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POSITIVELY AWARE JULY/AUGUST 2011
Cover Feature
Inflamed Response. HIV provokes the immune system into a hyperactive state that can lead to chronic inflamation. By David H. Shepp, MD
HIV is a viral infection that attacks the immune system. Without treatment, it progresses to a state of immune system failure, leaving the infected person vulnerable to severe and unusual infections and cancers. These diseases are referred to as “opportunistic” because they thrive only in the setting of severely compromised immune system function. Paradoxically, this immune system failure occurs as HIV stimulates the immune system into a hyperactive state.
This hyperactivity is only partially effective in controlling HIV, fueling the fire by providing new activated T-cells that are especially vulnerable to HIV infection, and interfering with the development of the coordinated immune response needed to prevent the opportunistic AIDS-related diseases.
Immune activation and chronic inflammation
The immune system is enormously complex and not completely understood. It has evolved to keep us protected from the sea of microbes and other potentially toxic substances that we inhale, ingest, and touch every day. The immune system uses two major mechanisms to recognize and respond to infection. Some immune system cells are stimulated by the general pattern of molecules found in different broad categories of microbes. For example, some are triggered by molecules present in many bacteria or fungi and some by the structure of the genes of viruses. This function is called innate immunity. Other immune system cells, T- and B-lymphocytes, have the ability to “learn” how to recognize short protein segments, know as antigens, that are unique to specific microbes. This function is known as adaptive immunity. When either type of immune cell encounters its trigger molecule, cell surface proteins known as receptors are engaged. A signal is then sent to the cell interior, producing cell activation.This results in a variety of functions, including celldivision and the production of signal molecules (known as cytokines), that attract and activate other types of inflammatory cells, alter blood coagulation, and generate fever. Activated cells may also secrete toxic substances that help kill microbes and may engulf and digest them. The end result is a state of inflammation, a process that limits the growth and spread of the infecting agent. This system is very effective, but it is not perfect. Inflammation can make a person feel ill. An overreaction to certain foreign substances is the cause of allergies. Even appropriately regulated inflammation can cause “collateral damage,” injuring healthy body tissues. Inflammation also alters normal body metabolism in ways that create a hostile environment for infection. Over the short term, this causes little trouble, but if inflammation becomes chronic, these metabolic disturbances increase risk for a variety of medical conditions.
Chronic inflammation and NAMIs
Chronic inflammation is now understood to be an important contributing factor to many medical illnesses common in the general population, including cardiovascular disease, kidney disease, diabetes, osteoporosis, and cancer. These same illnesses are occurring in HIV-positive people at a higher rate than in the general population and possibly at an earlier age as well. In countries with good access to antiretroviral therapy (ART), classic AIDS-related opportunistic illnesses still account for about 30% of all deaths. However, non-AIDS medical illnesses (NAMIs) now account for the majority of deaths.1 Liver failure, cardiovascular diseases, and non-AIDS–defining malignancies are most common. There are several potential explanations for increased rates of these illnesses. HIV disproportionately affects those of black race, as do chronic kidney disease, diabetes, and cardiovascular disease. Cigarette smoking, a strong risk factor for cardiovascular disease, cancer, and osteoporosis, is more common among HIV-positive patients. Hepatitis B, hepatitis C, and human papillomavirus (HPV) are more common in HIV-positive people because they share routes of transmission with HIV. These viruses can contribute to liver cirrhosis and to liver, cervical, and anal cancers. ART itself has toxic effects that may be a contributing factor to some diseases. Certain antiretrovirals may cause elevations of LDL (“bad”) cholesterol, loss of arm and leg fat, increased abdominal fat, altered glucose (blood sugar) metabolism, or loss of bone density. These conditions are risk factors for cardiovascular disease, diabetes, and bone fractures. Another important possibility is that HIV infection directly increases the risk of NAMIs. The interval from HIV infection to initiation of ART is quite variable but is often many years. The intense, chronic inflammation occurring during the period of untreated infection may cause irreversible organ system damage. Once ART is initiated, immune activation and chronic inflammation improve, but do not usually fall to levels seen in healthy, HIV-negative individuals. This residual inflammation may increase the risk of NAMIs.
