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��ࡱ�>��	9;����678�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������q`��w�bjbjqPqP4N::w��������>>>>>>>R8888��:LR۵,�:��A�A�A�A{B�B�BB�D�D�D�D�D�D�$�ho��h�->�I{B{B�I�Ih�>>�A�A����T�T�T�I�>�A>�AB��T�IB��T�T�@d0>>f�A�:`O����8�R�pe$&���0۵�elA�HT^A�Hff*2A�>*���B�kDD�T�E�F1�B�B�Bh�h��T�B�B�B۵�I�I�I�IRRR�6+�RRR6+RRR>>>>>>����Influence of L-lysine amino acid on the HIV-1 RNA replication in vitro

Evgeny Vlad. Butorov1

1The Municipal Center of HIV/AIDS prophylaxis, Surgut, Russian Federation

Running title: L-lysine amino acid and HIV-1 RNA replication
Keywords: HIV, plasma L-lysine, viral load.

Correspondence: Evgeny Butorov, M.D., Ph.D., Municipal Center of HIV/AIDS prophylaxis, P.O.Box 500, 628412, Surgut, Russian Federation. E-mail, HYPERLINK "mailto:butorov888@gmail.com"butorov888@gmail.com

















































Abstract
Virus replication strongly depends on host metabolic machinery and essential cellular factors, in particular, on amino acid profiles. Amino acids play an important role in the pathogenesis of virus-related infections both as basic substrates for protein synthesis and as regulators in many metabolic pathways, including gene expression. Our aim was to determine the direct effect of L-lysine on HIV replication in vitro. The study results show that there was evidence for an association between L-lysine supplementation and the quantity of HIV-1 RNA copies in plasma samples. We suppose that level changes of this host essential nutritional element play a key role in the retrovirus lifecycle. Although the impact mechanism of L-lysine on the viral load in the pathogenesis of HIV-infection is at present conjectural and requires further development, our findings and bold conclusions may be, in fact, a promising target for a new vector in antiviral therapy of patients with HIV.
Keywords: HIV, plasma L-lysine, viral load. 

Background
Despite the considerable efforts of the world community and the optimistic expectations of achieving the main goals in the response to new cases of HIV-infection (such as universal access to prevention, treatment, care and support) the HIV/AIDS pandemic remains a major health problem. UNAIDS estimates that about 35.3 million people are living with human immunodeficiency virus, with 2.3 million new infections in 2012 and an estimated 1.6 million deaths from HIV-related illnesses in the same year [1,2] . 
The development of new methods and approaches in the treatment of HIV-infection in the era of highly active antiretroviral therapy remains an urgent and pressing need. Understanding the pathogenesis of HIV infection and finding points of vulnerability in the relationships between the infecting organism and the virus is a key to achieving full control of HIV infection.
Viral infections usually cause the host significant metabolic disturbances associated with direct toxic and cytopathic effects like intracellular parasites using the host cell resources for their energy, construction, and information needs [3-20]. Monitoring of these metabolic changes is important for understanding the disease pathogenesis and getting a new approach for the possible potential effect on the infectious agent.
Significant changes in the host protein and lipid metabolism, catabolic effects and the negative nitrogen equilibrium lead to alterations in amino-acid profiles due to viral infection [21-23]. At the same time, observational studies indicate that amino acid imbalances in the extracellular medium were found to be critical in the life cycle of some viruses and are related to increased risk of diseases rapidly progressing [24-30]. However, there are few data in the literature about infection-related amino acid imbalance in HIV infected patients [31-35]. In virus infection, this basic element is not only useful for cellular and virus protein synthesis [36-38] but also act as regulators of gene expression via the mechanism of amino acid�regulated transcription factors [39-41]. 
The presence or absence of amino acids in the extracellular medium and its concentrations in the cell, modulate specific transcription factors to promote or repress the synthesis of multiple genes [42-44]. The same mechanism is well known in HIV pathogenesis. Human immunodeficiency virus requires a cellular tRNALys as a primer for initiation of reverse transcription and HIV is not infectious unless the cellular tRNALys interacts directly on the specific region of the viral RNA genome [45-49]. At the same time, only the presence of a sufficient concentration of the covalent amino acid in the cytoplasm activates the cellular tRNA [50-57]. We assume that it is a universal rule that also applies to the HIV-infection pathogenesis. 
For today, the data on the relationship between the plasma amino acid profile and viral load in HIV-infected patients requires further confirmation and the purpose of the present study was to detect a possible direct effect of the L-lysine amino acid on the HIV-1 RNA replication in vitro.

