Aerobic Exercise Dysfunction in Human Immunodeficiency Virus: A Potential Link to Physical Disability

Approximately 282,000 adults, adolescents, and children are currently living with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) in the United States as of the year 2002.1 With the advent of highly active antiretroviral therapy (HAART), the life span of these individuals has dramatically increased,2 and HIV infection is now considered a chronic illness with accompanying episodes of exacerbations and remissions of symptoms.3 Numerous conditions such as lipodystrophy syndrome4–6 and skeletal myopathy7–9 have been associated with HIV and its medical management, many of which may result in physical disability and diminished quality of life. Due to the chronic nature of this condition, physical therapists will continue to manage many of these conditions in increased numbers of people who are living with HIV. Although guidelines for physical therapy evaluation and management of this potentially disabling condition have not been established, it appears that aerobic exercise training may have a beneficial effect on the cardiorespiratory health of people who are living with HIV. Thus, an understanding of the factors that limit the oxidative metabolic response to physical activity is paramount in developing effective exercise training programs for people with this virus. The focus of this Update is to examine the biological factors that might limit the oxidative metabolic response to physical activity in people with HIV. HIV-related disability has been associated with fatigue and decreased physical functioning10–13 as well as other factors that may limit people's ability to carry out necessary life activities.12,14,15 Fatigue in adults with HIV has been identified using patient self-reports of physical and functional limitations while performing activities of daily living such as housework, climbing stairs, and walking15 and activities required for employment.10,11Asymptomatic HIV infection is defined as having no symptoms or as having symptoms related only to acute primary HIV infection, such as persistent generalized lymphadenopathy (swollen and firm lymph glands).11 Thirty-one percent of men and 53% of women with asymptomatic HIV infection have reported at least one limitation to physical activity as a result of fatigue.11 Among those with symptomatic HIV infection, defined as having a condition such as thrush (a fungal infection of the mouth, throat, and tongue) or having diarrhea or a fever longer than 1 month, who reported fatigue, 52.6% of men and 62.3% of women reported at least one or more limitations to physical activity resulting from fatigue.11 Seventy percent of men and 80% of women with AIDS reporting fatigue also were found to have at least one functional limitation resulting from fatigue.11 Moreover, approximately half the adults with HIV who reported fatigue in this particular study also reported a chronic inability to participate in other life activities, such as attending school or working at a job.11 Recreational activities that involve strenuous activity such as running, cycling, or hiking16 have been thought to be further limited in this population.17,18 The aerobic or oxidative system provides energy (adenosine triphosphate [ATP]) to working muscles during physical activity through the oxidation of glucose, fatty acids, and amino acids in the mitochondria.19 According to the Fick equation, the total volume of oxygen consumed (V̇o2), the primary measure of oxidative capacity, equals the product of oxygen delivery to the working muscles (cardiac output) and the ability of the muscle to extract and utilize the oxygen to produce energy (arteriovenous oxygen difference).19 Disruption of any part of the pathway—from pulmonary extraction of atmospheric oxygen to mitochondrial uptake and utilization, including inhalation into the lungs, diffusion from the alveoli to the lung capillaries, blood transport by the heart and circulatory system to the working muscles, diffusion across the capillaries into the muscle cell, and movement across the cell and into the mitochondria—would impair oxidative metabolism. Instrumental activities of daily living include tasks such as housework, meal preparation, grocery shopping, and light lawn work; these activities have energy requirements of between 3 and 5 metabolic equivalents (METs).20 One MET equals the average resting metabolic rate in the general population: 3.5 mL of oxygen consumed per kilogram of body weight per minute. Physical activity lasting over a minute requires the presence and use of oxygen, or aerobic respiration, to liberate energy.21 When activity is sustained at a high oxygen demand, the slow responsiveness of the oxidative system requires that the source of energy must be supplemented by a metabolic pathway that does not require oxygen: the glycolytic pathway. While the nonoxidative glycolytic pathway provides a small amount of energy supplement rapidly, among its by-products are hydrogen ions and lactic acid. These by-products tend to lower intracellular pH, and higher concentrations of these substances are associated with fatigue.22 Thus, in order for an individual to tolerate a particular intensity of physical activity without becoming fatigued, the effectiveness of the oxidative metabolic pathway must be high enough to meet the energy demand with minimal nonoxidative supplementation. Aerobic insufficiency, defined as aerobic capacity that is insufficient for meeting required energy demands, results in physical activity intolerance23 and may result in functional limitations placed on performance of daily activities and in physical disability. Age normative values for peak aerobic capacity, measured by indirect calorimetry during exercise testing, for sedentary men and women with no known pathology or impairments in the 50th percentile ranges16 are