Persons infected with HIV experience several comorbidities as the result of the pharmacological interventions, disease progression, malnutrition, decreased physical activity, or a combination of these factors. HIV is a debilitating disease and typical symptoms include loss of muscle mass, lipodystrophy, and declines in strength, functional capacity, and quality of life. Numerous studies have been carried out to examine the effects of exercise on both functional and cellular variables. Fortunately, research has shown that certain levels of exercise may be a method of treating the negative consequences of HIV.
Table of Contents
EFFECTS OF EXERCISE ON THE IMMUNE SYSTEM
Innate Immune System
Exercise-induced changes in the number of circulating and/or cytolytic activity per natural killer (NK) cell could have important consequences for an individual’s well-being. In a normally healthy immune system, NK cell level and cytolytic activity is increased during and immediately after sustained moderate (30-120 min, 50%-65% of VO2max) and intense (75%-90% of VO2max) exercise. Evidence suggests that NK cell count and cytolytic activity declines below pre-exercise values only after intense long duration (>60 min) exercise, but is not suppressed following moderate exercise. However, another study suggests there is a profound decrease in cell level and cytolytic activity during the first hour following sustained moderate exercise, and if exercise is both prolonged (>120 min) and intense, the decrease may begin during the exercise session. Immediately after resistance exercise, there is a small increment in NK cell count and cytolytic activity. Limited research exists regarding the timeline of cell recovery after a strengthening exercise bout, but levels have been observed to return to baseline within a few days. Following sustained moderate physical activity, it has been suggested that resting values return to baseline within 24 hours whereas in prolonged, intense, and stressful activity, the continuing depression of NK cells can last for several days resulting in an increased risk of infection. Several studies have examined the effects of resistance training in this specific population; however, the clinicians mainly focused on strength and muscle mass rather than immunological variables. Due to this lack of evidence, further research is warranted. The following studies explored the effects of aerobic exercise on NK cell level and cytolytic activity in patients with HIV. Overall results indicate that moderate-intensity as well as shorter duration, high-intensity exercise is safe and beneficial in HIV seropositive patients.
- Ulum et al. investigated the effects of 60 min of moderate to strenuous exercise (75% of VO2max for 40 min on a cycle ergometer, decreased to 56%-89% for the last 20 min) in asymptomatic HIV seropositive and seronegative (control group) males. It was observed that the HIV seropositive group had an insignificant increase in circulating NK cells when compared to the controls during and after exercise. These results indicate that in response to physical stress, HIV infected individuals may have an impaired ability to recruit NK cells to the blood, which may increase susceptibility to infection in very intense bouts of exercise. Both groups returned to baseline values 2 hours post-exercise. Ulum et al. concluded that patients may participate in moderate to high-intense aerobic exercise, but definitely not exhaustive exercise.
- LaPierriere et al. examined the immune and psychological effects of a 5-week, 3x/week, 45-min interval training program (3-min stages at 80% predicted maximum heart rate [PMHR] alternated with 2-min stages at 60%-79% PMHR on a cycle ergometer) in 50 homosexual males (aerobic exercise training group and assessment only control group) unaware of their HIV status. At the end of the 5 weeks, subjects were notified of their HIV status, and immune and physiological markers were re-evaluated 1 week later. Results showed that the seropositive controls demonstrated a sharp decline in NK cell number after learning their HIV status whereas seropositive exercisers showed an insignificant change over the same period of time. There was no significant change for cytolytic activity in either group. Also, seropositive controls exhibited significantly larger changes in anxiety and depression scores at 1 week post-notification when compared to seropositive exercisers who showed scores equivalent to college sample norms and practically no change from pre- to post-notification.
Adaptive Immune System
In a normally healthy immune system, T cells (CD4 and CD8) and B cells increase during exercise and decrease below pre-exercise values after intense long duration exercise, but is not suppressed after moderate exercise. There is much evidence regarding the effect of aerobic exercise on T cells in patients with HIV; however, research is very limited concerning exercise in relation to B cells in this population. Also, as mentioned in the previous section, there is a lack of evidence regarding the effects of resistance training on immunological variables resulting in the need for further research. The following studies examined the effects of aerobic and progressive resistance exercise (PRE) on T cells, mainly CD4 cells, in HIV seropositive individuals. Since HIV replication occurs with CD4 proliferation, we would not want these individuals to necessarily increase their CD4 count with exercise because this could further result in additional lymphocytes available for further infection and HIV replication. Overall results indicate that exercise does not significantly change CD4 cell level in patients with HIV leading to a conclusion that moderate-intensity as well as shorter duration, high-intensity exercise is safe and beneficial in the HIV infected population.
