Lysine arginine herpes virus

Again, growth problems in these animals were neutralized by feeding extra arginine. Experiments with weaned pigs showed no growth problems and no changes in arginine levels when fed lysine-rich food [ 30 ], suggesting that the antagonism is species-specific.

Lysine-arginine antagonism has not been well-studied in humans, but patients with hyperlysinemia, due to a mutation in a gene coding for a protein involved in the breakdown of lysine, do not show lowered plasma arginine levels [ 31 ], suggesting that humans may not be affected by an antagonism between these amino acids.

Fascetti et al. The basal diet for the control group contained 11 g lysine and 13 g arginine per kg food, meeting the minimal arginine requirement of 10 g per kg food for an adult cat. Different groups of cats were fed experimental diets containing 36, 61, 86, or g lysine per kg food. Higher lysine concentrations in the diet were associated with reduced food intake.

Plasma arginine levels remained unchanged at any of the lysine concentrations tested. Based on these results we conclude that, in the cat, excess lysine in the diet is unable to lower arginine levels in plasma. Similarly, Ball et al. However, only adult cats were studied, and arginine levels in plasma, not in tissue, were measured.

Growing animals appear to be more susceptible to the effects of excess lysine than fully grown animals [ 34 ]. It may be possible that, like in puppies [ 28 ], excess dietary lysine causes growth depression and other clinical signs of arginine deficiency in kittens, without affecting plasma arginine levels. Although research has been done on the requirements of lysine and arginine in young cats, the arginine requirement was established after the requirement for lysine was determined, and the effects of excess lysine on arginine requirements were therefore not investigated [ 35 ].

Several studies have tried to elucidate the mechanism by which lysine affects arginine levels. In theory, the decrease in plasma arginine can be caused by 1 inhibition of the absorption of arginine in the intestine, 2 inhibition of de novo synthesis of arginine, 3 increased protein synthesis, 4 increased metabolism of arginine, or 5 increased excretion of arginine see Fig.

Each of these mechanisms will be addressed in more detail below. Mechanisms by which lysine may lower plasma and tissue arginine levels. The top part of the figure shows the mechanisms that may decrease arginine levels due to a reduction in the supply to the arginine pool, while the bottom part depicts the mechanisms that may lower arginine levels due to increased loss of the amino acid from the pool.

Lysine and arginine use the same systems for transportation across the cell membrane of intestinal and other cells reviewed in [ 36 ]. However, it is unlikely that excess lysine prevents the absorption of arginine, since both amino acids can be absorbed throughout the entire length of the small intestine [ 37 ]. Furthermore, while another amino acid, leucine, inhibits the absorption of arginine in the intestine, excess dietary leucine in chicks was unable to induce signs of arginine deficiency [ 37 ].

In addition, supplementing small amounts of arginine to a diet high in lysine reversed the adverse effects of lysine [ 25 ]. Finally, results from some experiments suggested that lysine may reduce the availability of arginine in the intestine by inhibiting the activity of carboxypeptidase B or trypsin, digestive enzymes that cleave proteins and peptides at arginine and lysine residues [ 27 , 29 ].

However, the authors concluded it is unlikely that this significantly reduces arginine utilization. This conclusion is supported by the observation in chicks that excess lysine also resulted in growth depression when all dietary nitrogen was given in the form of amino acids [ 27 ].

Inhibition of enzymes involved in the synthesis of arginine would reduce arginine levels. However, it is believed that lysine does not have an effect on de novo synthesis of arginine, since a decrease in plasma arginine was also observed in animals that are unable to synthesize arginine and need to obtain all required arginine from their diet [ 25 , 27 ].

Levels of arginine may be reduced when the amino acid is used for the synthesis of proteins. The most striking sign of arginine deficiency, however, is reduced growth i. Therefore it seems implausible that arginine deficiency is the result of an enhancing effect of lysine on protein synthesis. In addition to arginine utilization for protein synthesis, the amino acid can also be used in the urea cycle for 1 the synthesis of urea, using the enzyme arginase and 2 the production of creatine in a reaction catalyzed by the enzyme arginine:glycine amidinotransferase AGAT see Fig.

In multiple experiments, Jones et al. On the other hand, the authors found that excess lysine was associated with increased arginase activity in chicks.

This finding is in agreement with the results of Austic and Nesheim, who showed a dose dependent increase of arginase activity and urea production in chicks when fed excess dietary lysine [ 38 ], and higher arginase activity in chicks with a higher arginine requirement for growth [ 39 ].

However, the authors concluded that increased arginase activity is unlikely to be the only mechanism behind the arginine antagonism of lysine in chicks, since plasma arginine levels decreased before arginase levels increased [ 27 ].

