The February 15, 2023 update to TAG’s HIV cure-related clinical research listing includes three newly registered studies:
The AIDS Clinical Trials Group (ACTG) is initiating a study of two long-acting broadly neutralizing antibodies (bNAbs) named VRC07-523LS and PGT121.414.LS combined with antiretroviral therapy (ART) in people with acute (recently acquired) HIV infection. The trial has yet to begin recruiting but will take place at multiple sites in the United States, Brazil and Peru. The primary goals of the research are to evaluate the safety of the bNAbs, assess whether they can delay the rebound of HIV viral load after an analytical treatment interruption (ATI), and measure any effects on the HIV reservoir and/or HIV-specific immune responses. The registry entry lacks information on how long participants will be treated prior to the ATI. The hope is to build on preliminary evidence that bNAbs may be able to slightly reduce the size of the intact HIV reservoir, enhance HIV-specific immunity, and promote enhanced control of HIV viral load after ART interruption in some recipients.
Researchers at the Masonic Cancer Center, University of Minnesota are conducting a trial that will administer a natural killer (NK) cell product, FT538, either alone or in combination with vorinostat, an HDAC inhibitor and candidate HIV latency-reversing agent. NK cells are a subset of immune system cells that can potentially kill virus-infected targets such as CD4 T cells harboring HIV. A prior study in people with HIV has investigated adoptive transfer of NK cells — which involves extracting them from the blood of matched donors, expanding them in the laboratory and then infusing them into study participants — but results have not yet been presented to our knowledge. FT538 takes a different off-the-shelf approach that generates the NK cells in the lab from specially engineered “mother” cells called induced pluripotent stem cells (iPSC). The company developing FT538 is Fate Therapeutics and there are several other ongoing trials in people with cancers. The HIV study will investigate the safety of intravenous dosing of FT538 and look for evidence of a reduction in the low amounts of HIV RNA that can be generated by the HIV reservoir in people on ART. If FT538 proves safe, vorinostat will be administered to attempt to reactivate latent HIV and make additional HIV-containing cells vulnerable to destruction by the NK cells. Recruitment for the trial has not yet begun.
A new trial sponsored by the Hospital Universitari Vall d'Hebron Research Institute in Barcelona, Spain will test the effects of lauric acid, a dietary fatty acid, on the HIV reservoir. At the XII Congreso Nacional GeSIDA in 2021, the researchers conducting the study presented laboratory evidence that lauric acid can promote activation of latent HIV without negatively effecting CD8 T cell responses (a problem that has been reported with other candidate latency-reversing agents). The conference abstract is appended below. The clinical trial is open for enrollment.
The other updates to the listing this month are the addition of links to newly published results from the Early Infant Treatment (EIT) trial in Botswana and the ACTG HIV reservoirs cohort study (A5321). The latter publication describes a careful evaluation of the levels of intact HIV in people on ART during long-term follow up.
Lastly, there’s bad news about the EHVA T02 trial that intended to evaluate a combination of a therapeutic vaccine (MVA HIV-B) and the anti-α4β7 integrin antibody vedolizumab in people with HIV. The clinicaltrials.gov entry has not yet been updated, but the research had to be stopped due to slow enrollment and an imminent expiration date for the MVA HIV-B vaccine, which made it logistically impossible to complete the study as planned.
XII Congreso Nacional GeSIDA y XIV Reunión Docente de la Red de Investigación de Sida (RIS) November 2021
CO-16. LAURIC ACID, A NATURAL SATURATED FATTY ACID, INDUCES THE METABOLIC REPROGRAMING OF T CELLS AND REACTIVATES LATENT HIV, WHEREAS PRESERVES CD8 T CELL RESPONSES
Grau Expósito1, A. Rull2, J.N. Howard3, J. Burgos4, J. Navarro4, A. Curran4, B. Planas1, V. Falcó4, M. Genescà1, A. Bosque3, F. Vidal2 and M.J. Buzon1
1 Vall d’Hebron Institut de Recerca, Barcelona.
2 Institut d’Investigació Sanitària Pere Virgili, Tarragona.
3 George Washington University School of Medicine and Health Sciences, Washington D.C.
4 Hospital Universitari Vall d’Hebron, Barcelona.
Introduction:
Elimination of the latent HIV reservoir that persists in antiretroviral treated (ART) HIV-infected individuals is recognized as the main barrier to cure HIV. Current latency reversal agents (LRA) do not impact the reservoir in vivo and are relatively toxic compounds, precluding their prolonged clinical use. Here, we study the effect of Lauric Acid (LA), a natural non-toxic compound, on the HIV reservoir and cytotoxic CD8+ T cell responses.
Methods:
HIV reactivation assays were performed in latency models (cellular and tissue models) and in primary CD4+ T cells obtained from ART-suppressed HIV-infected individuals. Using different techniques, as qPCR and flow cytometry, we assessed the capacity of LA to promote HIV viral transcription and p24 protein production in vitro. Functional assays were also performed to determine the effect of LA on CD8+ T cell cytotoxic activity. Moreover, metabolomic, proteomic and lipidomic analyses were performed to elucidate the impact of LA on CD4+ and CD8+T cells.
Results:
Lauric acid was able to promote a significant increase in the viral transcription and protein production in both latency models and in primary cells from HIV-infected individuals, with reduced cell-associated toxicity (p<0.001 and FC=2.6). Functional assays demonstrated that LA did not induce a global activation of CD8+ T cells, nor precluded their cytotoxic function. Moreover, lipidomic assays of CD4+ T cells suggested that LA modifies the composition of the lipid content upregulating diacylglycerols and producing de novo phosphatidylcholines, which are necessary for viral protein production during HIV transcription. Furthermore, LA impacted the metabolism of CD8+ T cells with a significant upregulation of the β-oxidation pathway and the proteasome activity, reprogramming cells to obtain energy not only from glycolysis but also from fatty acids.
Conclusions:
Using different models of HIV latency, including human lymphoid tissues and cells from ART-treated individuals, we prove the ability of LA to reprogram cell metabolism and serve as a potent natural LRA. Thus, the capacity of LA to reactivate the latent virus and preserve immune responses, together with the low toxicity found in human studies and its low cost, shapes LA as an excellent candidate for a cost-effective therapeutic strategy directed to impact the HIV reservoir.
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