- Ulum et al.’s (see study in previous section for details) results showed that for both groups, the percent of CD4 cells (percent lymphocytes that are CD4 positive) did not change in response to exercise whereas the total number of CD4 cells increased during exercise and fell below baseline values 2 hours post-exercise; however, levels were not significantly suppressed. The percent of CD8 cells were elevated in the HIV seropositive patients when compared to the controls and similar to the CD4 cells, there was a decrease in cell level 2 hours after exercise. No specific data was included regarding the amount of time it took for CD4 cell levels to return to baseline.
- LaPierriere et al. (see study in previous section for details) observed that on average, the seropositive exercisers increased their CD4 cell counts by 38 cells/mm3 whereas seropositive controls decreased their counts by 61 cells/mm3.
- Stringer et al. examined the effects of a 6-week, 3x/week exercise protocol in HIV positive patients. The subjects were divided into 3 groups: control (no regular aerobic exercise), moderate-intensity (60% of VO2max for 60 min), and high-intensity (75% VO2max for 30-40 min). All training sessions were performed on a cycle ergometer. At the end of 6 weeks, aerobic fitness increased significantly in both exercise groups (highest marked improvement occurred with the high-intensity group) when compared to the control group, and there was no significant change in CD4 cell levels among all 3 groups.
- Dolan et al. investigated the effects of a 16-week, 3x/week, 2 hour/session, supervised home-based progressive resistance training and aerobic exercise program in HIV seropositive females. The non-exercising control group was encouraged to maintain their normal activity level. Each training session began with a warm-up on the cycle ergometer at 50% of estimated maximal heart rate (MHR) followed by a flexibility routine. The duration of the aerobic component was 20 min during the first 2 weeks at 60% MHR and 30 min for the remaining 14 weeks at 75% MHR on the cycle ergometer. PRE consisted of concentric and eccentric phases of 6 selected upper and lower body exercises. Initially, subjects performed 3 sets of 10 repetitions (reps) for each muscle group at 60% 1-repetition max (RM). After 2 weeks, subjects performed 4 sets of 8 reps at an intensity of 70% 1-RM and then finally at 80% 1-RM after an additional 2 weeks. At the end of 16 weeks, no significant difference was observed in CD4 cell count between groups. The combined PRE and aerobic exercise group showed a significant increase in muscular strength and cardiorespiratory fitness as well as a significant decrease in waist circumference when compared to the controls.
- LaPierriere et al. (1997) conducted another study looking at how exercise effects asymptomatic (CD4 count: >500 cells/mm3), early symptomatic (CD4 count: 200-500 cells/mm3), and patients with AIDS (CD4 count: <200 cells/mm3). The asymptomatic and early symptomatic patients performed aerobic exercise for 45 minutes per day at 70%-80% of their predicted maximum heart rate for 3 days a week. Asymptomatic patients went for 10 weeks and the early symptomatic patients went for 12 weeks. Patients with AIDS went for 24 weeks, 60 minutes per day, 3 days per week and were split into two groups based on intensity: High (70%-85% of VO2 max) and Low (50%-60% VO2 max). They found the CD4 levels of asymptomatic patients increased by 115 cells/mm3, early symptomatic patients increase by 80 cells/mm3, and the patients with AIDS counts were maintained. La Pierriere and collegues found CD4 cells to increase with exercise which is contradictory to many other studies; thus, in a review article by Dudgeon et al., they proposed that this increase may not be a systematical increase in cell quantity but rather a measure of mobilization from the cells from the lymphoid tissue. Therefore, these results must be interpreted with caution.