Contrasting results were obtained in puppies, which showed, among others, decreased urea production and accumulation of ammonia upon excess dietary lysine [ 28 ]. If lysine would enhance arginase activity, catalyzing the reaction arginine to ornithine, higher urea levels may be expected. Arginase levels were indeed unaffected by the high concentration of lysine. Furthermore, no accumulation of ornithine in plasma or tissues of chicks or puppies was found, which would be expected if the activity of either arginase or AGAT was increased [ 27 , 28 ].

To the best of our knowledge, a possible role in the lysine-arginine antagonism of nitric oxide synthase, catalyzing the production of nitric oxide from arginine, and arginine decarboxylase, catalyzing the synthesis of agmatine from arginine, has not been investigated. Results from studies in rats and dogs do not support the hypothesis that high plasma lysine concentrations result in competition with arginine for reabsorption in the proximal tubules of the kidneys [ 28 , 29 ].

Rats and dogs fed diets high in lysine excreted more lysine in their urine than arginine, both in absolute numbers and proportionally, when compared to urine samples from animals fed a basal diet. Furthermore, the absolute amount of arginine excreted was an insignificant portion of the amount of arginine that the animals consumed. In conclusion, despite all efforts and after more than half a century of research, the precise mechanism of lysine-arginine antagonism remains poorly understood and may be different between species.

Furthermore, there is no evidence for lysine-arginine antagonism in the cat. The mechanism proposed by others by which lower arginine concentrations would reduce herpesvirus replication is rather simple: the virus needs a lot of arginine for protein synthesis and by restricting the supply of arginine, the virus cannot make sufficient viral proteins for the production of new virions. However, this proposed mechanism is based on two assumptions. It is assumed that 1 the virus needs more arginine than the cell can supply, and that 2 there is a means to limit intracellular arginine levels.

FHV-1 and HHV-1 need cellular arginine, as well as all other amino acids, for the synthesis of new virus particles. In tumor-derived cell lines cultured in arginine-free medium, HHV-1 was unable to replicate [ 14 , 16 ], because its late stage proteins were not synthesized [ 40 , 41 ].

In none of these studies, however, detailed information was provided on how the absence of arginine in the culture medium affected normal, non-viral, protein synthesis and cell growth, making it difficult to conclude that arginine supply was limiting for the virus. The effect of lysine supplementation in vivo is typically determined by measuring arginine levels in plasma, not intracellular. However, lowering the availability of intracellular arginine levels, and not plasma levels, is what, in theory, could prevent viral protein synthesis.

Intracellular arginine levels are an order of magnitude higher than extracellular arginine concentrations [ 42 — 44 ], and even after culturing primary bovine aortic cells in arginine-free medium for 24 h, intracellular arginine concentrations were higher than normal plasma arginine concentrations [ 42 ].

These findings do not support the hypothesis that depletion of intracellular arginine can contribute to halting synthesis of viral proteins. The block of HHV-1 replication at the level of late stage protein synthesis was observed in a cell line, whereas in primary endothelial cells intracellular arginine levels were higher than normal plasma concentrations after culturing in arginine-free medium.

Jeney et al. While the virus was unable to replicate normally in the cell lines, replication of HHV-1 in all primary cell types was similar to the controls cultured in medium with a normal arginine concentration. It was proposed by the authors that intracellular arginine stores in cell lines are lower because of increased metabolic demands due to continuous growth of the cells [ 45 , 46 ]. Indeed, tumor cells have an increased demand for arginine reviewed in [ 47 , 48 ].

In vitro studies performed by Scott et al. In contrast, primary cells survived for weeks in arginine deficient medium [ 49 ]. In conclusion, HHV-1 replication in primary cells was not affected by a lack of extracellular arginine, while results obtained from herpesvirus replication experiments in cell lines are likely to be less relevant because of the aberrant arginine requirements of these cells.

Furthermore, the in vivo situation will not be as extreme as some of the conditions tested in the in vitro experiments, such as complete lack of extracellular arginine. Even when arginine levels in the blood can be lowered by lysine, blood circulation will still continuously supply arginine to the infected cells.

Hence, it seems unlikely that it will be possible to reach a situation in vivo where arginine becomes limiting for HHV-1 or FHV-1 replication. In the very first paper published on the topic of lysine supplementation and HHV-1 infection by Dr. Kagan, it was mentioned that viral proteins contain more arginine than the host proteins in the infected cell [ 50 ], referring to the work of Olshevsky et al.