Levels of activated T-lymphoctyes and markers of inflammation in the blood are elevated in HIV-positive patients.2,3 Activated T-lymphocytes and certain inflammatory markers in the blood such as high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), D-dimer, soluble CD14, and fibrinogen also strongly correlate with the risk of HIV disease progression and death.4-7
Effects of ART
For most patients, combination ART reduces HIV replication to undetectable levels and restores immune function to levels that provide freedom from opportunistic illnesses. It also improves, but does not completely normalize, chronic inflammation and immune activation, which persist even after many years of successful treatment.8, 9 Mortality in HIV-positive individuals declined dramatically over the past 16 years, but life-expectancy remains substantially lower than in the general population.10 Immune activation also influences the degree of immune recovery during ART. Most patients who achieve full suppression of HIV in the blood have significant improvement in the CD4+ T-cell count, critical cells needed to resist opportunistic illness. Those patients with higher levels of activated immune cells are less likely to increase the CD4+ T-cell count above 200/mm3,11 the level that confers protection against opportunistic illnesses. Understanding the causes of chronic inflammation in those on ART and developing new treatments for it is now a major area of HIV research.
- ART intensification
- differentiate effects of standard ART regimens
- n new antiretrovirals with fewer toxicities
- prebiotics/probiotics to alter intestinal flora
- antibodies against microbial components
- improve function of gut-associated lymphoid tissue (eg IL-7, IL-17, IDO inhibitors)
- anti-CMV antivirals
- treatment of hepatitis C
- adjunctive anti-inflammatory therapy (e.g. statins, hydroxychloroquine)
- new antiretrovirals with anti-inflammatory effects
- earlier ART initiation
Causes of immune activation
Why does effective ART that durably suppresses HIV growth, improves immune system function, and extends life still permit residual immune activation? There are several potential causes (see table next page). HIV itself may still be driving inflammation. Standard ART suppresses HIV in the blood to levels below the threshold of detection for most commonly used tests, but more sensitive assays employed in research laboratories show that many patients have detectable low-level HIV that does not decline even with prolonged treatment. Although their overall effect is beneficial, certain antiretroviral drugs might directly stimulate an inflammatory response, either by a toxic effect on certain cells or by triggering an allergic response. In addition, HIV causes damage to tissues that line the intestines and are normally rich in T-lymphocytes. These tissues, known as gut-associated lymphoid tissue (GALT), form an important defense that keeps bacteria, fungi, and the other microbes that are normally present in the intestines from entering the blood stream. A subset of T-lymphocytes called TH17 cells are especially important in carrying out this function and are abnormal in HIV-infected GALT. When GALT functions abnormally, gut microbes or their components may enter the blood stream, a process called microbial translocation, which triggers a powerful inflammatory response. ART does not adequately repair GALT, leaving microbial translocation as a cause of chronic immune activation and inflammation in HIV.12 Co-infections such as hepatitis C virus (HCV) and cytomegalovirus (CMV) may persist or recur periodically, even in patients responding well to ART. As with HIV, these viruses directly trigger immune responses that do not fully resolve infection, leading to chronic immune activation and inflammation. Finally, certain components of a properly regulated immune response may be irreversibly damaged by HIV during the highly variable period of time that HIV remains untreated, causing failure to turn off immune responses appropriately. A subset of T-lymphocytes known as regulatory T-cells are thought to be important in this process. These cells frequently are abnormal in HIV infection and may account for the failure of some immune responses to subside.
Treatment research on chronic inflammation
Effective treatment to reduce immune activation to normal levels is not established and represents an important unmet need in HIV treatment. Since early use of ART is now the standard of care, treatment research should study adjunctive therapies given with standard ART, or explore the anti-inflammatory effects of new antiretrovirals or novel antiretroviral combinations. All such studies will need first to demonstrate consistent and sustained reduction in markers of immune activation and/or inflammation. Ultimately, studies that demonstrate reduced NAMIs and longer life expectancy will be needed to prove that reducing inflammation improves health outcomes.
To address residual HIV infection as a cause of chronic immune activation and inflammation, many ART intensification studies have been conducted. In these studies, patients well controlled on standard ART have one or more potent antiretrovirals added to their regimen. Using very sensitive assays, most studies have not shown any consistent reduction in residual HIV infection,13, 14 although some studies have suggested possible effects on inflammation, which are currently unexplained and require further study and confirmation.14,15
Mitochondria are structures within cells that generate energy. They are thought to be derived from primitive bacteria. Mitochondrial injury is a well known adverse effect of certain antiretroviral drugs of the class called nucleoside reverse transcriptase inhibitors (NRTIs). Damage to mitochondria may cause the release of molecules that trigger an inflammatory response from cells of the innate immune system, similar to the response triggered by bacteria. In resource-rich areas, the most toxic of the NRTIs are no longer used. However, studies comparing the effect on inflammation of standard ART containing NRTIs and newer ART regimens that do not use NRTIs should be undertaken.