- Terry and collegues (1999), performed a randomized clinical trial with 21 people with HIV and a CD4 count >200 cells/mm3. The subjects performed 60 minutes of aerobic exercise for 3 times a week for 12 weeks. They were divided into two groups based on intensity: moderate (60% of max HR) and heavy (84% of max HR). The results were that there was no difference in immunologic markers (CD-4, CD-8, or CD-4/CD-8 ratio) between the two groups. Both groups had significant increase in exercise capacity as indicated by an increased time on the treadmill. This article demonstrates that both moderate and high intensity exercise were beneficial to these patients with HIV and more importantly, did not have a negative effect on the immune system.
Effect of Exercise on Viral Load
Exercise effects on viral load have been studied by several researchers. Bopp et al. found a negative correlation between physical activity and viral load. Their study, however, merely looked at physical activity, as in activities of daily living, not particularly exercise. While this study encourages individuals infected with HIV-1 to remain active, true effects of more strenuous activity, namely exercise, cannot be inferred from their information. Exercise studies typically have measured plasma HIV-1 RNA, as Bopp et al. did, to indicate viral load levels. Hoshino et al.,  however, have correlated the plasma levels of Vpr with viral load. They found elevated levels of peripheral Vpr when latent HIV- infected cells were induced to activate HIV replication. Vpr is involved with upregulating HIV replication. It also disrupts the mitochondrial membrane potential to trigger host cell apoptosis secondary to consequent oxidative stress. The cytokine interleukin-6 (IL-6) binds a product of this oxidative stress to signal NF-kB, which in turn augments HIV replication. Higher levels of Vpr lead to translocation of this viral protein from HIV-infected cells to the blood and greater amounts of extracellular Vpr are seen. These findings by Hoshino et al.  therefore, suggest the need for monitoring plasma levels of Vpr as another immunological biomarker to indicate elevated HIV replication and recurrent infection. This study did not examine this pathway as a result of exercise, but based on these findings, future exercise studies may be better to assess plasma Vpr levels as an indicator of HIV replication activity. No studies to date have shown a significant effect on viral load with any level of exercise, but in light of the Hoshino et al. report, previous studies may need to be regarded cautiously in terms of exercise effects on viral load.
Awareness of Vpr presence in the blood, through blood analysis reports, would benefit therapists and trainers. In the absence of Vpr, heat shock protein 70 (HSP70) can facilitate HIV replication rather than inhibit it. Exercise acts as a stressor to the cell, which elevates HSP70 levels. Minimizing environmental stressors, such as intense exercise, is advised by Iordanskiy et al. to curtail promotion of HIV replication in patients with absent/undetectable plasma Vpr. Please see the cell biology section of this WIKI topic for a review of HSP70 and Vpr interactions with HIV replication.
MITOCHONDRIA AND REACTIVE OXYGEN SPECIES
Mitochondrial complex 1, the initiator of fat metabolism in the electron transport chain, is affected in HIV. Damage at this site and other electron transport chain complexes can produce more reactive oxygen species (ROS) and less ATP as the electron transport chain cannot optimally metabolize glucose or lipids., , ,  Glucose, amino acids, and lipids that cannot be used correctly accumulate in the cytoplasm leading to glycation (binding of sugar molecules to amino acids) and lipodystrophy. Characteristically, excessive ROS content in the mitochondria induces oxidative stress and leads to apoptosis when antioxidant activity is insufficient. The ROS released from mitochondria into the cytoplasm act as secondary messengers to trigger cytokine secretion and activation of NF-kB pathways. HIV-1 replication is promoted through NF-kB, potentially leading to greater infection.
The effect of exercise on oxidative stress at a cellular level in the population of HIV-infected persons has not been researched well. One recent study by Deresz et al.,  seems to have directly examined exercise effects on cellular oxidative stress for this population. Glutathione is a mitochondrial enzyme involved with eradicating free radicals (i.e. ROS). The abstract of the Deresz et al. article (restricted access did not allow review of the full article at this time) stated that lower levels of total glutathione activity existed before and after a single bout of exhaustive exercise in HIV-infected subjects compared to non-HIV infected subjects. Enzymatic activity of glutathione S-transferase did normalize to a level equal to non-infected patients after exercise, though. While this information suggests a positive effect on augmenting possible mechanisms to control ROS in the mitochondria of individuals infected with HIV, further research likely will coordinate exercise effects with emerging information involving this mitochondrial system.
