Boosting Cellular Defense Mechanisms
Developing new anti-HIV drugs that target the host cell rather than viral proteins
By Jeffrey Laurence, M.D.
Research question
Ancient retrovirus infections of germ cells—cells that develop into sperm or eggs—began leaving footprints in the human genome over 30 million years ago. This genetic material comprises about 1% of our genome today.
Thanks to evolution, cells have developed their own natural defenses against such infections, including HIV. One mechanism of defense involves A3G and A3F, two members of a family of normal cell proteins known as APOBEC. However, HIV can counteract this defense through a viral protein of its own, Vif. Vif causes degradation of A3G and A3F in HIV-infected cells to ensure infectivity of viruses subsequently released from those cells.
But this cellular defense mechanism suggests a potential new target for antiretroviral therapy (ART): Could a drug be developed to boost levels of A3G/F?
Findings
About 15 years ago scientists from China and McGill University in Montreal, Canada, discovered a compound, IMB-26, able to inhibit Vif-mediated destruction of A3G and boost its levels. It was identified using an automated screen of chemicals and natural products derived from the Chinese Academy of Medical Sciences in Beijing.
In the current study, three analogs of IMB-26 were developed. The most potent of them, NU-611, could increase cellular levels of A3G and A3F and decrease HIV infectivity in the test tube, with less toxicity than IMB-26. These agents blocked only cell-directed, not HIV-directed processes, suggesting they may be less likely to become ineffective in the presence of HIV mutations. In preliminary work presented at the 2024 Conference on Retroviruses and Opportunistic Infections, NU-611 suppressed HIV in HIV-infected, ART-treated humanized mice when ART was stopped.
Impact
The authors conclude that “the novel compounds described here are a starting point for the development of therapeutics that decrease the infectivity of [HIV] virions reactivated from cells harboring latent proviruses after stopping ART … and that minimize[s] risk of escape mutation. … Such agents could be an adjunct in a broader strategy to cure HIV.”
amfAR’s role
amfAR was a funder of this research. amfAR grantee Richard T. D’Aquila, MD, of Northwestern University Feinberg School of Medicine was a co-author of this paper.
Original article
http://www.ncbi.nlm.nih.gov/pubmed/40284957
Dr. Laurence is amfAR’s senior scientific consultant.
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