The availability of the genome sequences of human, cat and herpesviruses enables us to perform a much more detailed comparative analysis of arginine content in these organisms. Interestingly, when we compared the human exome protein coding part of the genome with the HHV-1 exome, we found that human cells code for proteins with even higher arginine content than the virus see Additional file 2.

However, on average, the HHV-1 exome contains more arginine 8. We are aware that this exome analysis does not necessarily reflect the proportion of arginine among the total protein pool in the cell, since the abundance of individual proteins varies. However, comparing the absolute fraction of arginine in the HHV-1 proteome with that of the human proteome is difficult since the exome provides qualitative data, not quantitative, and, to the best of our knowledge, quantitative proteomics data sets of uninfected and HHV-1 infected human cells are not available for analysis.

It seems unlikely, however, that the fraction of arginine in the HHV-1 proteome is much different from that of its exome since the average number of arginine residues for capsid, tegument, envelope and the remaining proteins is 8. While the fraction of arginine in the cat exome is similar to that in the human exome 5. The difference in arginine proportion between host and pathogen is thus smaller for cats and FHV-1 5.

It has been demonstrated that excess dietary lysine does not affect plasma arginine levels in adult cats [ 32 ]. Furthermore, it seems that FHV-1 is less dependent on arginine than human herpesvirus 1 is our data. Irrespectively, trying to lower arginine levels in the cat is undesirable. Arginine is an essential amino acid in cats. In fact, arginine is so critical for this species, no attempts should be made to restrict this amino acid in their diets. Humans fed a diet completely lacking arginine for 5 days showed no clinical signs and no toxic ammonium levels, demonstrating that we can synthesize arginine when needed [ 53 ].

Because of the protein-rich diet of cats, large amounts of ammonium, a by-product of protein and amino acid metabolism, need to be excreted from the body, which in turn requires a lot of arginine [ 33 ]. Arginine is an essential component of the urea cycle, the pathway by which mammals get rid of ammonia see Fig. Urea is produced in the conversion of arginine to ornithine, by the enzyme arginase.

Cats lack the ability to synthesize ornithine and hence also citrulline, because of relatively low activity of the enzymes pyrrolinecarboxylate synthase and ornithine aminotransferase, that can generate ornithine from glutamate and proline [ 55 , 56 ]. However, also when ornithine was added to an arginine-free diet, cats still lost weight [ 57 ], indicating that not enough citrulline can be made from ornithine, because of low levels of ornithine carbamoyl transferase [ 58 ].

Arginine can be synthesized from citrulline, and cats fed an arginine-free diet supplemented with citrulline did not show any clinical signs [ 57 ]. The synthesis of arginine from citrulline is limited in cats because of low plasma citrulline levels. The inability to synthesize any of these other urea cycle intermediates make cats completely dependent of arginine in their food.

Therefore, lowering plasma arginine, either by restricting arginine in the diet or via other indirect ways, is undesirable, especially when lysine amino acid is added to their diet. Simplified version of the urea cycle in the cat. The names of enzymes are italicized. Enzymes shown in red are present at low levels in cats, making cats dependent of arginine in their food.

Cell cultures are an excellent tool to test for antiviral activity of molecules. Although the results do not always translate well into in vivo systems, interesting data can be obtained in a relatively timely manner, experiments are relatively inexpensive and ethical issues are avoided in most cases.

Indeed, the outcome of several in vitro experiments with human herpesvirus stimulated clinical research with patients suffering from herpes labialis or genitalis, but also led to similar experiments with feline herpesvirus 1 [ 7 ] and experiments with cats [ 10 , 11 , 13 ]. In this section, we describe the experiments that were performed to evaluate the effect of lysine on the in vitro replication of HHV-1 and FHV-1, and their results. It was Tankersley, in , who for the first time described that human herpesvirus 1 requires the amino acid arginine for its replication in vitro [ 16 ].

His experiments were performed using an esophageal epithelial cell line of human origin. The inhibition, however, although significant, was not dose dependent and not complete.

Cell lines are homogenous and easy to maintain, but are often derived from tumors and have adapted to growth in culture. Primary cells, obtained directly from tissue, are more difficult to work with, but do better resemble in vivo conditions. A few years after Tankersley published his results, Jeney et al.

However, when primary cells were used primary monkey kidney cells, primary chick embryo fibroblasts and human embryonic fibroblasts the authors discovered there was no difference in HHV-1 replication between cells cultured in arginine-free or control medium.

Many years later, in , Griffith et al. However, again, inhibition was not dose dependent and not complete. Lower arginine levels were associated with a stronger inhibitory effect of lysine.