Exercise studies with subjects infected with HIV usually assess maximal oxygen consumption (VO2 max) as a means to investigate oxidative stress and mitochondrial function. A study of 8 HIV-infected subjects with lipodystrophy or an elevated plasma lactate level and undergoing highly active anti-retroviral therapy (HAART) showed a trend towards lower VO2 max and significantly lower workload capacity as compared to healthy controls in a single bout of exhaustive exercise. The authors concluded, however, that skeletal muscle mitochondria were not damaged because ATP levels and all other expected exercise-induced physiological changes were identical to the healthy subjects. They stated that the observed effect may have been due to impaired physical fitness. Decreased maximum work output was found also, however, in another study comparing lipatrophic (LA; i.e. lipodystrophic) patients versus non-lipodystrophic subjects, both of which were on antiretroviral medication. The researchers found that the lactic acidosis threshold was reached sooner during exhaustive exercise in the LA group, suggesting mitochondrial dysfunction secondary to the medication and not other conditions, such as heart disease. Mitochondrial DNA (mtDNA) encodes for the proteins comprising complexes (e.g the aforementioned complex 1) along the electron transport chain. Any disruption in mtDNA would indicate poor mitochondrial function/cellular respiration, which could lead to previously mentioned accumulation of lipids in the cytoplasm leading to lipodystrophy seen in patients with HIV. Lower mtDNA content was found in adipose tissue of the LA group in one study, perhaps offering an explanation for the central adiposity seen in lipodystrophy. Skeletal muscle mtDNA content was found to be the same, however, in HIV patients with lipoatrophy compared to those without lipoatrophy. Both groups were undergoing antiretroviral treatment and showed comparable aerobic exercise metabolism. This finding indicates that HIV does not necessarily impair functional capacity of infected patients. Medication side effects have been implicated in mitochondrial dysfunction rather than the virus itself.
Better function is possible, though, as studies point to the effectiveness of exercise as a means to improve aerobic capacity, thus implying better mitochondrial function. A review by Hand et al. cited studies showing increased VO2 max in patients treated via HAART with as little as 6 weeks of aerobic exercise 2-3 times per week. Various intensities (50-80% VO2 max) were used in each study, therefore a meta-analysis to indicate optimal intensity was not feasible. Studies combining aerobic exercise with resistance training also have yielded favorable results with overall benefits to the infected persons.
Most research with the HIV-infected population has focused on systemic effects of exercise, such as strength gains, fitness levels, and muscle growth. Cellular level alterations are inferred. Elucidating the mechanism of these modifications at a cellular level in future studies will provide better exercise interventions/recommendations that will maximize patient function without progressing the disease.
Although not completely understood, many comorbidities of HIV/AIDS have been linked to abnormal endocrine function and chronic inflammation. These abnormalities result from disrupted levels of anabolic and catabolic cytokines and hormones, in addition to other factors. Overall, a catabolic environment is created by the HIV infection. The primary cytokines associated with these HIV-related comorbidities include tumor necrosis factor-α (TNF- α), interleukin-1 (IL-1), and interleukin-6 (IL-6).  (Refer to HIV Cell Bio page for further details on cytokines). Research investigating the release and/or suppression of circulating cytokines in response to exercise is limited within the HIV population. However, a preliminary study reveals beneficial changes in catabolic and anabolic factors following both moderate-intensity and low-intensity exercise.  In general, low- and moderate-intensity exercise results in anti-inflammatory effects and proanabolic effects, which may have clinical implications for HIV comorbidities including muscle wasting, body composition changes, and cardiovascular disease.  In this study performed by Dudgeon et al , HIV-infected men were randomly assigned to one of three exercise groups: a low-intensity group (LOW), who participated in a 60 minute bout of aerobic exercise; a moderate-intensity group (MOD), who participated in 30 minutes of aerobic exercise followed by 30 minutes of resistive training; or a control group (CON), who participated in no exercise. Low-intensity aerobic exercise was defined as 50% of age-predicted maximal heart rate (MHR) and consisted of treadmill walking or cycle ergometer. Moderate-intensity aerobic exercise was defined as 60-65% of age-predicted MHR, as moderate-intensity resistive exercise was performed as approximately 60% of 1-rep max. The effect of different exercise protocols on circulating cytokines in subjects with HIV described below, refers to these defined intensities.
