HIV, the virus that causes AIDS, has a secret life. Though anti-retroviral therapy can reduce its numbers, the virus can hide and avoid both treatments and the body's immune response.
Researchers at UC Davis Health, together with colleagues at UC San Francisco and the University of North Carolina at Chapel Hill, have found that increased crotonylation, an epigenetic mechanism that governs gene expression, might be the key to making HIV come out of hiding and become susceptible to anti-HIV drugs. Their study is published in The Journal of Clinical Investigation.
"We have been working on mechanisms that could be used to disrupt HIV latency," said Satya Dandekar, chair of the UC Davis Department of Medical Microbiology and Immunology and senior author on the paper. "The goal is to force the virus to be expressed so it is visible to the immune system and can be targeted through immuno-therapeutics. This is the first study to identify histone crotonylation as a driver for HIV transcription and de-crotonylation of histone as an epigenetic marker for HIV silencing."
While medical science has transformed HIV/AIDS from a deadly disease to a chronic one, there are still millions of people living with the virus. HIV's ability to become dormant makes it invisible to both the immune system and treatments. Researchers have dedicated years to deciphering the mechanisms that help HIV hide and finding ways to reverse that process.
In this study, the researchers focused on histone crotonylation, an epigenetic mechanism that modifies the proteins that package DNA, affecting gene expression.
"Histone crotonylation regulates HIV latency," said UC Davis associate project scientist Guochun Jiang, first author on the paper. "If we can modulate that, the virus can be more efficiently flushed out."
To better understand this mechanism, the team focused on an enzyme called ACSS2, which plays an important role in fatty acid metabolism in the gut. HIV has often been linked to impairment of lipid metabolism, making ACSS2 a promising potential target for an HIV cure.
To test it out, the researchers studied peripheral blood samples from HIV-infected patients and several HIV latency cell models. Activating the ACSS2 enzyme increased viral transcription manifold. The results from patient samples were particularly encouraging.
"We examined well-characterized cell models of HIV latency and immune cells from HIV patients who had been undergoing antiretroviral therapy and had undetectable viral loads," Dandekar said. "In those samples, we were able to disrupt the HIV silencing by inducing histone crotonylation."
To further validate the results, the researchers treated samples with an ACSS2 inhibitor, which reduced detectable virus levels, highlighting the important role of decrotonylation in establishing HIV latency.
One of the more intriguing findings in the study was that increasing histone crotonylation works synergistically with other known anti-HIV latency molecules, such as the protein kinase C agonist PEP005 and the HDAC inhibitor vorinostat. Dandekar and her colleagues are now searching for more molecules that attack viral latency to develop an overall strategy of combining therapeutic agents to compel HIV expression.
"We are looking for synergistic disruption, by combining histone crotonylation with other mechanisms to reactivate HIV," Dandekar said. "This research positions us to screen and identify small molecules, which can be optimized to carry out HIV modification."
Virusi vya Ukimwi, kama vile HIV, vina maisha ya siri. Ingawa tiba ya anti-retroviral inaweza kupunguza idadi yake, virusi vinaweza kujificha na kuepuka matibabu na majibu ya kinga ya mwili. Watafiti wa UC Davis Health, pamoja na wenzake wa UC San Francisco na Chuo Kikuu cha North Carolina huko Chapel Hill, wamegundua kuwa kuongezeka kwa crotonylation, utaratibu wa epigenetic unaoongoza usemi wa jeni, inaweza kuwa ufunguo wa kufanya virusi vya Ukimwi vionekane na kuwa na uwezo wa kupata dawa za kupambana na virusi vya Ukimwi. Utafiti wao umechapishwa katika jarida la The Journal of Clinical Investigation. "Tumekuwa tukifanya kazi kwenye utaratibu ambao unaweza kutumika kuvuruga muda wa kusubiri kwa virusi vya Ukimwi,"" alisema Satya Dandekar, mwenyekiti wa Idara ya Microbiolojia ya Matibabu na Immunolojia ya UC Davis na mwandishi mwandamizi wa karatasi hiyo." Lengo ni kulazimisha virusi kuonyeshwa ili iweze kuonekana na mfumo wa kinga na inaweza kulengwa kupitia immunotherapeutics. Hii ni utafiti wa kwanza kutambua histone crotonylation kama dereva kwa ajili ya HIV transcription na de-crotonylation ya histone kama epigenetic marker kwa HIV silencing. Ingawa sayansi ya kitiba imebadilisha virusi vya Ukimwi kutoka kuwa ugonjwa hatari hadi ugonjwa wa kudumu, bado kuna mamilioni ya watu wanaoishi na virusi hivyo. Kwa sababu ya uwezo wa virusi vya Ukimwi kutoweka, haviwezi kuonekana na mfumo wa kinga na matibabu. Watafiti wametumia miaka mingi kugundua njia ambazo zinasaidia kufunika virusi vya Ukimwi na kutafuta njia za kugeuza mchakato huo. Katika utafiti huu, watafiti walizingatia crotonylation ya histone, utaratibu wa epigenetic ambao hubadilisha protini ambazo hufunga DNA, na kuathiri usemi wa jeni. "Histone crotonylation inasimamia HIV latency, "alisema UC Davis msaidizi wa mradi mwanasayansi Guochun Jiang, mwandishi wa kwanza kwenye karatasi. "Ikiwa tunaweza kurekebisha hali hiyo, virusi hivyo vinaweza kuondolewa kwa njia bora zaidi". Ili kuelewa utaratibu huu, timu ya wataalamu ilizingatia enzyme inayoitwa ACSS2 ambayo ina jukumu muhimu katika kimetaboliki ya asidi ya mafuta katika matumbo. HIV mara nyingi imehusishwa na kupungua kwa kimetaboliki ya lipid, na ACSS2 inakuwa lengo linaloweza kuahidi kwa tiba ya HIV. Kwa ajili ya utafiti huo, watafiti walichunguza sampuli za damu ya watu walioambukizwa virusi vya Ukimwi na vipimo kadhaa vya chembe za HIV. Kuongeza kwa enzyme ya ACSS2 kwa kiasi kikubwa huongeza transcription ya virusi. Matokeo kutoka kwa sampuli za wagonjwa yalikuwa yenye kutia moyo hasa. "Tuliangalia mifano ya seli ya HIV na seli za kinga kutoka kwa wagonjwa wa HIV ambao walikuwa wakipitia matibabu ya antiretroviral na walikuwa na mzigo wa virusi usioweza kugunduliwa, ""Dandekar alisema." "Katika sampuli hizo, tuliweza kuvuruga ukimya wa UKIMWI kwa kusababisha crotonylation ya histone". Kwa hivyo, kwa sababu ya athari za virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi vya virusi. Utafiti huo ulionyesha kuwa kuongeza kwa histone crotonylation hufanya kazi kwa ushirikiano na molekuli nyingine zinazojulikana za anti-HIV, kama vile agonist ya protein kinase C (PEP005) na inhibitor ya HDAC (Vorinostat). Dandekar na wenzake sasa wanatafuta molekuli zaidi ambazo huathiri muda wa kusubiri kwa virusi ili kuendeleza mkakati wa jumla wa kuchanganya dawa za kuzuia maambukizi ya HIV. "Tunatafuta usumbufu wa ushirikiano, kwa kuchanganya crotonylation ya histone na taratibu zingine ili kuamsha tena HIV", Dandekar alisema. "Utafiti huu unatuweka katika nafasi ya kuchunguza na kutambua molekuli ndogo, ambazo zinaweza kuboreshwa ili kufanya marekebisho ya HIV".