How T Cells Are Defining the Future of HIV Therapies and Beyond

The human immune system deploys a remarkable array of defenses designed to protect us against invaders that seek to do us harm. In the vanguard of this army: the T cell.

At any given moment, your body hosts about a trillion T cells—more than 100 times the number of people on Earth. Unlike antibodies, which mostly float in blood or fluids, only about 2% of T cells circulate in the blood. The rest are patrolling lymph nodes, spleen, gut, skin, and other tissues, quietly screening our body for infected or cancerous cells. When they find one, they act with surgical precision, eliminating it and summoning other immune cells to the site.

Remarkably, once a T cell has fought off an infection, a fraction of it becomes a memory T cell, capable of surviving for decades. That’s why some childhood vaccines can protect you for life!

Versatility

• T cells are not only soldiers on patrol, but can also act as engineers, or even peacekeepers. Some T cells secrete molecules that help repair damaged tissues, stimulating lung tissue to regenerate after flu, or muscles to repair after an injury.

• Specialized “regulatory” T cells prevent friendly fire, keeping the immune system from attacking its own organs.

• T cells also control processes beyond immunity: They help regulate blood pressure and bone turnover, and they contribute to shaping our metabolism by patrolling fat tissue.

• In the brain, meningeal T cells secrete signals that affect processes like learning and memory, a reminder that the immune and nervous systems are deeply intertwined.

T cells and HIV

The importance of T cells is underscored by what happens when they are targeted by pathogens. HIV, for example, primarily infects a subset of T cells—CD4⁺ T cells—that is specifically tasked with coordinating the body’s immune responses at large. By disabling or destroying this key subset, HIV gradually dismantles the body’s defenses, leaving it vulnerable to infections and cancers. The single fact that HIV can destabilize the entire immune system by eliminating just one subset of immune cells explains why this virus is so devastating without treatment.

Genetically modified T cells

In the late 1990s, scientists pioneered the concept of genetically modifying T cells to attack HIV with a precursor to today’s CAR T cells—patient-derived T cells engineered to hunt down specific targets such as infected cells.

First-generation CAR T trials in the 1990s were underwhelming, but newer genetic engineering tools made second-generation approaches far more potent, leading in 2021 to a clinical trial of CAR T cells in HIV-positive individuals on antiretroviral therapy (ART). In this study, researchers observed a reduction in viral load and in the number of HIV-infected cells in the treated individuals, representing the first human evidence that CAR T cells could dent the HIV reservoir.

amfAR moves the field forward

Subsequent studies by amfAR-supported research teams and others have led to incremental improvements in the effectiveness of CAR T cells against HIV. These advances have enabled CAR T cells to expand more vigorously, remain active longer, attack infected cells more effectively, and most importantly, reduce the size of the HIV reservoir, the virus’s deepest hiding place.

amfAR cure trial

Because HIV is so elusive, many experts now believe that multi-pronged strategies are essential, echoing the combination approach that made ART successful. In 2020, amfAR launched a bold multi-stage trial at UCSF, layering together a therapeutic vaccine, an immune stimulant to lure HIV out of hiding, and broadly neutralizing antibodies. The trial established proof of concept that such a combination could induce post-treatment control of HIV. When treatment was interrupted, seven of the 10 participants were able to achieve at least partial HIV control. The study represents the most comprehensive attempt yet to train, expose, and empower T cells simultaneously, while also removing the virus’s hiding places.

Today, T cell therapy for HIV is at its most promising stage in history. The coming years will be crucial, as ongoing trials reveal whether new innovations can finally turn T cells, HIV’s favorite target, into its most powerful enemy.

Even after decades of study, T cells remain at the frontier of science. Researchers are studying ways to help them fight cancer and pathogens, control autoimmunity, and repair organs. The more we discover about these marvelous cells, the more certain we are that T cells will continue to define the future of medicine as much as they already control our day-to-day health.

Dr. Gramatica is amfAR’s vice president and director of research.

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