TNF-α is a powerful activator of transcription factor, NF-kB, which results in initiation of or increase in viral transcription. In HIV, TNF-α has been attributed to skeletal muscle catabolism and degradation, by inhibiting the secretion of the hormone testosterone.  Testosterone functions to regulate muscle mass, control tissue sensitivity to cellular signaling, and directly stimulate protein degradation.  TNF-α has also been identified as a key mediator of anorexia, weight loss, and overall body wasting.  At rest, the release of TNF-α is elevated in individuals infected with HIV when compared with healthy control subjects. 
In healthy individuals, an increase in TNF-α is observed following exercise bouts of varying intensities, because damaged muscle releases TNF-α.  Conversely, individuals with HIV demonstrated a decrease in TNF-α in both LOW and MOD exercise groups. It has been theorized this decrease in TNF-α results from an increase in IL-6.  These results imply physiological benefits to both types of exercise regimens defined by Dudgeon et al.  A decrease in TNF-α theoretically may result in decreased viral transcription, and may slow the process of skeletal muscle catabolism.
IL-1 functions as a strong upregulator of HIV viral replication in infected monocytes and macrophages.  At rest, HIV patients demonstrate elevated levels of IL-1, as infected individuals release increased amounts of IL-1 from blood monocytes in comparision to uninfected individuals.  IL-1 functions as an inflammatory cytokine, and has been documented as a contributor to the loss of lean body mass and anorexia (both symptoms of HIV wasting syndrome). 
Within the study performed by Dudgeon et al, no significant change in IL-1 levels occurred in the individuals of the LOW or MOD exercise protocols. This is contradictory to the typical response observed in uninfected individuals, an increase in IL-1 following exercise.  The researchers contributed this lack of change to the increase in IL-6, because it has been shown the anti-inflammatory functions of IL-6 suppresses the response of IL-1.  Based on the effect of IL-1 on the pathogenesis of the HIV infection, this lack of IL-1 change may be beneficial within infected individuals. Steady circulating levels of IL-1 may theoretically prevent increased rates of HIV replication and slow the loss of lean body mass.
IL-6 works with TNF-α to increase HIV expression within latent HIV infected monocytes and macrophages.  In addition, IL-6 potentiates the transcription of NF-κB and viral transcription mediated by TNF-α. In addition to increasing HIV replication, IL-6 has also been identified as a main contributor to HIV wasting syndrome. 
Dudgeon et al  demonstrated an increase in circulating IL-6 levels following acute exercise in the MOD group in HIV-infected men. This change was not observed in the individuals of the LOW exercise group (refer to previously described protocol for details). These results correlate with previous studies performed in healthy individuals, which revealed a direct correlation between degree of IL-6 increase and level of exercise intensity performed.  Higher intensity exercise was correlated with a higher increase in circulating IL-6 when compared to lower intensity exercise.  The time period of elevated IL-6 in response to exercise is also similar between uninfected and infected individuals. Aerobic exercise results in immediate IL-6 increases post exercise, while resistive exercise causes elevated IL-6 as a slightly delayed response.  As previously mentioned, IL-6 suppresses the production of IL-1 and TNF on the level of transcription. Previous studies indicate a decrease in IL-1 and TNF can result secondary to an increase in IL-6, consistent with these exercise findings.  Because of the anti-inflammatory effects of increased IL-6 levels, moderate-intensity exercise may have important clinical implications on cardiovascular disease in HIV patients. Inflammation has been shown to play a key role in heart disease. Arterial inflammation, an immune system reaction, has been found to be the most powerful contributor to heart attack, after cholesterol.  This suggests inflammation of the arteries can be just as hazardous as high cholesterol levels in the blood. Furthermore, Dr. Paul Ridker discovered individuals with low cholesterol but high arterial inflammation were just as likely to have a heart attack as those individuals with high cholesterol and low arterial inflammation. 
