Best Supporting Actors: Other Immune Cells Shaping the Future of HIV Research

For decades, the CD4+ T cell has been the central character in the story of HIV. However, the immune system is not a one-man show. A diverse cast of immune cells each play distinct, complex, and sometimes surprising roles. Increasingly, scientists are turning their attention to some “supporting actors”—B cells, natural killer (NK) cells, and macrophages—uncovering how they contribute to HIV persistence, immune dysfunction, and potentially the path toward a cure. Here, we spotlight how emerging research, including work supported by amfAR, is reshaping our understanding of these immune cells in the context of HIV.

B Cells: Antibody Architects
B cells are the immune system’s antibody factories. When functioning properly, they produce proteins that recognize pathogens, including viruses, and neutralize them.

• Role in HIV
  In HIV, despite producing antibodies, many B cells are ineffective at neutralizing the virus. Furthermore, B cells can become exhausted and disorganized, contributing to impaired immune responses even in people on long-term antiretroviral therapy.
• Ongoing research
  Prior research has helped define how HIV disrupts B cell function, showing that chronic inflammation can reduce antibody quality. Current research is focused on two primary themes: (1) vaccines that can “wake up” native B cell antibody production, and (2) engineering B cells to make specific neutralizing antibodies directly. Other ongoing studies are exploring how broadly neutralizing antibodies (bNAbs)—which work against multiple strains of HIV—might be harnessed for therapy and prevention.
• amfAR’s role
  Prior amfAR grants have supported research into B cell biology and antibody responses, helping to lay the groundwork for novel antibody-based HIV therapies and vaccine strategies. An active amfAR Target grant is supporting research on genetically engineered B cells.

Natural Killer Cells: Innate Assassins
Natural killer (NK) cells are part of the innate immune system. These rapid responders can detect and kill infected cells without prior exposure.

• Role in HIV
  NK cells can recognize and eliminate HIV-infected cells, but the virus has evolved ways to evade or suppress their activity. In chronic infection, NK cells often become less effective, contributing to viral persistence.
• Ongoing research
  Recent studies suggest that NK cells could be harnessed to control the latent HIV reservoir. Ongoing work is converging on two main strategies: (1) NK cell engineering, and (2) boosting native NK responses with cytokines or antibodies.
• amfAR’s role
  A recent Krim Fellowship is supporting cutting-edge work on NK cells, investigating how they interact with HIV-infected cells and how their activity can be boosted or redirected. This builds on earlier amfAR-supported efforts and reflects a broader shift toward harnessing innate immunity in HIV cure strategies.

Macrophages: Hidden Reservoirs
Macrophages are versatile immune cells involved in detecting pathogens, clearing debris, and coordinating inflammation. They are found throughout the body, including the brain.

• Role in HIV
  Unlike CD4+ T cells, macrophages can survive HIV infection without dying. This makes them potential long-lived reservoirs of the virus. They may also contribute to chronic inflammation and HIV-associated comorbidities.
• Ongoing research
  Researchers are investigating how HIV establishes and persists in macrophages, and whether macrophage reservoirs differ across tissues. There is also growing interest in how these cells contribute to neuroinflammation and aging-related complications in people living with HIV.
• amfAR’s role
  amfAR-funded research has extensively explored the role of macrophages as HIV reservoirs. Most recently, a Target grant supported work on identifying targeted approaches to eliminate HIV-infected macrophages.

Recognizing the Whole Cast: Mapping the Full Immune Landscape

As HIV research evolves, one theme is becoming clear: the CD4+ T cell is only one actor in a star-studded cast. The supporting actors—B cells, NK cells, and macrophages—play critical roles in HIV transmission, persistence, and resistance to cure.

That’s why amfAR’s new Horizon grant initiative will build a comprehensive “immune atlas” of HIV. This work aims to map how HIV interacts with the whole immune system, generating thorough understanding that could reveal new therapeutic targets, identify previously hidden reservoirs, and guide the development of combination strategies that go beyond CD4+ T cells alone.

Because in the story of HIV, the supporting cast may ultimately help write the ending.

Kelsey Hopland is the program officer of amfAR’s research department.

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