Many novel treatment strategies to reduce microbial translocation are under investigation or being considered. The cytokine interleukin-7 (IL-7) recently has shown promise as a treatment that reverses T-cell depletion in GALT,16 and could, as a result, reduce translocation. Enhancing TH17 cell function by inhibiting enzymes known as indolamine dioxygenases (IDO) or administering interleukin-17, the cytokine produced by these cells, may reduce microbial translocation. Altering the composition of microbes in the gut to render them less harmful might be achieved through ingestion of dietary supplements and harmless bacteria, substances referred to as prebiotics and probiotics. Antibiotics to reduce the overall number of bacteria might also be effective, but would likely be limited by overgrowth of undesirable antibiotic-resistant microbes. Injection of antibodies to bind and neutralize microbial products that enter the blood stream could limit the ability of microbial translocation to stimulate inflammation.
In patients on effective ART, a substantial proportion of activated CD8+ T-cells are responding to CMV infection.17 A small pilot study reported that eight weeks of treatment with the anti-CMV drug valganciclovir significantly reduced levels of these cells.18 Although it was safe in this very brief study, valganciclovir has potential for serious side effects and so may not be suitable for long-term use. There is an opportunity for newer, safer anti-CMV therapy to be investigated to reduce chronic immune activation in HIV-positive patients.
If the underlying cause of chronic inflammation cannot be specifically corrected, use of anti-inflammatory, immunosuppressive, or immunomodulatory agents as adjunctive therapy to ART could be effective. There are now a very large number of such drugs in clinical use for other debilitating or life-threatening conditions. Some have serious adverse effects or predispose patients to opportunistic infections, making them less suitable for study of the prevention of NAMIs in those who are otherwise doing well. A few with a more favorable safety profile have been studied. Statins are drugs widely used to lower cholesterol and are generally safe. They decrease the risk of death in patients at high risk for a heart attack, but only part of the benefit is due to lower cholesterol. Statins also have anti-inflammatory effects. A short course of atorvastatin lowered levels of T-cell activation better than a placebo in HIV-positive patients.19 However, these patients were not receiving ART. It is not known if the use of statins in patients already responding to ART would provide additional benefit. Hydroxychloroquine (HCQ) is a licensed drug with immunomodulatory properties used primarily in the treatment of lupus. It is thought to work by interfering with certain aspects of the innate immune response. A recent pilot study suggested improvement in some markers of inflammation when adjunctive HCQ was added to standard ART.20 These findings are very preliminary and require further study. In separate studies, the rheumatoid arthritis drug salsalate and cyclosporin, a drug used to prevent rejection of organ transplants, also have been tested in patients with HIV. Neither appeared promising.21, 22
As an alternate to adjunctive therapy, some antiretrovirals, such as the CCR5 inhibitor maraviroc (Selzentry), have immunomodulatory properties which could give them a dual mechanism of action in HIV-positive patients. Studies adding maraviroc to standard ART have produced conflicting results, suggesting either reduced23 or increased24 immune activation. An investigational CCR5 inhibitor with additional anti-inflammatory properties, called cenicriviroc (TBR-652), is currently in development.
Earlier initiation of ART may improve the chances that HIV-associated immune activation will return to normal levels. A small study has suggested early initiation of ART leads to greater improvement in immune activation.25 A large, randomized trial known as START should help determine if early ART initiation leads to greater improvement in inflammation. The START study is also one of the only ongoing studies that will also assess the effects on NAMIs and mortality.
Conclusions
Chronic immune activation and inflammation is a central feature of HIV infection and is implicated in the increased risk for NAMIs in the general population and in people living with HIV. NAMIs are now the leading cause of illness and death in patients treated with ART. Effective ART reduces chronic inflammation but does not necessarily resolve it. Research to improve our understanding of the causes of chronic immune activation and chronic inflammation is needed. Many ART-based and non-ART–based approaches to treatment are open for study. Treatments will need to reduce markers of inflammation, NAMIs, and improve life expectancy to become a standard of care in HIV therapy.
David H. Shepp, MD, is Associate Professor of Medicine at the Hofstra North Shore-LIJ School of Medicine, Division of Infectious Diseases, North Shore University Hospital in Manhasset, New York.
Read a supplement to this article - Does America need a new healthcare system? Duh. By Sue Salmarsh
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