Material and methods
Patients
We performed a case-control study of 100 HIV-1-infected males (age range, 23�38 years; mean�s.d.; 32�4.3 years), who were periodically monitored in the Municipal Center of HIV/AIDS prophylaxis, Surgut, Russian Federation. The patients were in stage A of the disease according to the 1993 Centers for Disease Control (CDC) classification system for HIV-infection. We ascertained patients' general attributes (age, sex), medical history, co-infections and the simultaneous survey period. From the entire cohort, all patients did not receive highly active antiretroviral therapy (HAART).
Blood samples for this study were collected during routine clinical control and analytical monitoring, which included immunological and virological evaluation. The plasma samples of 100 HIV-1-infected males were separated into next groups. 
Three test samples from each of 100 HIV-1-infected patients without HAART (Group 1), 
plasma samples (1) after 24 hours incubation at 25�C.
plasma samples (2) after adding 10.0 mg L-lysine and following incubation for 24 hours at 25�C.
standard plasma samples (controls) studied on the date of blood tests.
Three test samples from each of 15 the same HIV-1-infected patient without HAART (Group 2), 
plasma samples (1) after 24 hours incubation at 25�C.
plasma samples (2) after adding 10.0 mg L-arginine instead of L-lysine and following incubation for 24 hours at 25�C.
standard plasma samples (controls) studied on the date of blood tests.
Author warrants that the Municipal Center of HIV/AIDS prophylaxis has approved the protocol for any investigation involving humans and that all experimentation was conducted in conformity with ethical and humane principles of research. Blood samples were obtained after informed consent from the patients.

Laboratory studies
Fasting venous blood samples for measurement of immunological parameters and HIV-1 RNA levels were collected in two 5.0 ml tubes containing 1.6 mg/ml K2 EDTA (BD Vacutainer�, USA). To determine the CD3, CD4 and CD8 lymphocytes count, venous blood was carefully mixed and analyzed at the Center laboratory on the same day. A laboratory survey of the immune function was conducted by use of a flow cytometer according to the method, defining CD3, CD4 and CD8 lymphocytes count (Coulter Epics XL, Beckman Coulter, USA).   
For the analysis HIV-1 RNA levels, venous blood was centrifuged (3500 r.p.m.; 10 min). Aliquots, the plasma of 1000 �l, were pipetted into Eppendorf tubes and were enriched peripheral blood mononuclear cells (PBMC) the same patient, and immediately analyzed on the date of blood tests in the same laboratory (control samples). The plasma samples 1 were analyzed after 24 hours incubation at 25�C. The plasma samples 2 were enriched peripheral blood mononuclear cells (PBMC) the same patient and were analyzed after adding L-lysine in quantity 10.0 mg and following incubation for 24 hours at 25�C.
Quantification HIV-1 RNA assay was performed by quantitative competitive (RT-PCR) reverse-transcriptase polymerase chain reaction using the commercially available Amplisens� HIV-monitor-FRT kit (Amplisens�, Russian Federation) with a sensitivity limit of 500 HIV-1 RNA copies/ml and real-time PCR cycler (Rotor-Gene Q, QIAGEN, Germany). No significant differences in plasma HIV-1 RNA levels were observed in repeat samples obtained from any given patient. The overall reproducibility of results was consistent to within �7%.
Statistical analysis
Plasma HIV-1 RNA copies/ml values follow a Gaussian distribution (Kolmogorov-Smirnov), so the Student's t-test was applied to compare viral load in comparison groups, with a 95% confidence interval. Data are reported as mean � s.d. (standard deviation), and P values below 0.05 were considered to indicate statistical significance. Statistical analyses were performed using the statistical software package Biostat�. 