reported in the Table. Fiftieth Percentile Age Normative Values for Peak Aerobic Capacity16 V̇o2peak=peak volume of oxygen consumed. METs=metabolic equivalents (1 MET=3.5 mL O2·kg−1·min−11). Fiftieth Percentile Age Normative Values for Peak Aerobic Capacity16 V̇o2peak=peak volume of oxygen consumed. METs=metabolic equivalents (1 MET=3.5 mL O2·kg−1·min−11). Diminished aerobic capacity in both adolescents and adults with HIV appears to be one mechanism of fatigue and physical disability.17,18,24 Diminished peak V̇o2 has been identified among adults with HIV25–28 and ranges approximately 15% to 40% below that predicted for sedentary age-matched controls without HIV.17,18,25,26,28Functional aerobic impairment, defined as peak V̇o2 of ≥27% below predicted values for age, sex, and physical activity level, was found in both adolescents17 and adults24 who had asymptomatic to mildly symptomatic HIV infection. Ventilatory threshold, a physiological marker of the onset of fatigue, was found to occur earlier during maximal exercise tests25,27 in people with HIV than in people without HIV.21 Ventilatory threshold occurs at a point during a progressive physical activity load where expired carbon dioxide (V̇co2) and minute ventilation begins to increase more rapidly than V̇o2.29 This increase in expired V̇co2 has been associated with increases in blood lactate and hydrogen ions and results from pulmonary buffering of these metabolites due to an increased need for glycolytic metabolic supplementation.21 If the oxidative system is inadequate (ie, during pathology) to meet the energy requirements of a particular activity, the glycolytic system will increase its contribution in order to meet the energy needs and the ventilatory threshold, and thus the onset of fatigue will occur at a lower intensity of activity. Ventilatory threshold has been shown to occur during the energy requirements associated with light instrumental activities of daily living (3.0–4.0 METs [10.5–14.0 mL·kg−1·min−1]) in adolescents with HIV.17 In combination with the finding of low peak V̇o2, this report suggested that adolescents with HIV may not have had the ability to sustain some activities of daily living or to perform recreational or occupational activities at even slightly higher energy requirements.17 Indexes of aerobic impairment and oxidative metabolic dysfunction might provide quantitative evidence for fatigue-related disability in adolescents and adults with HIV. Several possible mechanisms for exercise and activity dysfunction in people with HIV have been reported. Structural and inflammatory muscle abnormalities in people with HIV, which may impair the muscle's ability to extract or utilize oxygen during exercise, have been widely reported. HIV infection-mediated myopathy, as identified by the presence of necrosis (cell death), nemaline rod bodies (rod-shaped inclusion bodies consisting of alpha-actinin and desmin), inflammation, and vasculitis (inflammation of microvasculature) were found in 26% of individuals infected with HIV who either had never taken antiretroviral therapy or had a low lifetime dose, indicating a deleterious effect of HIV infection on skeletal muscle.30 Mitochondrial abnormalities also were found in people with HIV who had never taken HAART, including abnormal size, shape, and cristae (inner and outer mitochondrial membrane) structure.31 Cytokine expression (ie, interleukin-1 and tumor necrosis factor-α) and macrophages were detected in muscle, indicating proteolysis and inflammation, in 5 individuals with HIV and known polymyositis or wasting syndrome.32 Although there has not been strong evidence for direct HIV infection of skeletal muscle, antigens have been identified in macrophages invading the muscle, implicating inflammation33,34 as a potential mediator of muscle tissue infection by the virus. Clinical manifestations of HIV-associated myopathy have been reported to include proximal weakness, myalgia, abnormal electromyographic activity, elevated creatine kinase, and diminished physical functioning of the muscle.7–9 Medical management of HIV includes a combination of antiretroviral drugs aimed at stopping the replication of the virus and restoring and preserving immune function. Initial therapy recommendations for both people with asymptomatic HIV infection and those with advanced HIV disease include at least one nucleoside analog reverse transcriptase inhibitor (ie, stavudine, didanosine), a protease inhibitor (ie, ritonovir, indinavir), or a non-nucleoside reverse transcriptase inhibitor (ie, efavirenz). Intervention considerations include the quantity of the plasma viral burden, immunological function (ie, CD4 count), known antiretroviral drug resistance genotypes, adherence, and potential drug toxicities.35 Nucleoside analogs were first introduced in the late 1980s, followed by the introduction of other components of HAART (non-nucleoside reverse transcriptase inhibitors and protease inhibitors) in the 1990s. Therefore, physiological complications associated with HIV and their interventions appear to have changed since the initial advent of the disease. Substantial evidence for the mediating role of nucleoside analog therapy with respect to mitochondrial dysfunction has been presented. Nucleoside analog-mediated inhibition of HIV replication occurs by substitution of the phosphorylated drug into the DNA in place of deoxythymidine triphosphate (dTTP). This alteration results in termination of the elongating DNA chain, which, in turn, blocks reverse transcription. A similar action of nucleoside analogs on the mitochondrial transcription enzyme, DNA polymerase γ, and mitochondrial DNA (mtDNA) chain terminators has been proposed as a mechanism of mitochondrial dysfunction.36–39 Mitochondrial abnormalities secondary to the effects of nucleoside analog therapy have been found in both human and animal studies. The mitochondrial