New study sheds light on how HIV can stay dormant
This year’s World AIDS Day celebrations have been boosted by a breakthrough in the study of dormant HIV-1 proviruses in the body.
The presence of these dormant, or latent, proviruses in the T-cells of people infected with HIV is the main barrier to finding a cure for AIDS – and means patients must take lifelong medication to control the disease’s viral load.
But a just-published study from Duke University has shed new light on a likely key mechanism underlying HIV-1 latency – and identified a potential therapeutic strategy based on shutting down part of the body’s immune response to the virus. It also proposes a recently discovered anti-cancer drug as a promising candidate for inhibiting the SUMOylation activity behind the establishment of latent proviruses.
The new research identifies a host protein complex involved in structural maintenance of chromosomes, SMC5/6, as responsible for the epigenetic silencing of the HIV provirus before it joins with the host chromosomes of a small number of cells. When HIV enters the body, it makes a genome-length DNA molecule that it integrates into a host cell chromosome, where copies are made that generate viral RNAs and proteins. However, the Duke team found that, in a small number of infected cells, SMC5/6 initiates a process that silences the DNA provirus before that integration process can happen. The resulting inert proviruses contain latent HIV infections which can lurk in the body until activated by external stimuli to rekindle active infection.
“Our data… identify the SMC5/6 complex as being directly involved in promoting the establishment of HIV-1 latency,” says the report, published in the journal Nature Microbiology.
“(The findings) suggest that latency results not from any intrinsic properties of the incoming retrovirus but rather from an unfortunate side effect of a cellular innate immune response that probably evolved to silence invasive foreign DNA.”
Analysis of how the SMC5/6 complex stimulates SUMOylation of unintegrated HIV-1 DNA and leads to epigenetic silencing also helped the group to identify the SUMO-Activating Enzyme inhibitor TAK-981 as a candidate for blocking the latency pathway.
“If chromatin SUMOylation is crucial for the epigenetic silencing of unintegrated HIV-1 DNA, then drugs that inhibit SUMOylation should rescue gene expression by IN− HIV-1,” the group wrote.
“The anti-cancer drug TAK-981 is a specific inhibitor of the SUMO-activating enzyme, which catalyses the first step in protein SUMOylation…
“Loss of SMC5/6 expression, or inhibition of chromatin SUMOylation using…TAK-981, rescues gene expression from unintegrated HIV-1 DNA and even allows IN− HIV-1 to establish a spreading infection in cultured T cells.
“Surprisingly, we also demonstrate that loss of SMC5/6 expression, or treatment with TAK-981, markedly inhibits the establishment of HIV-1 latency in both the CEM-SS T cell line and in primary CD4+ T cells.”
Finding a way to inhibit latent infections and reactivate the proviruses – which would then be vulnerable to immune system responses and current antiretroviral drugs – would represent a significant breakthrough in our search for a functional cure for AIDS. After publishing the report, its senior author, Professor Bryan R. Cullen, claimed: “Our study represents a potentially important step toward achieving this goal.
“Although antiretroviral therapies can reduce the viral load in AIDS patients to below the level of detection, these drugs fail to eradicate HIV-1," Cullen added.
“While there has been considerable effort expended on trying to develop therapies that can activate latent HIV-1 and help antiretroviral therapies clear the body of infectious virus, this effort has so far failed to identify drugs that are both effective and non-toxic.
“Clearly, understanding the mechanism that results in HIV-1 latency may provide insights into how latent HIV-1 proviruses can be reactivated and then destroyed.”
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