Additional research is warranted to confirm links between these cytokine responses and physiological outcomes within this patient population. These results suggest an exercise program consisting of moderate-intensity aerobic and resistive exercise has greater effects than lower-intensity aerobic exercise. Greater effects are observed in both the magnitude of change and the number of variables changed. Further research is needed to determine the minimal exercise dosage required to result in positive changes in patients infected with HIV.
EFFECTS OF EXERCISE ON THE NEUROENDOCRINE SYSTEM
In healthy individuals, aerobic exercise and resistance training result in increased release of cortisol. The cortisol levels are directly proportional to the exercise intensity. However, this relationship appears to differ in individuals with HIV. A study by Dudgeon et al., which is described in the cytokine section, examined the effects of both low and moderate-intensity aerobic and resistance exercise on circulating hormones in HIV-infected men. The results revealed that, immediately after the exercise sessions, there was a 35% decrease in cortisol levels in the moderate-intensity group compared to the baseline. Interestingly, there was no change in cortisol levels in the low-intensity exercise group. Hypercortisolemia is typical in patients with HIV and it is associated with a state of catabolism. Thus, the results of this study suggest that moderate-intensity exercise may reduce the destructive metabolism that results from the HPA-axis dysfunction in HIV.
Growth hormone is released from the anterior pituitary gland. It helps maintain bone and skeletal muscle mass by triggering the release of insulin-like growth factor(IGF)-1 from the liver. IGF-1 is an anabolic agent that is important in the regulation of protein metabolism. When locally produced in the muscle, IGF-1 is a powerful controller of muscle mass. Growth hormone resistance and/or decreased growth hormone levels are a common presentation in HIV. This is especially prevalent when the person infected with HIV develops lipodystrophy. Central adiposity results in attenuated growth hormone production as a result of decreased sensitivity to stimulation from growth hormone-releasing hormone (GHRH). Diminished growth hormone levels are also present in malnourished or atrophied individuals, which is typical in those infected with HIV.
The response of growth hormone to exercise is more related to the peak exercise intensity rather than to total work output or duration of activity. Thus, increases in growth hormone levels are common following high-intensity exercise in healthy persons. However, the exercise intensity necessary to significantly increase growth hormone in the HIV-infected population was found to be lower than the normal population. This additional finding further supports the possible anabolic effects of moderate-intensity exercise in individuals with HIV.
HIV infection is associated with decreased adrenal androgen levels. Probably the most well-known androgen is testosterone. Testosterone triggers release of growth hormone from the anterior pituitary, which results in increased production of IGF-1. Additionally, testosterone directly influences expression of protein by binding to skeletal muscle receptors. Testosterone has an antiglucocorticoid influence and the net effect is increased protein synthesis. Not surprisingly, testosterone is typically decreased in individuals with HIV wasting and correlates with lean tissue mass loss, decreased body mass, and decreased exercise capacity.
In healthy individuals, short bouts of high intensity exercise as well as moderate physical activity have been shown to increase serum testosterone levels. However, a study by Kujala et al. demonstrated that testosterone levels decrease with exhaustive prolonged exercise, possibly due to a suppression in gonadotropin-releasing hormone. While the current research does not show the direct effects of exercise on testosterone levels in individuals HIV, one can hypothesize that moderate-intensity exercise may be beneficial for testosterone levels in HIV.
Furthermore, research has been done to examine the anabolic effects of supplemental testosterone as an adjunct to exercise in this population. Studies performed by Bhasin et al. and Fairfield et al. both revealed that combining resistance exercise with testosterone had an anabolic effect in men with HIV and wasting, though the combined effect was not superior to exercise or testosterone therapy alone. Nonetheless, this type of anabolic therapy may slow the progression of the catabolism associated with HIV.
Both exercise and acute psychological stress activate the autonomic nervous system (ANS), which is regulated by catecholamines such as norepinephrine and epinephrine. During exercise in healthy individuals, norepinephrine is released from the sympathetic nerve terminals and epinephrine is released from the adrenal medulla. Arterial plasma levels of epinephrine and norepinephrine increase proportionally with length of exercise and exponentially with intensity. These neurotransmitters target cells with α-adrenergic and β-adrenergic receptors and stimulation is generally associated with the fight-or-flight response. It is important to note that autonomic dysfunction sometimes occurs as a progression of the disease. Fortunately, a study by Spierer and colleagues revealed that regular exercise training in individuals with HIV improves autonomic function.
