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Developmental Biology - Immune Function

Killing HIV

Learning from people with a natural ability to illiminate HIV...

Cells from rare individuals who control their active HIV infection naturally, have been the focus of investigation for nearly 15 years. Science wants to more precisely understand their very specific immune system ability to master HIV's destructive influence.

Following research on the ANRS CO21 CODEX and CO6 PRIMO cohorts, scientists from the Institut Pasteur described the characteristics of CD8 immune cells in these "HIV controller" patient/subjects.
The unique antiviral power of these immune cells can be attributed to an optimized metabolic program which grants persistence, with the ability to react effectively against infected cells.

Working ex vivo, in an external environment with minimal alteration of natural conditions, the scientists successfully reprogrammed cells from infected non-controller individuals to give them the same antiviral potency as controllers' cells.

These findings were published in the journal Nature Metabolism on July 12, 2019.

Some people have the ability to control HIV naturally, without treatment. In these very rare individuals (less than 1% of people living with HIV), no multiplication of the virus in the blood can be detected after more than 10 years of infection without treatment. In 2007, scientists from the Institut Pasteur described the extraordinary antiviral activity of these patients' CD8 lymphocytes. Unlike in non-controllers, CD8 cells of HIV controllers are able to rapidly destroy infected CD4 cells.

Scientists from the Institut Pasteur's HIV, Inflammation and Persistence Unit continued their research with the aim of identifying the specific characteristics of these cells so that they could confer the same characteristics onto cells of non-controller subjects.

CD8 cells (or "memory cells") of controllers outwardly appear to be identical to those of non-controllers. But the scientists demonstrated that they have a different molecular program. Their research shows that anti-HIV CD8 cells in controllers not only have huge antiviral potential — they are also programmed to survive, whereas in non-controllers, the cell program predisposes them to exhaustion and cell death.
CD8 cells of controllers use a variety of metabolic resources, drawing in particular on the energy supplied by their mitochondria, which enables cells to survive in conditions of stress.

Conversely, cells of non-controllers depend on a single energy source — glucose — and they have limited mitochondrial activity.

"We identified that the antiviral activity of CD8 cells in controllers is associated with an optimal program that gives them plasticity in using a cell's energy resources,"

Asier Saez-Cirion, Institut Pasteur, HIV, Inflammation and Persistence Unit and coordinator of the study.

In the laboratory, scientists managed to stimulate mitochondrial activity in the anti-HIV cells of non-controllers. Using a substance secreted by the immune system known as interleukin 15 (IL-15), they boosted mitochondrial activity of non-controllers' cells and increased their anti-HIV potential.
Reprogrammed CD8 cells of non-controllers are able to destroy infected CD4 cells, much like controllers' cells.
"Our research shows that even if the anti-HIV CD8 cells of non-controllers are relatively ineffective compared with those of controllers, the differences can be overcome," says Asier Saez-Cirion.
Metabolic reprogramming of immune cells is a strategy that is already being tested in clinical trials for cancer treatment. Scientists hope to be able to test the anti-HIV capabilities of the strategy in vivo in the near future.

Spontaneous control of human immunodeficiency virus (HIV) is generally associated with an enhanced capacity of CD8+ T cells to eliminate infected CD4+ T cells, but the molecular characteristics of these highly functional CD8+ T cells are largely unknown. In the present study, using single-cell analysis, it was shown that HIV-specific, central memory CD8+ T cells from spontaneous HIV controllers (HICs) and antiretrovirally treated non-controllers have opposing transcriptomic profiles. Genes linked to effector functions and survival are upregulated in cells from HICs. In contrast, genes associated with activation, exhaustion and glycolysis are upregulated in cells from non-controllers. It was shown that HIV-specific CD8+ T cells from non-controllers are largely glucose dependent, whereas those from HICs have more diverse metabolic resources that enhance both their survival potential and their capacity to develop anti-HIV effector functions. The functional efficiency of the HIV-specific CD8+ T cell response in HICs is thus engraved in their memory population and related to their metabolic programme. Metabolic reprogramming in vitro through interleukin-15 treatment abrogated the glucose dependency and enhanced the antiviral potency of HIV-specific CD8+ T cells from non-controllers.

Mathieu Angin, Stevenn Volant, Caroline Passaes, Camille Lecuroux, Valérie Monceaux, Marie-Agnčs Dillies, José Carlos Valle-Casuso, Gianfranco Pancino, Bruno Vaslin, Roger Le Grand, Laurence Weiss, Cecile Goujard, Laurence Meyer, Faroudy Boufassa, Michaela Müller-Trutwin, Olivier Lambotte and Asier Sáez-Cirión.

The authors wish to thank A. Tadesse, S. Hendou, A. Essat, C. Jung and K. Bourdic for help with the inclusion of HIV-infected individuals. They also wish to thank D. Desjardin and N. Bosquet for help with the macaque studies, and especially the investigators, clinical personal and HIV-infected individuals participating in the ANRS CO6 PRIMO and ANRS CO21 cohorts for their cooperation. The authors thank the Cytometry and Biomarkers UTechS platform at Institut Pasteur and the personnel from the Infectious Disease Models and Innovative Therapies (IDMIT) platform for technical support. D. Young, a medical English editor, supported with funds from the AS-C laboratory, provided English editorial assistance during the preparation of this manuscript. The present study was conducted with funds from the French National Agency for Research on AIDS and Viral Hepatitis (ANRS), MSDAVENIR and the European Union (EU)’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 706871. M.A. received support from the EU (grant no. 706871) and complementary support from Sidaction. C.P. received support from the ANRS. J.C.V.-C. received support from Institut Pasteur through the Roux-Cantarini programme. The ANRS CO6 and CO21 cohorts were sponsored and funded by the ANRS. IDMIT infrastructure was supported by the French government Programme d’Investissements d’Avenir under grant no. ANR-11-INBS-0008.

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Jul 16 2019   Fetal Timeline   Maternal Timeline   News  

CD8 lymphocytes (RED) of HIV controller patients in contact with CD4 cells (GREEN) infected with HIV. Cell nuclei are BLUE. Cytotoxic molecule secreted by CD8 cells (PINK) destroys CD4 cells.
CREDIT © Anastassia Mikhailova / Institut Pasteur.

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