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Discovery of protein's 'Achilles heel' paves way for novel class of anti-HIV drugs

Publicado em 16 novembro 2020

All these drugs have led to remarkable progress in terms of reducing AIDS morbidity and mortality, but viral resistance and the drugs’ side effects require a non-stop search for new ways of combating the virus.

Some 38 million people were living with the virus worldwide in 2019, including 1.8 million children aged 14 or less, according to the Joint United Nations Program on HIV and AIDS (UNAIDS), which also says 67% had access to antiretroviral therapy. In Brazil, the Health Ministry’s statistics show about 866,000 people with HIV in 2019.

Other binding pathways

Silva and his research group at FMRP-USP published a study early this year showing how Nef uses another cellular protein, AP-1G2, and the link between the two pathways. The study was supported by FAPESP.

The group analyzed the effects of Nef on host cell endomembranes, describing the mechanisms by which it uses AP-1G2 and sends CD4 to lysosomes (cell organelles containing enzymes that break down proteins and other molecules). This removes them from the cell surface and helps viral release from cells to spread the infection.

CD4 is the receptor used by HIV to invade cells. If it remains on the cell surface, viral release is blocked: hence its removal by Nef from infected cells. “We pointed to the common point between these two pathways,” Silva said. “In order to send CD4 and MHC-I to lysosomes, Nef hijacks a third cell protein common to both pathways. These findings can help other groups show exactly how Nef interacts with the third protein to identify a novel target, just as was done with AP-2.”

Silva and his group are currently working on another study, also supported by FAPESP. The goal is to discover other targets of Nef. “Several ingredients are available. Now someone has to come along to bring it all together and obtain this molecule capable of inhibiting Nef,” he said.


Fundação de Amparo à Pesquisa do Estado de São Paulo