Not only does norepinephrine cause bronchodilation and increased blood pressure, it also has anti-inflammatory effects. β-adrenergic agonists have been shown to inhibit production of pro-inflammatory cytokines TNF-α, IL-1, and IL-6. This is particularly important in individuals with HIV as these markers are associated with increased viral replication.
Furthermore, a study by Moriuchi et al. examined the effects of norepinephrine on HIV-1. The results of this experiment revealed that norepinephrine downregulated HIV-1 LTR activity in peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM). Administration of the neurotransmitter on these cells also caused deletions of NF-κB binding sites and directly increased cytoplasmic levels of IκB-α. IκB-α suppresses the activity of NF-κB by binding to it and retaining it in the cytoplasm. This prevents NF-κB from entering the nucleus and inducing gene expression. Thus, it appears that norepinephrine inhibits HIV-1 infection through NF-κB inactivation. These findings indicate that, because it stimulates the release of norepinephrine, exercise may be beneficial in slowing the progression of HIV-1 infection.
EFFECT OF EXERCISE ON COMMON HIV COMORBIDITIES
The use of highly active antiretroviral treatment (HAART) has led to a recent increase in the survival rate in the HIV infected population. The increased survival rate has drawn attention to comorbidities, including metabolic syndrome (refer to cell bio page of metabolic syndrome), which affects the quality of life of people living with HIV. Treatment for metabolic syndrome includes modification of risk factors including exercise, adjustment of HAART to exclude protease inhibitors, addition of medications to treat symptoms of metabolic syndrome, and treatment of psychological impact. Data also shows that increasing lean body mass can result in greater protection against metabolic complications associated with HIV and HAART, and the younger a person starts increasing lean body mass, the more beneficial the outcomes.
Multiple studies have researched the effect of both resistive strength training and aerobic exercise on lipodystrophy in patients infected with HIV. Lipodystrophy can be defined as “the loss of fat, frequently observed in the face, arms, and legs (subcutaneous lipoatrophy); the accretion of adipose tissue in the abdomen and dorsocervical spine (lipohypertrophy); and sporadic lipomas.” Yarasheski et al.  found that 64 sessions of resistance training (1-1.5hr/day, 4 days/wk starting at low intensity [50-65% of maximal strength] and high repetitions progressing to high intensity [75-85% maximal strength] in three upper and four lower body muscle groups) decreased the amount of triglyceride levels and showed an increase in fat free mass in individuals with HIV. Another study found that 8 weeks of highly intensive progressive resistance training decreased fat mass in the trunk by 13% and increased fat-free mass. Thoni et al.  looked at aerobic training and the effect on lipodystrophy in people with HIV. The results showed that four months of light aerobic activity consisting of at least two supervised, 45 minute sessions on a cycle ergometer a week while monitoring the heart rate reduced visceral fat and lipid disorders. Although the study did not specify intensity or how many unsupervised sessions the subject completed during the four months, one can conclude that at least 2 sessions a week will render beneficial results.
Exercise, in addition to dietary changes, has been shown to improve insulin resistance in HIV infected individuals as demonstrated by improved insulin levels and an improved score on the Homeostasis Model Assessment of insulin resistance. Robinson et al. found that an exercise program consisting of 16 weeks (preceded by a 2-week phase-in period) of three endurance sessions (20 min at 70%-80% of VO (2max)) and two resistance sessions per week (one set of 8-10 repetitions at 80% of one-repetition maximum on seven exercises) decreased insulin resistance levels by 15.7%.A study done with children who have HIV showed that exercise is both safe and beneficial for the improvement of HIV symptoms.  Miller et al. found that a moderate home based exercise program maintained the benefits of a structured inpatient exercise program 3 months following completion. The home based exercise program was not very structured, encouraging each child to participate in 20 minutes of aerobic activity and complete individualized theraband and dumbbell exercises for all major muscle groups. The data showed an increase in lean body mass indicating an improvement in insulin sensitivity.