Results
HIV-1 RNA replication in plasma samples of HIV-infected patients in vitro (Group 1, 2)
The amount of HIV-1 RNA copies were evaluated in three plasma samples from each of 100 HIV-infected individuals divided into three groups: 
plasma samples (1) after 24 hours incubation at 25�C;
plasma samples (2) after adding L-lysine and following incubation for 24 hours at 25�C;
standard plasma samples (controls) studied on the date of blood tests. 
We observed that viral load (copies/ml) in plasma samples patients with HIV markedly increased after adding L-lysine amino acid in vitro. The increase viral load was found in 92/100 (92%) of HIV-infected subjects before HAART (group 1). Viral load was not increased after replacement of L-lysine for L-arginine in plasma samples of HIV-infected subjects before HAART (group 2). No previous studies are available for comparison. 
The data obtained showed that viral replication in patients with HIV in one stage A has significant differences. The results of this study allow us to quantify and evaluate the dynamic of viral replication using a comparison of plasma samples after 24 hours incubation at 25�C and standard sample (control) in the same patient before HAART.
No significant differences were found between hematological parameters and CD3, CD4, CD8 count lymphocytes (251.3�132.5 s.d., cells/�l) in HIV-infected in comparison groups.
Table 1 summarizes the results on virus replication in samples 1, 2 and control of HIV-infected patients (Group 1, 2).

HIV-1-infected patient without HAART (Group 1, n=100)
The mean HIV-1 RNA copies/ml were significantly higher in the plasma samples (1) after 24 hours incubation at 25�C than in the usual plasma samples (controls) of the same patients studied on the date of blood tests (140,500 � 16,400 and 91,300 � 12,100, P<0.0001, Student's t-test). The number of HIV-1 RNA copies increased in 1.5 times after 24 hours of incubation. 
We found that in samples (2) (365,500 � 42,400) of the same HIV-infected patients after adding L-lysine amino acid and following incubation for 24 hours at 25�C, viral load increased significantly in comparison with the samples (1 and controls) (140,500 � 16,400 and 91,300 � 12,100, P<0.0001, and P<0.0001 respectively, Student's t-test). The average number of HIV-1 RNA copies in samples (2) has increased in 4.0 times (P<0.0001, Student's t-test) in the total cohort.
L-lysine amino acid was added in an amount of 10.0 mg in each plasma sample. 10.0 mg amino acid was optimal for the virus replication process in this experiment. Additional quantities of L-lysine did not cause a further increase viral replication.

HIV-1 RNA replication in plasma samples with replacement of additional L-lysine to L-arginine (Group 2, n=15)
The survey shows a significant increase of HIV-1 RNA copies/ml in plasma samples 1 and 2 HIV-infected patients (159,300 � 14,120 and 183,400�203,300) compared to controls (89,150 � 9,900, P<0,01 and P<0,001, Student's t-test). However, we found no difference in viral load after replacement of L-lysine for L-arginine between samples (1 and 2) (195,900�216,300 and 157,400 � 12,950, P=0.8, Student t-test).  
It is obvious that the addition of L-arginine does not increase viral replication in vitro as L-lysine amino acid supplement does.

Discussion
Virus replication strongly depends on host metabolic machinery and essential cellular factors, in particular, on amino acid profiles. Amino acids play an important role both as basic substrates for protein synthesis and as regulators in many metabolic pathways, including gene expression in virus diseases [18-23]. Specific abnormalities or deficiencies of these essential elements, associated with virus-related conditions are widely appreciated [15-17, 19-31]. The available data clearly showed the inhibition of the multiplication and abortive replication cycle of some viruses by low levels of amino acids in extracellular medium [24-30]. The production of significant amounts of empty virus particles, free of viral nucleic acids has been reported for several virus systems in the absence of essential amino acids in cell cultures [21-26]. 

Not many data exist on the amino acids imbalance in HIV infection [32-38] but numerous studies have thoroughly examined the key role of tRNALys as a primer activation of reverse transcriptase in the HIV pathogenesis [45-48]. There is strong evidence of the presence, in each viral particle, a number of host tRNALys able to make a rapid and guaranteed next replication initiation. HIV-1 virions appear to contain approximately 8 to 25 tRNALys molecules per two copies of viral genome [49]. Meanwhile, any amino acid tRNA activity depends on the concentration of homonymous covalent substrate in the host cytoplasm [57]. This is one of the vulnerable and weak points in the life cycle of HIV and in the absence or insufficient quantity of this essential intracellular element, an �effective� replication of the virus will be under threat. 