enzyme, cytochrome-c oxidase, which is essential in ATP production via oxidative phosphorylation, has been found to be deficient in both in vitro and in vivo muscle treated with a nucleoside analog.40–43 Numerous other nucleoside analog-induced mitochondrial alterations also have been identified, including oxidative damage to and decreases in mtDNA44–49; decreased mitochondrial RNA (mtRNA)50; ultrastructural damage to mitochondria (eg, swelling, cristae disruption, inclusion-body presence)31,50–52; presence of mitochondrial-bound interleukin-1μ in zidovudine-treated muscle fibers32; inhibition of both NADH-linked respiration and NADH-reductase activity53; and a diminished aerobic training response of cytochrome-c oxidase by means of chronic electrical stimulation.54 These abnormalities were further evidenced by the presence of lactic acidosis, which has frequently been found in people with HIV who were receiving nucleoside analog therapy.55–57 Other reported nucleoside analog-mediated muscle abnormalities have included diminished muscle cell and myoblast (somite cells, which will develop into muscle cells) proliferation58; increased amounts of intramuscular lipid, glycogen, and lipofuscin (the pigment remaining after the breakdown and digestion of damaged blood cells)7; and ragged red and necrotic fibers (histological features that are associated with myopathy).59 Deleterious effects of nucleoside analog therapy may be seen during in vivo metabolism as well. A delayed recovery and larger depletion of phosphocreatine following muscular exercise were reported in a group that received nucleoside analog therapy as compared with a group that did not receive nucleoside analog therapy.60 A recent study61 further demonstrated decreased arteriovenous oxygen difference during peak treadmill exercise in a group of individuals with HIV who received HAART compared with a group of individuals with HIV who did not receive HAART and with a non-HIV-infected control group, indicating a deleterious effect of HAART on peak peripheral muscle oxygen extraction and utilization during exercise. This decrease in peripheral muscle extraction and utilization during exercise appears to reduce peak exercise capacity and would likely limit participation in many recreational activities for individuals with HIV who are receiving HAART. However, it also appears that HIV infection alone, apart from the effects of HAART, independently impairs oxygen on-kinetics (the speed with which the muscle is able to extract and utilize oxygen to create energy upon the initiation or change in the intensity of activity) during exercise intensities above the ventilatory threshold in both those receiving and not receiving HAART.62 How impaired oxygen on-kinetics affect activity tolerance is not yet clear, but early indications are that people with HIV appear to have a reduced ability to quickly obtain a steady state of oxidative metabolism for certain activities above the ventilatory threshold. The effect of protease inhibitors on muscle function is unclear, but it appears that at least one protease inhibitor, indinavir, has a direct effect on glucose uptake. Indinavir has been shown to be inhibitory to the skeletal muscle glucose transporter, GLUT-4, in rats.63 If this inhibition also occurs in humans, it could potentially impair plasma glucose uptake and limit the amount of plasma glucose used for glycolysis and subsequent oxidation. This inhibition could potentially limit the amount of fuel that could be used for energy production during activity. An impairment of glucose transport also might reduce the amount of glycogen that could be stored in the skeletal muscle, thereby further limiting a potential substrate for energy production. The combination of these impairments would most likely be seen during higher-intensity activities such as sports and other recreational activities. The prevalence of abnormalities in adults with HIV and AIDS has been reported to between and in with HIV and AIDS due to has increased manifestations of seen in people with HIV infection have included pulmonary and have been associated with such as and and the resulting inflammatory to the as well as direct infection of muscle by HIV also have been reported in people with When compared with people with individuals with HIV-related had a lower of indicating an among HIV infection, and the use of protease has been associated with abnormal including glucose and abnormal (ie, and peripheral of these conditions are known to increase the of However, increased in those with HIV also have been independently to HIV infection indicating that HAART does not for of the inhibitors also have been associated with dysfunction via impaired and an increased of disease through The effect of nucleoside analog on function among people with HIV also has been has been demonstrated that a was more likely to develop than a who was not the treated with and mitochondrial with and cristae and decreased mitochondrial expression compared with control these abnormalities may impair lower oxygen delivery to working and exercise and activity This in function may to physical and peripheral muscle potentially further limiting exercise and activity Although the of HIV-related dysfunction has been reported in with recent have that dysfunction may be seen of in with asymptomatic and mildly symptomatic HIV infection. that the onset of abnormalities during the initial of HIV infection with the disease and with to as well as the potential effects of HAART. abnormalities might with other complications of HIV infection, fatigue and physical activity and resulting in functional limitations and physical disability. The exercise dysfunction that HIV infection appears to have in with those seen in people with heart with heart also dysfunction and muscle mitochondrial and weakness, but further muscle and increased Physical disability in people