: Medical researchers have known for a long time that despite the advancements in antiretroviral therapy, varying amounts HIV virus remains in infected individuals forever, hiding in small reservoirs of cells of the immune system. Should ever these individuals discontinue the antiretroviral therapy, the HIV virus almost always rebounds rapidly from the reservoirs, causing deadly symptoms to re-emerge fast.
Unfortunately it is these virus reservoirs that remain the main obstacle to curing HIV/AIDS. There is at present no easy way of targeting reservoir cells for elimination nor can medical researchers efficiently extract reservoir cells from patients to study them so as to eventually find ways to control them.
In a recent paper in PLOS Pathogens, Gladstone Visiting Scientist Nadia Roan,
PhD, and her team describe a class of cells that preferentially support latent
infection by HIV. Credit: Gladstone Institutes
One of the main issues is the HIV virus in these cells is ‘silent’ in that the cells do not carry on their surfaces the viral proteins that would make them easy to find and identify. Hence researchers have therefore been looking for other means to pinpoint reservoir cells.
In a new research, Gladstone Visiting medical researcher Dr Nadia Roan and her team describe a class of cells that preferentially support latent infection by HIV. These cells are characterized by a surface protein called CD127 and are found in tissues such as lymph nodes, which are thought to harbor a larger share of the HIV reservoir than blood does. The research finds are published in the journal PLOS Pathogens
Dr Roan, who is also an associate professor of urology at UC San Francisco told Thailand Medical news, "Our research findings suggest that CD127 cells from tissues may be an important population to target for an HIV cure."
Significantly, researchers can potentially use the CD127 protein as a handle to isolate reservoir cells from patients, and study what makes them able to silence the virus, and occasionally reactivate it.
Typically, HIV targets immune cells, known as T cells, that reside primarily in lymphoid tissues, such as lymph nodes and tonsils. Yet HIV infection studies have largely focused on T cells circulating in the blood, which are relatively easy to gain access to as volunteers are more likely to submit to a blood draw than a tissue biopsy.
However focusing on T cells present in the blood is probably giving scientists a skewed view of the reservoir composition.
Dr Roan added, “Researchers have long suspected that reservoir cells come in different types, and that different tissues harbor different types of reservoir cells. But that has been difficult to show because reservoir cells in infected individuals are rare. The vast majority of in vitro models of latency use cell lines or cells circulating in the blood."
Dr Roan’s research team by contrast, have been studying HIV infection using tissue specimens. In past work, her team exposed tonsil cells to HIV in the lab to see which ones were most susceptible to infection. Using a variety of experimental approaches, the team found that tonsil cells with the surface protein CD127 efficiently took up the HIV virus but only rarely let it replicate. By contrast, another type of tonsil cells, carrying CD57 on their surface, readily supported a productive infection.
Despite being intriguing, it did not necessarily mean that CD127 were reservoir cells.
Dr Feng Hsiao, a former research associate in Roan's lab and co-first author of the present study said, "After HIV enters a cell, the cell still has ways to escape infection."
One solution is to prevent the virus from copying its genome. Unlike the genome of human cells, the HIV genome is made of RNA. One of the virus's first tasks upon entering a cell is to make DNA copies of its RNA genome, using a viral enzyme called reverse transcriptase.
It has been observed that cells can hamper this step by activating an enzyme called SAMHD1 that depletes the stores of building blocks the virus needs to copy its genome. There was some evidence that this mechanism might be at play in blood cells.
In research however, Dr Roan’s team found that eliminating SAMHD1 by genetic manipulation did not allow CD127 cells to churn out virus, even though it boosted viral production by CD57 cells.
Dr Julie Frouard, Ph.D., a postdoctoral scholar in Roan's lab and the other first-author of the study added, "This suggested to us that CD127 cells blocked the virus at a later step in its life cycle."
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Normally the next step for the virus is to integrate a copy of its genome into the host cell's DNA. Once there, the viral genes can take advantage of the cell machinery to produce their own proteins, which assemble new viral particles that can go infect other cells.
However, reservoir cells harbor HIV's genetic material integrated in their own genomes, though they somehow silence it. The occasional mobilization of this material permits the release of infectious virus.
The researchers extracted the genome of CD127 and CD57 cells that had been exposed to virus in the lab. Using genetic tools that can specifically detect integrated viral DNA sequences, they found that both cell types harbored copies of the virus's genome, even though CD127 cells produced far less virus than CD57 cells did. The CD127 cells appeared to favor a latent infection.
However the virus integrated in CD127 cells is not silenced forever. Dr Roan and her team found that by treating latently infected CD127 cells with agents known to stimulate T cells, they could coax the cells to reactivate the virus.
Hence, CD127 tissue cells could very well serve as reservoir cells in the body, keeping the virus dormant most of the time, yet able to occasionally activate it and release the seeds of a new round of infection.
Dr Raon added, "The ability of a specific type of tissue T cell to preferentially support latent infection is very intriguing, and can teach us much about how the tissue reservoir becomes established initially.”
The issue of to what extent CD127 cells are a major component of the reservoir in people living with HIV awaits follow-up studies analyzing these cells from multiple tissue sites.
Initial studies from DrRoan's team are encouraging, as they show that the CD127 marker on the cells' surface can indeed be used to purify enough infected tissue cells from infected individuals to allow further analyses.
Interestingly "CD127 tonsil cells exposed to HIV in vitro provide a novel model to study viral latency in tissues.”
Dr Roan and her team have already started analyzing what makes CD127 cells uniquely prone to silent infections. By comparing all the genes expressed in CD127 and CD57 tonsil cells, they found evidence that CD127 cells are in a quiescent state that may prevent the expression of the virus's genes.
Furthermore, they also found that the virus's gene products, or RNAs, failed to undergo the necessary processing that would allow them to make viral proteins.
Dr Roan and her team of researchers hope eventually that the mechanisms they uncover can be harnessed to control the latent reservoir and move them closer to achieving a cure for HIV."
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