We formerly hypothesized that L-lysine presence in extra and related intracellular media can be particularly significant for pathogenesis human immunodeficiency virus and directly related to HIV viral load. 

The replication of human immunodeficiency virus in blood samples continues for a certain time and for this experiment, it was necessary to create conditions favorable for the HIV replication within 24-48 hours. We suggested that optimal stimulation period for the virus replication in plasma samples in vitro depends primarily on the number of cells in the aliquot, and the incubation time, after which cytolysis becomes a problem. For this reasons, patients were enrolled in one stage (A) of the disease with the average amount target cells (CD4 lymphocytes) in the range of 200-300 cells/�l and the incubation time not exceeding 24 hours at 25�C. Further, plasma samples with HIV frozen at -40�C for stopping the replication process were analyzed within the following fortnight in the same laboratory. 

In first stage of experiment, we found that HIV-1 RNA levels were significantly higher in the plasma samples after 24 hours incubation at 25�C than in the plasma samples of the same patients before HAART when studied on the date of blood tests. The number of HIV-1 RNA copies increased an average 1.5 times after 24 hours of incubation. 

Viral load is constantly changing during HIV-infection and is a widely recognized marker in the monitoring of disease progression and treatment efficacy. Now the HIV-1 RNA level is determined as the static parameter, which does not reflect the real dynamic of the virus replication process. We observed that patients before HAART in one stage A had significant differences in viral load and the results of this study allow us to quantify the rate of formation virus particles per unit time via comparison of standard plasma samples with sample after the following incubation of 24 hours at 25�C. Using this simple technique will allow us to assess the dynamic of HIV replication for better monitoring of the disease in the context of clinical trials. 

The next stage of the experiment allowed us to determine the reproduction rates by the addition of L-lysine amino acid in plasma samples in the same HIV-infected patients before HAART. We found that after adding L-lysine amino acid (10.0 mg/ml) and following incubation for 24 hours at 25�C, viral load increased significantly in comparison with the standard samples (controls for this study). Additional quantities of L-lysine above 10.0 mg/ml did not cause a further increase in viral replication, which is probably due to the cytotoxicity of amino acid for this model study in vitro. At this stage of the study, the average number of HIV-1 RNA copies has increased by 4.0 times or from 91,300 to 365,500 copies/ml in 92% of plasma samples of HIV-infected subjects.

Moreover, we found no increase in viral load after replacement of L-lysine for L-arginine in plasma samples in patients. It is obvious that the addition of L-arginine does not increase viral replication in vitro as L-lysine supplement does and these findings confirm the exceptional role of L-lysine amino acid in the virus reproduction. Thus, the simple L-lysine-related model in vitro can be widely used for practical purposes to evaluate the effect of this essential nutrient on HIV-1 RNA replication dynamic, disease prognosis and new approaches in treatment of patients with human immunodeficiency virus in the era of HAART. 

Overall study results show that L-lysine amino acid excess in vitro is characterized by a significant increase of HIV-1 RNA copies in plasma samples of HIV-infected patients before HAART. There was evidence for an association between L-lysine supplementation and HIV-1 RNA reproduction and level changes of this host essential nutritional element play a key role in the synthesis of the virus proteins and in transcription initiation of the retrovirus life cycle though transcriptional activation by cellular tRNALys. Based on the obtained data, we can confidently assert that the intake limitation or deficiency of L-lysine can reduce HIV replication level in vivo.

Although the impact mechanism of L-lysine amino acid on the viral load in the pathogenesis of HIV-infection is at present conjectural and requires further development, the study results and bold conclusions may be, in fact, an interesting and promising target for a new vector in antiviral therapy, and this statement remains to be proved in further research and clinical trials.

Conflicts of Interest and Source of Funding
Author has no�conflict of interest and�source of funding for�this research.

Acknowledgments
The author thanks the laboratory staff of the Municipal Center of HIV/AIDS prophylaxis (Surgut, Russian Federation) for their technical support and for their performance of routine hematological analyses. 

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