treatment ISSUES MARCH 2011 Treatment HIV andISSUES Inflammation By Liz Highleyman Inflammation has become a major concern of HIV medi- At the local level, these chemicals cause physiological cine in recent years. Experts now recognize that persistent changes responsible for the classic inflammatory signs HIV infection leads to long-term immune activation and of redness, swelling, heat, and pain. They also play a chronic inflammation, even among people on antiretroviral role in blood clotting and tissue repair. System-wide, pro- therapy (ART) with undetectable viral load. Ultra-sensitive inflammatory chemicals act on the brain and elsewhere, tests show that a small amount of residual HIV remains in causing fever, loss of appetite, fatigue, and other “flu-like” the body despite effective treatment, and a growing body symptoms. of evidence shows that even this low-level virus can cause This innate response is active against a range of invad- a range of problems long before a person’s CD4 T-cell ers. Early responders also trigger adaptive or specific count falls into the danger zone for opportunistic illness. immune responses carried out by lymphocytes, known as B-cells, T-cells, and natural killer cells. These cells learn What Is Inflammation? to recognize and directly target particular antigens (for Inflammation is a broad term for what happens when the example, pieces of bacteria or virus displayed by macro- immune system recognizes and responds to a threat. Many phages). different types of immune cells go into action, including T-cells differentiate into CD4 helper cells and CD8 kill- macrophages that ingest invaders, CD4 helper T-cells that er cells. CD4 T-cells, which direct the immune response, coordinate the overall immune response, and CD8 killer are the primary target of HIV. Young B-cells (which pro- T-cells that disable virus-infected and malignant cells. duce antibodies) and T-cells are naive, meaning they can In response to an acute threat, injured tissues alert respond to new antigens. After an immune response, a white blood cells such as macrophages that are pres- ent throughout the body. A protein called nuclear factor kappa-B (NF-kB) is released, switching on genes involved HIV infection leads to long-term immune in immune response. activation and chronic inflammation. Immune cells communicate using chemical messengers known as cytokines. These signals exert a variety of effects, from calling white blood cells to a site of injury, to stimulat- subset of these cells become long-lived memory cells that ing cell proliferation, to making blood vessels more perme- remember a specific threat in order to respond quickly if it able so immune cells can more easily maneuver. appears again. Activated macrophages and other early responders Normally immune responses are self-limiting and produce pro-inflammatory cytokines including interleu- “turn themselves off” when no longer needed. Just as kin 1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-alpha), pro-inflammatory cytokines trigger immune activation, and interferon gamma. Neutrophils and other immune anti-inflammatory cytokines such as IL-4, IL-10, and trans- cells migrate to the affected area, where they ingest or forming growth factor-beta (TGF-beta) inhibit or shut down poison pathogens and release their own chemicals. In immune responses. addition, the liver produces acute-phase proteins such While a robust immune system is key to good health, as C-reactive protein (CRP), fibrinogen, and plasminogen. it is not designed to sustain a continuous inflammatory Some of these chemicals can be detected in the blood response over the long term. But when faced with an and are used as biomarkers to assess inflammation. ongoing threat such as chronic HIV infection, the immune response remains engaged, leading to problems through- naturally control the virus without treatment, show greater out the body. immune activation than HIV-negative people, and they are Over time, persistent cytokine elevation and other at higher risk for cardiovascular disease and other non- immune processes can damage organs including the AIDS conditions. heart and brain. Furthermore, continuous activation accel- HIV proteins including Tat and gp120 appear to directly erates progression of immune cells though the cycle stimulate immune responses by altering cytokine signal- of growth and division, causing them to “burn out” pre- ing. HIV also contributes to inflammation in less direct maturely, a state known as immunosenescence. In an ways. At the earliest stages of infection, the virus estab- article published in Topics in HIV Medicine, Steven Deeks lishes itself in lymphoid tissue in the gastrointestinal tract, reports that middle-aged HIV-positive people show signs the body’s largest reservoir of susceptible CD4 T-cells. of immunosenescence resembling those of HIV-negative Brenchley et al. explained in a 2006 report in Nature people over age 70.