Cardiovascular disease is emerging as the most important cause of death and comorbidity in individuals infected with HIV based on its prevalence in the aging HIV population. As a result of HAART and chronic viral infection, cardiovascular risk factors such as decreased lean body mass, hyperlipidemia and insulin resistance are very common in both HIV infected adults and children and get worse as the person ages.
Hypertension is found in around 25% of people with HIV because of sedentary lifestyles and other increased cardiovascular risk factors.  The current recommendation for treating hypertension in the population with HIV is the same as in the general population: lifestyle changes, including exercise, are recommended with the possible addition of anti-hypertensive drugs if needed. The body has the same cellular reaction to exercise as the non-infected individual but the reaction is slightly blunted. A study by Mutimura et al  found that exercise increased VO2 max and decreased per cent body fat, waist circumference, and waist to hip ratio. The participants in this study completed a 6 month supervised exercise program consisting of "proper warm up", stretching, 15 minutes brisk walking, 45-60 minutes of jogging, running, stair climbing, lowback and abdominal stabilization and strengthening exercises, followed by a 15 minute cool down and stretching exercises for a total of a 1.5 hour session. Intensity gradually increased over the 24 weeks to encourage participants to reach at least 45%, 60%, and 75% VO2 max at weeks 1-3, 4-8, and 9-24, respectively.
People with HIV are at increased risk for dyslipidaemia and hypertriglyceridemia.High levels of LDL-cholesterol increase the cardiovascular risk while high levels of HDL-cholesterol act as a protecting factor against cardiovascular disease in the HIV population. One study found exercise increased HDL-cholesterol and decreased LDL-cholesterol in patients with HIV. Another found aerobic training consisting of four months of at least two supervised, 45 minute sessions on a cycle ergometer a week while monitoring the heart rate reduced total cholesterol and fasting triglycerides, and increased HDL-cholesterol. Again, the exact exercise parameters where not reported in this study making it challenging to apply the intervention to other people with HIV.
Decreased bone density continues to be a symptom of both HIV and HAART.  Current recommendations for treating decreased bone density include nutritional supplements, hormone therapy, and exercise. Because there are no current studies solely addressing treatment for decreased bone density in people with HIV and the mechanisms are poorly understood, guidelines for the general population are followed. Based on a review of current literature for people with decreased bone density, a review by DeKam et al.  reported that weight bearing exercise should be incorporated into daily lifestyles for people with HIV to increase bone density and improve trabecular patterns.
SUMMARY OF CELLULAR EFFECTS OF EXERCISE IN HIV
- Increases NK cell count and cytolytic activity without a post-exercise decrease of these immune system variables
- Has no significant effect on CD4-count or viral load
- IL-6 increase suppresses IL-1 and TNF-alpha levels, which prevents HIV replication because transcription pathways are not activated 
- Anti-inflammatory and pro-anabolic effects as a result of elevated IL-6 levels to prevent a higher level of infection 
- Cortisol levels can decrease up to 35% after exercise to counteract the catabolic effects of hypercortisolemia often associated with HIV infection
- Growth hormone increases to trigger release of IGF-1 to prevent muscle tissue degradation and to promote muscle tissue building
- Increases levels of norepinephrine, which downregulates HIV-1 LTR activity and causes deletions in NF-kB binding sites that impede HIV transcription
- Norepinephrine also increases IkB-alpha. This protein retains NF-kB in the cytoplasm, thus preventing NF-kB from acting as a trigger of HIV transcription within the nucleus.
Based on the literature, it is safe and beneficial for individuals with HIV to perform an exercise regimen consisting of moderate-intensity aerobic, resistance, or combined aerobic and resistance exercise. No detrimental effects have been observed regarding CD4-cells and viral load with this level of exercise. Furthermore, this exercise protocol results in a shift from a catabolic to an anabolic state which may have positive clinical implications for HIV comorbidities. High intensity (75%-90% of VO2max), prolonged (>60 minutes) exercise has been found to depress the immune system and have catabolic effects in healthy subjects, resulting in increased susceptibility to infection. Therefore, individuals with HIV, who are already immunocompromised, should avoid this level of exercise. No gender differences with a moderate level exercise regimens have been observed in the literature.