The ratio lysine to arginine did not seem to be of importance. While complete inhibition was observed by the authors at lysine to arginine ratios of 10, 13, 10 and 8 at arginine concentrations of 5, 7. No information was provided about cell viability of the infected cells cultured with subnormal arginine concentrations.

Park et al. Trigeminal ganglia mouse cells were cultured in EMEM. These primary nerve cells may better resemble the in vivo conditions than the cell lines used by Tankersley and Griffith, most certainly when studying viral latency and reactivation. The authors concluded that lysine supplementation was unable to prevent viral reactivation. Unfortunately, Dr. Park was not able to clarify this issue personal communication. Two in vitro studies examined the effect of lysine on the replication of feline herpesvirus.

In the study by Maggs et al. The authors showed that FHV-1 was unable to replicate in arginine-free medium. Unfortunately, the authors did not test the effect of lysine in culture medium resembling the in vivo physiology of cats more closely, since only subnormal arginine concentrations were used. The results from their own study indicate that they used subnormal conditions, since at 2. Cave et al. The same cell line was used as in the study of Maggs et al.

The authors found that viral replication did not differ between cells cultured in media with different concentrations of lysine and concluded that lysine does not inhibit replication of FHV-1 in vitro. In summary, the results from the in vitro studies with HHV-1 are inconsistent [ 14 , 16 ] and sometimes unclear [ 15 ].

In two studies, one with HHV-1 [ 14 ] and one with FHV-1 [ 7 ], the effect of lysine was only studied with arginine concentrations that did not support normal cell growth or maintenance. The observed inhibition of viral replication may have been the result of increased cell death, rather than an inhibitory effect of lysine.

Cave mentioned that at the arginine concentrations used by Maggs et al. Lysine did not inhibit FHV-1 replication at any of the tested lysine concentrations when arginine levels allowed normal cell growth. It should be noted that cell lines, and not primary cells, were used in all but one studies. One study that was not cited by any of the authors was the work by Jeney et al.

Based on the results described above, we conclude that lysine does not inhibit replication of FHV-1 in vitro. The results for FHV-1 are summarized in Table 1. Summary of studies that investigated the effect of lysine on FHV-1 replication in vitro, or on the prevention or treatment of FHV-1 infection and its disease manifestations in cats.

Human herpesvirus 1 and feline herpesvirus 1 are members of different genera Simplexvirus and Varicellovirus, respectively , but both belong to the alphaherpesvirinae, a subfamily of the herpesviruses. Publications claiming a positive effect of lysine supplementation on the treatment or prevention of herpes labialis or genitalis outbreaks in humans were at the basis of research on the efficacy of lysine supplementation in cats infected with FHV-1, both in vitro [ 7 ] and in vivo [ 10 , 13 ].

In this section we will therefore critically evaluate all clinical studies investigating the efficacy of lysine supplementation in humans infected with HHV-1, in a chronological order. The first publication suggesting a possible role for lysine in the treatment of herpetic lesions was a letter written by Dr.

Kagan [ 50 ] in Four years later a first study appeared, under the leadership of Dr. Kagan, in which the authors claimed a beneficial effect of lysine supplementation on the treatment and prevention of herpes simplex outbreaks [ 61 ]. However, this study was not blind patients knew which medication they received and what the goal of the study was and there was no control group receiving a placebo.

These types of studies are of no scientific value. Indeed, shortly after this study by Griffith et al. This group Milman et al. The results of this randomized, double-blind, placebo-controlled case—control study in which patients were followed for almost a full year showed there was no difference in the recurrence of herpes outbreaks between the group receiving mg lysine per day mg twice a day and the group receiving a placebo [ 20 ].

Patients were instructed to start taking their pills for the duration of about a week when they first started noticing symptoms. The authors argued that they may have missed an effect of lysine in their study because virus replication may have started before the first symptoms were noticed.

Walsh et al. This article, however, describes the results of a questionnaire given to people who bought lysine in a nutrition store. It was uncontrolled and therefore, like other, similar reports [ 63 , 64 ], results are not reliable.

These papers cannot be used to help determine the efficacy of lysine on the prevention or treatment of herpetic lesions. Despite the poor quality of these articles, some authors, unfortunately, still cite these publications, sometimes selectively, using their untrustworthy results to support their claims [ 7 , 10 , 13 , 14 , 18 , 19 , 23 , 61 — 63 , 65 ]. A study performed by McCune et al. The authors did not find a positive effect of lysine on healing rate, but did describe that oral ingestion of mg lysine daily for a period of 24 weeks lowered the number of recurrences when lysine was taken as compared to when the patients took a placebo.

A newer study 20 published in evaluated the effects of lysine and arginine and their ester derivatives on influenza A and SARS-CoV The researchers found that in the lab study, lysine and the ester derivative could efficiently block infection and arginine boosts viral infection of both viruses.

