The Immune System and HIV

1. The Immune System and HIV Daniel Raymond NATAF 2002 daniel.raymond@verizon.net

2. Topics • Overview of the Immune System • Immune System and HIV pathogenesis • HIV-specific immunity

3. Overview of the Immune System • Defends against infections (viruses, bacteria, etc.) • A complex and interdependent system throughout the body • Includes white blood cells (such as T cells) and antibodies, lymph nodes, and many other organs

4. Keeping the Immune System Healthy • Even without taking HIV medication, people do different things to keep their immune system healthy. • Some people use nutrition, vitamins, or herbs; researchers don’t know much yet about what affects these have on the immune system, good or bad. • Some people also find exercise helpful. • Other people focus on reducing stress through techniques such as meditation and acupuncture.

5. Innate Immunity • Innate immunity is nonspecific – doesn’t depend on recognition of a particular pathogen (virus, bacteria, etc.) • Includes anatomic barriers (skin, tears, mucous), physiologic barriers (temperature, pH levels [acidity]), phagocytic barriers (cells that ingest pathogens), and inflammatory barriers (inflammatory response – heat, swelling, special chemicals such as histamines)

6. Adaptive Immunity • Adaptive immunity is specific – it depends on recognizing a particular pathogen and mobilizing the appropriate response • Includes T cells and antibodies, and antigen-presenting cells (dendritic cells, macrophages) • Works with innate immune response

7. Signaling • The cells of the immune system communicate through signals – sending and receiving chemical messengers • These messengers are referred to as cytokines • Examples: interleukin 2 (IL-2), interferon alpha

9. How the Immune System Fights Infection • Skin and other barriers try to block infections from entering the body • If a virus or bacteria gets into the body, certain cells can detect organisms that don’t belong in the body and can notify the immune system • CD4 cells are a special kind of T cell that coordinates the immune response, figuring out how to fight off an infection and then giving instructions to other immune system cells

10. Properties of Adaptive Immunity: Specificity Specificity: CD4 T cells can “recognize” infections your body has never seen before. Your body makes CD4 T cells with special receptors (“docking bays”) shaped to “fit” (connect to) different parts of viruses and bacteria (called epitopes). Since each virus and bacteria has a different shape, each CD4 T cell is able to match a specific virus or bacteria.

11. Properties of Adaptive Immunity: Diversity Diversity: The immune system makes about 100 million different CD4 T cells. Each different CD4 T cell can recognize a specific part of a virus or bacteria. When you combine all of your different CD4 T cells, your immune system can recognize an incredibly broad and diverse range of viruses and bacteria. Each different CD4 T cell can also have many identical copies of itself, and several different CD4 T cells can react to different parts of the same virus.

12. Properties of Adaptive Immunity: Memory Memory: When a CD4 T cell “recognizes” a new virus that the body hasn’t encountered before, it will “remember” that virus and how to best fight it off. The next time your body encounters that infection, your immune system is prepared and can fight it off more quickly and more powerfully. That’s why people generally only get certain diseases like measles once in our lives – after the first time, the immune system is ready and watching.

13. CD4 T cells and Immune Deficiency • When a person loses CD4 T cells, they lose the cells that coordinate the immune response to infections. • They lose diversity – there are less CD4 T cells, and they can’t “recognize” as many different kinds of infections. • They lose memory – the CD4 T cells that “remember” how to fight off the infections which the person has already encountered die off, and the immune system can’t respond as quickly or as strongly.

14. Where did all the CD4 T cells go? • HIV prefers to infect CD4 T cells – those cells are easiest for HIV to get inside of and use to replicate (make copies). • As HIV infects CD4 T cells and makes copies, it hijacks the cell so it no longer functions, and the cell becomes a virus factory. • As the new HIV copies are released, the cell ultimately dies, while the new HIV copies look for more CD4 T cells to infect – starting the cycle over again. • As HIV kills CD4 T cells both directly and indirectly, the immune system gets weaker and weaker.

15. Is that the whole story? • Cells infected with HIV make up only a small portion of all CD4 T cells at any time, suggest that direct killing of CD4 T cells by HIV does not fully account for immune depletion seen in HIV disease • HIV infection increases levels of immune activation, leading to activation-induced cell death – this means a higher rate of turnover in the T cell population • HIV infection may affect the production and/or maturation of new CD4 T cells from the bone marrow and thymus

16. A Closer Look at CD4 cells • CD4 cells are T cells, a kind of white blood cell – there are also CD8 cells • T cells and B cells (white blood cells which produce antibodies) are created in the bone marrow • T cells go on to the thymus to “mature” – that’s where they become either CD4 or CD8 cells and get their T cell receptors

17. Life of a CD4 T Cell • After leaving the thymus, CD4 T cells enter into circulation – traveling through the bloodstream to lymph nodes, tissue and organs. • Lymph nodes are the ‘cafes’ or meeting places for T cells – this is where they can go to find the latest antigens (bits of virus or bacteria) that have been trapped by dendritic cells

18. CD4 T Cells in Action • When a naïve CD4 T cell first encounters an antigen that fits its specific T cell receptor, it gets a signal from the antigen-presenting cell that ‘activates’ it • The activated CD4 T cell starts proliferating, producing dozens of effector CD4 T cells which can send out signals coordinating an immune response

19. Effector and Memory • CD4 effector cells can signal B cells to produce antibodies (humoral immunity) or signal CD8 cells to generate cytotoxic T-lymphocytes (CTLs) which can kill infected cells (cell-mediated immunity) • Activated cells are short-lived, but after the initial immune response is over, some cells live on as memory cells which can go into action faster the next time they’re needed

20. HIV-Specific Immunity • The immune system mounts a response specific to HIV that continues throughout infection • The strength of this response can be seen by the long time between infection and the development of AIDS, even in people not on treatment

21. Measures of HIV-specific immunity • Quantity – how many T cells can respond to HIV? • Quality – how effective are they at killing infected cells? • Diversity – how many different epitopes (slices of HIV) can the T cells recognize? • Antigen presentation – how many epitopes can antigen-presenting cells display effectively? (relates to genetics – HLA types)

22. Problems in the Immune Response to HIV • In most people, the immune system ultimately cannot control HIV on its own • HIV preferentially infects HIV-specific CD4 cells – the very cells needed to control the virus • Some HIV-specific T cells don’t function very well as measured by their ability to proliferate and release cytokine signals and other chemicals • HIV also damages the structure of the lymph nodes

23. Case study: LTNPs and CD8s • Long-term non-progressors (LTNPs) have been infected with HIV for several years but seem to be able to control the virus without significant immune depletion • In a recent study, LTNPs had the same numbers of HIV-specific CD8 T cells as people with progressive HIV disease • However, these CD8 T cells were better at proliferating and producing perforin (a chemical CD8 T cells use to kill infected cells)

24. Questions and Implications What does this mean for: • Antiretroviral treatment decisions? • Potential immune-based therapies? • Future research directions?