[1] Medicine that HIV infection damages the intestinal lin- ing and makes it more permeable, allowing bacteria that How does HIV Cause Inflammation? normally reside in the gut to escape, a process known Inflammation is implicated in almost every type of health as microbial translocation.[3] As they enter the blood- problem and its consequences tend to be worse for peo- stream, these bacteria and a toxin they produce called ple with HIV since the ongoing presence of the virus main- lipopolysaccharide (LPS) trigger a strong systemic immune tains CD4 and CD8 T-cells in a constant state of activation. response. Combination ART has dra- Viral and bacterial coin- matically reduced the risk fections also play a role in of AIDS-defining oppor- HIV-related inflammation. tunistic illness and death. Chronic immune activation and inflammation Decreased immune func- But as HIV-positive people tion, even while CD4 cell survive longer thanks to contribute to higher rates of cardiovascular counts are still relatively effective treatment, they disease in people with HIV. high, can lead to loss of are at increased risk for a control of other disease- variety of non-AIDS condi- causing organisms in the tions even while CD4 cell body. HIV-positive people counts are relatively high. with active chronic viral coinfections, such as herpes sim- At a recent forum, Deeks suggested AIDS should plex virus, cytomegalovirus (CMV), and hepatitis B and C perhaps be thought of as “acquired inflammatory dis- viruses, typically have higher HIV viral load, lower CD4 ease syndrome.” “HIV is causing high-level inflamma- T-cell counts, and faster progression to AIDS. tion and inflammation-associated disease,” he explained. UCSF researchers showed that HIV-positive people with “Antiretroviral therapy can help people live longer, but it stronger CMV-specific CD8 T-cell responses had higher does not restore health and they do not have a normal levels of inflammation biomarkers and more early athero- lifespan.” Starting treatment earlier, he said, might mitigate sclerosis. At CROI 2010, they reported that treating CMV these effects. with valganciclovir reduced CD8 cell activation.[4] Similarly, Experts think chronic immune activation and inflamma- Kovacs et al. found that among HIV-positive women coin- tion contribute to higher rates of cardiovascular disease fected with hepatitis C, those with the most activated CD8 and other non-AIDS conditions seen in people with HIV. cells had three times the risk of progression to AIDS.[5] But given that HIV disease is characterized by immune Finally, metabolic abnormalities such as elevated low- suppression, how can it also cause excessive immune density lipoprotein (LDL) cholesterol and body composi- activation and inflammation? The answer lies in the com- tion changes associated with HIV and its treatment can plexity of the immune response. As Peter Hunt and col- trigger inflammation, and these inflammatory changes in leagues from the University of California, San Francisco turn can affect metabolism. (UCSF) explained at the 2010 Conference on Retroviruses While some antiretroviral drugs can contribute to meta- and Opportunistic Infections (CROI), “HIV has its foot on bolic abnormalities, the overall effect of ART is to reduce the accelerator and the brakes at the same time.”[2] inflammation. Experts advise that lowering viral load as much While late-stage HIV/AIDS involves severe immune as possible is the most effective way to reduce persistent deficiency, immune activation and dysregulation are more immune activation and inflammation in people with HIV. common at earlier stages. Throughout the course of dis- ease, however, the percentage of infected CD4 T-cells Inflammation Biomarkers does not seem large enough to explain the extent of It is increasingly clear that complications seen in HIV- immune dysfunction. Most CD4 cells in the blood and positive people are not only due to the effects of the virus lymph nodes of people with chronic infection do not on the immune system, but also the immune system’s carry the virus, but it appears that only a small amount is response to the virus. The idea that persistent immune acti- needed to sustain an inflammatory state. Even “elite con- vation and inflammation influence HIV disease progression trollers,” the small proportion of HIV-positive people who is not new. Since the early years of the epidemic, research- 2 MARCH 2011 ers have reported that HIV-positive people have elevated While SMART revealed more inflammation among par- levels of various markers of inflammation. Hunt et al. have ticipants who interrupted