These findings have suggested: The assumption the researchers made was that the participants were not consuming arginine, which sped the response time. This small group of people demonstrated a significant reduction in fever and nonfebrile symptoms from four to 18 hours. While symptoms appeared to rapidly decline, D-dimer levels were high in some participants.

In the participants, only a small percentage continue to have fever after 24 hours. The researchers found it was the combination of lysine supplementation and arginine restriction that offered the best results. The researchers wrote of past evidence demonstrating that lysine influences interleukin, interleukin-6, tumor necrosis factor and interleukin-1 beta that are all implicated in fever. Data demonstrate that lysine has an inhibitory effect on interleukin-6 and increases interleukin anti-inflammatory cytokines.

The researchers also wrote of evidence demonstrating lysine decreases production of nitric oxide, which limits the pathogenesis of inflammation and reduces proinflammatory cytokines. This suggests that independent of its role in suppressing arginine, lysine may also suppress viral replication.

The researchers 23 wrote that in , a researcher from the Bio-Virus Research team proposed in an article published in the Lancet 24 that lysine could be effective against the herpes virus. Four years later a clinical follow-up study confirmed the effectiveness 25 and another study in 26 demonstrated that lysine inhibited arginine in vitro.

In , experts estimated that A literature search published in 29 concluded that without a low-arginine diet, supplementation with lysine at 1 gram per day was not effective. Studies using 3 grams per day appeared to reduce the number of herpes outbreaks. The effectiveness of lysine with herpes virus is related to the herpes virus dependency on arginine to replicate.

Your body needs a balance between lysine and arginine to function optimally. Foods that are rich in lysine 31 include lean meat, tuna, low-fat ricotta cheese and milk. Foods that are rich in arginine include soy-based flour, seed flours, seeds, nuts, egg and chocolate. Benefits of lysine are not limited to your immune system.

For example, studies have demonstrated that lysine can reduce anxiety levels 33 , 34 and reduces vascular calcification. One of the symptoms of lysine deficiency is high blood pressure. In one study 38 of 50 adults with lysine-deficient diets and high blood pressure, supplementation produced a significant reduction in blood pressure. Of course, women who are pregnant or nursing should consult with their doctor before taking a lysine supplement.

One of the best ways to balance your lysine and arginine levels is through diet modification. However, during a viral illness lysine supplementation at levels lower than 3 grams per day may help shorten the length of your illness. Open in a separate window. Potential Risks and Adverse Effects or Long-term Lysine Use Arginine deficiency may occur with kidney or small bowel pathology, sepsis, sickle cell disease, burns, trauma, or surgery.

Discussion Of the 12 studies analyzed in this paper, only 8 were placebo controlled, 7 of which were double-blind, 7 randomized, and 3 of which used cross-over methodology to minimize time effects.

Appendix 1. Lysine-arginine balance is thought to affect HSV expression. References 1. Johnston C, Wald A. Herpes simplex infection. Accessed August 29, Wright EF. Clinical effectiveness of lysine in treating recurrent aphthous ulcers and herpes labialis. Gen Dent. Gaby AR. Natural remedies for Herpes simplex. Altern Med Rev. No author listed Lysine and cold sores. Med Update. Robb-Nicholson C. By the way, doctor.

I keep hearing that aspirin can help prevent colon cancer, but I have no idea how much I should take. Can you help? Harv Womens Health Watch. Lysine for management of herpes labialis. Am J Health Syst Pharm.

A multicentered study of lysine therapy in Herpes simplex infection. Prophylaxis against Herpes Simplex Virus reactivation in patients with facial burns: A potential role for L-lysine. J Burn Care Res. Lysine prophylaxis in recurrent herpes simplex labialis: A double-blind, controlled crossover study. Acta Derm Venereol.

Subjective response to lysine in the therapy of herpes simplex. J Antimicrob Chemother. Use of lysine in treating recurrent oral herpes simplex infections. Lysine as a prophylactic agent in the treatment of recurrent herpes simplex labialis. Failure of lysine in frequently recurrent herpes simplex infection.

Arch Dermatol. Beauman JG. Genital herpes: A review. Am Fam Phys. Interventions for prevention of herpes simplex labialis cold sores on the lips. Cochrane Database Syst Rev. August ; 8 :CD Clinical success of lysine in association with serumal and salivary presence of HSV-1 in patients with recurrent aphthous ulceration. J Exp Integr Med. Bumpstead L. Long-term use of supplemental lysine: Is it safe? J Austral Trad Med Soc. Support Center Support Center.

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