Scientists reveal new phase of HIV infection
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A new life cycle stage of HIV infection has been identified by researchers at the University Of Massachusetts Medical School with the help of a novel technique they developed that enables then to take images of intact infected cells. This staged is named as intra-nuclear migration and it relies on the human protein CPSF6 to guide the virus through the host cell’s nucleus and position it at active genes where it prefers to make its home explained principal investigator Abraham L. Brass, MD, PhD.
HIV, DNA
Dr. Brass who is also an assistant professor of microbiology & physiological systems said that the findings of the study are significant as it reveals an important stage and mechanism in HIV infection that was previously unappreciated. The details of the finding and imaging techniques used were published in Cell Reports.
ViewHIV is the technique vital to this finding; it was developed by Brass and his colleagues, Jill Perreira and Chris Chin, both research associates at UMMS; and Eric Feeley, a PhD candidate at Duke University. Using this technique, close monitoring of the migration of HIV was possible. HIV is made up of a protein capsule that contains the virus’s DNA, as it passes through the nuclear membrane and moves around inside the nucleus. Scientists have been unable to generate good images of HIV inside the nucleus using standard techniques.
Perreira, a co-lead author on the study opined that there are certain characteristics of a virus that can be learnt by keeping it intact and seeing it in action in single cells. Even though researchers have been studying HIV for 30 years, there is no good way to look inside infected cells. The aim of the research has been to find a way to see what’s going on inside which in turn will help in getting a better idea of what the virus is doing and how to stop it.
ViewHIV developed by the research team, is capable of generating images of both the viral genome and protein capsid simultaneously inside an infected host cell. ViewHIV pairs a very sensitive type of fluorescence in situ hybridization (FISH) with a monoclonal antibody that binds to the viral capsid. This allowed the capsid, tagged with a fluorescent antibody, to be seen in the images of the nucleus. This technique enabled scientists to visualize the movement and fate of the viral capsid, DNA and RNA inside the cell. Standard confocal microscopy is then used to take both horizontal and vertical photos of the cell that are re-assembled into detailed three-dimensional images of the cell.
With the help of the images produced by ViewHIV, Perreira and Chin, were able to track the virus and its capsid as it moved through the cytoplasm, across the nuclear membrane and finally into the nucleus where it permanently integrates into the host cell’s DNA. By knocking down certain host proteins, the researchers were able to observe what impact these proteins had on the virus’ ability to enter the nucleus and integrate into the host genome.
The viral capsid seemed to have a vital role to play in the virus’s ability to enter and navigate through the nucleus. The images clearly show that a portion of the capsid is still present and associated with the viral DNA after nuclear entry, with the final shedding of capsid occurring when the virus reaches its final destination. The capsid’s uses the host proteins CPSF6 and TNPO3 to enter and navigate through the nucleus. Typically, the CPSF6 protein works to modify the cells newly made messenger RNAs and its aim is to find active genes once it gets into the nucleus. This study reveals that when a cell is infected with HIV, the virus takes a ride on the protein, which is transported across the nuclear membrane by the nuclear importer, TNPO3. Once inside the nucleus, it is carried to active gene areas where it prefers to integrate.
This stage in HIV’s life cycle taking place between the time the virus enters the nucleus and the time its DNA is integrated into our genome, has been discovered thanks to the development of ViewHIV. When we have knowledge about these early infection events, new ways can be designed to stop the HIV virus from becoming a part of our DNA and infecting us for life.
References:
https://www.ibtimes.com.au/viewhiv-reveals-new-phase-hiv-infection-1494542