with heart is well and may provide into evaluation and management of physical function limitations in people with The for and reported the of to be in adults with HIV infection, in those with AIDS or CD4 and in those with may be by an of including medical therapy such as the use of (a nucleoside analog used in management of and an an alteration of via in such as and and to has been reported to lower exercise capacity by the and of oxygen of the thus peak V̇o2, in people with heart in at a appear to for the in blood However, the of on V̇o2, and peak exercise capacity, in both people with and without HIV, as of not well also may a role in activity in people with in a of aerobic exercise training of people with HIV have suggested that a training effect was reporting an increase in peak V̇o2 and ventilatory threshold and a decrease in resting heart One of these was that aerobic impairment in people with HIV may be due only to However, the finding of functional aerobic impairment in adolescents17 and adults24 with HIV that aerobic capacity was limited below that as a result of that it was likely that a part in aerobic and activity in HIV infection, but that could not have for the of the limitation or the functional limitations associated with HIV infection. Numerous of dysfunction in individuals with HIV, those with symptomatic it that for the decreases in aerobic function. results from recent that the ability to extract and utilize oxygen for peak aerobic exercise dysfunction in individuals with asymptomatic HIV infection and that HAART, than alone, appears to limit peak aerobic may to exercise and activity limitation by and the capacity in the has been reported to with oxygen for on the thus the amount of oxygen and the amount of oxygen to the working has been reported to have a but effect on peak but not evidence decreases in aerobic The of in exercise with HIV from to may for a small decrease in exercise capacity due to the high prevalence of in but it is not likely to have the decreases in aerobic capacity seen in individuals with HIV. total lung capacity, capacity, and other lung have been seen in some with AIDS and pulmonary including and have been in volume in 1 and capacity in people with capacity also has been reported to be lower in some people with In a study by exercise was found in of individuals with with an average of oxygen as measured by Diminished was further seen in with HIV who had no of disease compared with In found no evidence for in with asymptomatic HIV infection. other found resting and to have been to of predicted values in with HIV who had no or evidence of pulmonary disease. Although no study to has associated pulmonary ventilation limitations with reduced exercise capacity and activity in people with HIV, this has been reported in other Therefore, in people with HIV with acute or chronic pulmonary limitations might to exercise and activity the of exercise dysfunction in people with HIV is most likely associated with other Other possible mechanisms that might be related to fatigue and associated physical limitations include decreased immunological function as by decreases in CD4 to at the low and including increased of at increased and and activity in people with HIV has been as decreased peak aerobic capacity, ventilatory threshold during MET associated with instrumental activities of daily and oxygen peak aerobic capacity in people with HIV an impaired ability to participate in recreational activities that are associated with a A reduced ventilatory threshold in these individuals that early energy and the onset of fatigue may occur during activities of daily living such as housework, lawn and activities. These impairments may have for physical disability in this Moreover, these impairments provide an for and to mechanisms and interventions for these for an aerobic training effect has been in the a potential role for physical therapy in the management of this in aerobic capacity have been reported as increased on the treadmill during a maximal exercise increased peak V̇o2 and increased ventilatory threshold Other beneficial effects of aerobic exercise training may include decreased body and and of quality of Although of the effect of aerobic exercise on immune function in people with HIV are it appears that aerobic exercise training does not affect immunological function in people with HIV and is These physiological to aerobic exercise training may fatigue, decrease functional and reduce physical disability resulting from HIV infection. appears that performing or aerobic exercise for at least at least 3 per for may to and with an accompanying of immunological Among people with HIV who have known pulmonary or muscle exercise be to the and the any for exercise as in people without HIV or resistance training may muscle and body in those with muscle wasting and weight Aerobic exercise and activity dysfunction in individuals with HIV appears to be including inflammatory effects of the HIV virus as well as the in skeletal and This oxidative dysfunction in HIV may be as fatigue and physical functional and physical in both people with asymptomatic and symptomatic HIV infection. from HIV infection may now occur to a from a viral since the advent of HAART in the However, the prevalence of impairments resulting from HAART may be due to of the (ie, protease Moreover, people who have HIV infection are living the effects of also may result in physical disability in those with HIV. A limitation of this Update includes the of direct evidence for the between physiological alterations and exercise and physical activity limitations in people with HIV. The nature of HIV disease also may of the and exercise limitation in this Physical therapists an role in and management of aerobic and the related physical dysfunction in people with HIV. are on the role of aerobic dysfunction and disability in people with HIV infection.