A team of researchers at Ohio State University, headed by molecular virologist Dr. Richard Fishel, has inadvertently discovered that two human nuclear proteins that might protect cells against the AIDS virus, HIV.

Point of action in HIV life cycle by conventional anti-AIDS drugs (Credit: chem.wisc.edu)
Could the cell defend itself against infection of the human immunodeficiency virus (HIV)? Well apparently it might be able to using nuclear DNA repair proteins that normally function in the repair of DNA lesions. In the future these proteins might help fight off HIV infection as an alternative to or in conjunction with today's anti-AIDS drugs to which HIV is more likely to become resistant by rapid mutation. Those drugs are designed to inhibit specific stages of the HIV life cycle.

Life-cycle-of-HIV (Credit: chem.wisc.edu)
The life cycle of the retrovirus HIV can be described from the point of viral attachment by binding of HIV membrane proteins to a host cell surface receptor. Subsequent membrane fusion causes injection, into the cytoplasm of the cell, of the HIV nucleocapsid or nucleoprotein core, which contains its genetic material in the form of two copies of a single stranded RNA genome, as well as several viral enzymes and other proteins. Using the viral reverse transcriptase enzyme, the retroviral RNA genome is copied in the cytoplasm into a double stranded DNA form by a process known as reverse transcription. The DNA copy – also known as cDNA, for copy DNA – is then transported to the nucleus of the cell where it is integrated into the host cell's chromosomal DNA using the viral enzyme integrase in concert with various host proteins.

At this point, the integrated viral DNA, termed a provirus, is replicated as part of the host chromosomal DNA. Using the provirus as template, the host cell transcription machinery synthesizes RNA that is used for template for more copies of the viral RNA genome and as mRNA for translation of viral protein products in the cytoplasm. Progeny viruses are assembled from the RNA genome and viral protein products and then liberated by budding from the cell surface to go on to infect surrounding uninfected cells, eventually causing AIDS.

Apparently by accident, Dr. Fishel's team discovered that cells with high levels of the cellular proteins XPB and XPD harbor lower levels of the HIV provirus. Both proteins are nuclear DNA repair proteins that repair damaged DNA. When researchers tried to deliberately damage the ability of the repair proteins to repair DNA by introducing mutations into the XPB and XPD genes, provirus levels rose again. Further research suggested that the two proteins degraded some of the HIV cDNA before its integration into the chromosome of host cells.

Dr. Richard Fishel

In an interview with TFOT, Dr. Fishel answered a few questions about his current research, and its possible applications for fighting AIDS.

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