May 22, 2017 - EntSun -- The Boston Biotech Meetup is featuring the work of Dr. Parmit Kumar Singh at Advances in Gene Therapy on June 6, 2017. RSVP for this free event at http://meetup.com/bostonbiotech.

Dr. Singh will be presenting HIV-1, cancer and splicing: the triangle.

HIV-1-based vectors are popular in gene therapy to avoid oncogene activation by gamma retrovirus-based vectors in gene therapy recipients. However, there is not much information about whether HIV-1 shows preference for cancer genes.

HIV-1 prefers integration in actively transcribed genes. This bias preference for integration into genes depends on the interaction between HIV-1 integrase and the host chromatin-binding factor LEDGF/p75. LEDGF/p75 is a transcription factor, and it has a chromatin binding PWWP domain and an integrase-binding domain. However, the cellular role of LEDGF/p75 is not well understood. It is also not known how LEDGF/p75 recognizes actively transcribed genes.

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Therefore, to understand the mechanism of LEDGF/p75-dependent integration, Dr. Singh determined 1 million unique integration sites of HIV-1 in human cultured cells by pair-end Illumina sequencing.

Bioinformatic analysis of these integration sites showed that HIV-1 prefers integration into cancer genes were preferentially targeted. The result is significant as it stresses the need for further study to design a safe HIV-1-based vector for gene therapy by considering the associated risk.

Further, Dr. Singh developed new methods to do bioinformatics analysis of these one million integration sites. By this new method it was found that HIV-1 prefers integration into genes with a higher number of introns or highly spliced genes. Also, it showed that the preference for integration into highly spliced genes depends on LEDGF/p75.

This was a very significant result as it not only suggests the cellular role of LEDGF/p75 in splicing but also it suggests a link between the normal cellular process splicing, HIV-1 integration and cancer as it is known that misregulation of splicing causes many diseases like cancer.

Interestingly, Dr. Singh showed LEDGF/p75's role in splicing by studying the change in splicing human genes in the absence of LEDGF/P75. Almost 4000 genes changed their splicing compared to their splicing pattern in the presence of LEDGF/p75. Further studies to understand the mechanism of LEDGF/p75-dependent splicing and its role in HIV-1 integration are needed to develop a better picture.

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Dr. Parmit Kumar Singh completed his PhD at the Centre for Cellular and Molecular Biology (CCMB), Hyderabad, India. Dr. Singh determined the threshold size of duplicated DNA that titrates repeat induced point mutation (RIP) machinery. Moreover, he identified the first wild-isolate strain of Neurospora as a dominant suppressor of meiotic silencing. Both RIP and meiotic silencing are genome defense processes in Neurospora.

During his postdoc at the National Institutes of Health, he researched the integration preference of HIV-1 and his results, based on one million integration sites of HIV-1 in human cultured cells, showed that HIV-1 has a preference for the highly spliced and cancer genes. The result was published in Genes and Development.

Dr. Singh has also taught at the Foundation for Advanced Education in the Sciences (FAES) and Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA.