RU2021810C1 - Method of action on disease development caused by hiv-virus or virus causing similar biochemical or clinical picture - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves RNA-ase L activity assay in extract of mononuclear cells of patient peripheral blood by determination of cleavage products of 28S-RNA and 18S-RNA and bioactive 2¹-5¹-oligomers. If activated RNA-ase L is not detected then ampligen ^® is administrated at the dose 50-250 mg at rate which is sufficient for attainment of g3 RNA 0.01-1 mcg/ml in blood. EFFECT: increased effectiveness of recovery. 3 tbl

Description

 AIDS (Acquired Immunodeficiency Syndrome) is one of the main threats to human health in the twentieth century. Owing to its changing biological nature, insidious ways of spreading from individual to individual, the “hidden” period of the disease development, which makes its detection difficult, AIDS is undoubtedly one of the epidemiological problems requiring unprecedented efforts. Even with the significant costs invested in increasing the reliability of AIDS diagnostics, the methods created to date still insufficiently meet the necessary requirements for a clear control of this problem for any group of the population (see, for example, the materials of the working group entitled "Experiments on testing antibodies to HTLV -III, current data on screening, laboratory and emidemiological correlation, "under the auspices of the FDA Center for Drugs and Biological Products, National Institutes of Health and Centers for Disease Control Nij, 31 July 1985, at the National Institute of Health, Befezda, pieces Meridaid;. See also Budianskys, Nature 316, c, 96, 11 July 1985 YG)..

 There are several names for the human immunodeficiency virus (HIV), for the HIV virus isolated at the Pasteur Institute (Paris, France), the designation is LAV, and for the HIV virus isolated at the National Institute of Health, Befesda, pc. Marydaid USA, the designation is HTLV-III (human lymphotropic T-cell virus). In the present text, the HIV virus will often be referred to in its general sense or will be designated as HTLV-III or LAV, or HIV, but without the intention of distinguishing between them. Moreover, the term HIV in the present description includes any other any viruses associated with infection with AIDS, regardless of whether they are isolated or not. It is understood that the HIV virus in the singular includes any type of HIV, regardless of its genomic content. Similarly, the symptoms of AIDS in general will be referred to as including the symptoms caused by HIV (as defined above), CSC (AIDS-related complex), lymph node syndrome (lymph nodes) and other viruses that cause essentially the same clinical symptoms.

 Currently, one of two approaches has been outlined in medical practice: immunological (creating a vaccine) and a direct attack on the virus itself (antiviral therapy). Initially, the creation of a vaccine seemed very promising, at least theoretically. However, new information about the nature of the virus has largely eliminated these expectations. The fact is that the virus, apparently, easily undergoes a mutation or a change in its basic biochemical structure, as a result of which the defining viral antigenic “determinants” necessary for the effectiveness of the vaccine are easily mutated or modified. For example, HTLV-III, isolated in California, Maryland and England, as was recently found, significantly differ from each other by a careful analysis of their genomic content. As a result of the studies, it was concluded that vaccination against HIV does not produce sustainable long-term results, in contrast to the truly positive long-term results that have historically been achieved in the case of most other vaccines, for example, against poliomyelitis virus, measles virus, etc.

 In the second approach to the problem (direct attack of the virus), scientists tested a number of compounds, including: AZT, HPA-23, suramin, ribavirin, interferon, fascarnet, etc. These compounds were included in laboratory or clinical studies with limited or unqualified data. about their therapeutic effect. In fact, in almost every case there is evidence of high toxicity and / or adverse side effects (see, for example, a review by M. Clark, Newsweek, p. 71, August 5, 1985, as well as G. Wallis, Timl, pp. 40-47, August 12, 1985). None of these drugs is essentially new and is not capable of being selectively directed against the root cause of the disorder, namely against the multiplication of HIV in certain cells. For example, HPA-3 is a combination of heavy metals (an echo of the use in the twenties - in the era preceding the discovery of penicillin, arsenic for the treatment of sexually transmitted diseases), suramin is essentially an antiparasitic drug (sleeping sickness) and faskarnet is an anti virus depriving. The last two compounds can inhibit an HIV-related enzyme called "reversible transcriptase", but there is insufficient information that such enzymatic inhibition will in fact lead to a significant therapeutic effect or prevention of the disease, or its relief. The use of AZT may be associated with a slight increase in the life span of AIDS victims, but in itself it is highly toxic and does not kill HIV (R. Yarchoan et al., Lancer, March 15, p. 575, 1986; REChaisson and et al., New England (Journal of Medicine, vol. 315, p. 1611, 1986).

 AIDS causes progressive disorders in the immune system as a result of infection with the human immunodeficiency virus (HIV). In the early stages of the disease, the cells responsible for immunity lose their properties as a result of the loss of T cells (produced by the thymus) expressing the so-called T4 antigen, i.e. that part of T cells, which consists mainly of helper phage and T-cell inducer. Deficiency of T4 in cells can lead to certain types of deficiency in cell-transmitted immunity, including deficiency of EU (natural killer cells), ALU (lymphonin activated killer cells) and cytolytic T cells. In AIDS, a defect in lymphocytes originating from the bone marrow is also noted.

 AIDS seems to be a progressive disease, although the transition time from one phase to another may vary. There is a classification for the phases of AIDS development. Asymptomatic HIV-infected individuals are sometimes called seropositive due to the presence of antibodies to the virus in their blood (M. G. Sarigadharan et al., Science, vol. 244, p. 506, 1984). If they do not have other markers, they are assigned to BPI-stage patients according to the classification of Walter Reed (R.R. Pedfield et al., New England Journal of Medicine, t. 224, p. 131, 1986). This stage is also called pre-RCC (RAC - a complex related to AIDS), although some individuals at this stage may not show the characteristic symptom of RAC. Some of these patients may have symptoms of lymph node disease (BP2) and have T-cell deficiency (VRH). After this, the ability of lymphocytes to undergo proliferation-stimulated proliferation and antigen-stimulated gamma-interferon production decreases, and patients at this BP4 stage begin to lose delayed skin hypersensitivity. Patients at the BP5 stage usually become lethargic. They are susceptible to shingles, aphthous stomatitis (thrush), or they show symptoms of CSC, which include prolonged chills, night sweats, weakness, diarrhea, and / or weight loss. This period of CSC is also characterized by a progressive decline in immunity. Finally, patients at the BPG stage are susceptible to any infections, i.e. we are talking about overt AIDS or “full bloom” AIDS, when 50% of patients die within 12 months (H.W. Murray et al., New England Journal of Medicine, t. 310, p. 883, 1984).

 SUMMARY OF THE INVENTION

 An open substance is an inhibitor that is secreted or forced to be excreted by cells infected with human immunodeficiency viruses. This inhibitor is apparently physically associated with the enzyme PHase L, the end product on the pathway to the formation of 2 -5-oligadenylate-PHase L, which leads to the failure of the entire immune system, which allows viruses to multiply uncontrollably. A technique is described for identifying such inhibitors, either directly or indirectly by the absence of PHase L or the inactivity of PHase L, or by the presence of inhibitors of intermediates in the formation of 2-5-A-PHase L, while the inhibitor (s) serves as a marker for detecting the presence of HIV or related viruses giving essentially the same clinical symptoms. The predictive value of such a marker from the point of view of the full development of AIDS in patients, in particular in patients with antibodies to HIV in peripheral blood and tissues, including blood, blood fractions, organ transplant cells and cell extracts, is also discussed. Techniques for activating PHase L and / or removing or deactivating a PHase L-inhibiting substance are described. Part of the invention are therapeutic methods for the deactivation of PHase L-inhibiting substances (a) or a virus directed to such inhibitors. The invention includes methods for producing antibodies to viruses such as in vivo and in vitro using a specific PHase L inhibitor or a virus aimed at inhibiting biochemical intermediates in the formation of 2'-5'-A-PHase L as antigen.

 The invention includes the use of dzRNA in a pharmaceutical composition and a method for activating PHase L, removing or deactivating a specific PHase L inhibitor or virus, aimed at inhibiting biochemical intermediates in the formation of 2'-5'-A-PHase L in both animals and humans , the composition is a combination of dzRNA, preferably unpaired dzRNA, and a lymphokine, such as interferon or another specific antiviral agent, whose effect is enhanced by the isolation and maintenance of dsRNA formation way 2'-5 'A.

 It is recommended that the composition contains dzRNA and interferon in the ratio of 0.01-1000 mg of dzRNA per 0.1-100000 I RV of interferon.

 The invention further includes a method of conferring resistance to biological fluids or cells (preferably human fluids or cells) against viral infections by increasing their resistance or by mitigating the effects of HIV infection, the method comprising mixing or contacting said biological fluids or cells with an effective amount dsRNA, i.e. the amount of dzRNA that inhibits HIV or activates PHase L. The biological fluid may be human blood or a fraction of the blood, for example, intended for transfusion or dialysis. Cells may originate from a skin or transplanted organ intended for transplantation.

 In addition, the invention also includes a method for removing or deactivating substances inhibiting the formation of PHase L from a device for treating parenteral fluids or mitigating the effects of HIV infection from such a device, and the method comprises contacting said device with a composition comprising an effective HIV inhibiting PHase activating agent L is the amount of dsRNA.

 The invention also includes therapeutic methods and compositions for treating HIV-infected patients, including patients with AIDS symptoms, by suppressing or eliminating HIV-specific inhibitors or virus-directed inhibitors of intermediates in the conversion of 2'-5 'A-PHase L and / or activation of PHase L. The composition includes dzRNA and a pharmaceutically acceptable carrier or diluent, as well as instructions for use in the treatment of retroviruses or lymphotropic T-cell virus, disease virus conditions, e.g., AIDS, or other human viruses on whose animation will act activation dormant RNase L.

 Thus, in the form of examples, therapeutic methods are described for the selective inhibition of human viruses, especially HIV, without noticeable toxicity to ordinary cells; methods for inhibiting, slowing down or preventing an individual from becoming infected with HIV; methods for the prevention or treatment of AIDS-related complex and AIDS-related disorders in humans; methods for treating human biological fluids, cells and tissue products to prevent or fix HIV infection or contamination of HIV, as well as methods for correcting certain HIV-related disorders, including the loss of interferon receptors on cells within the immune system in all cases based on reduction or a decrease in the level of intracellular 2'-5 'A synthetase and deactivation of PNase L and a decrease or loss of intracellular dsRNA in selected cells of the immune system. Also described are pharmaceutical compositions intended for use in the above methods. In addition to treating humans, the invention also includes the treatment of animals.

 The use of dzRNA is suitable for the correction of specific disorders associated with HIV infection, including: the loss of PHase L and dzRNA-dependent enzymes (for example, protein kinases) on various defining cells within the immune system, reduction - reduction of intracellular 2'-5 'A- synthetases in various defining cells within the immune system protecting the body and a decrease or loss of intracellular dsRNA and a decrease or loss of bioactive 2'-5 'A oligomers in various decision cells within the immune defending organ ism system.

 Disorders in the cellular "first line of defense" (pathways for the formation of 2'-5 'oligoadenylates) in AIDS.

 Various studies indicate that the pathway for the formation of 2'-5'-oligoadenylate (also referred to in the medical literature as 2'-5 'by the formation of interferon) is violated in AIDS. This way of education is an integral part of the body's defense system against infections. In AIDS and various preceding conditions, for example, CSC and LHF (lymph node disease syndrome), enzymes that are directly involved in this pathway of formation are factors “turned on” or activated, and yet the AIDS virus multiplies. For example, the level of interferon, as a rule, is increased, as well as the level of the enzyme 2'-5'-synthetase. However, the mechanism of this increase, in particular the inability of the system, at least partially included, to inhibit HIV, at least to some extent, remained a complete mystery to the studies reported here.

 As a result of our own studies, an inhibitor that is secondary to HIV infection was identified, and it was found that this inhibitor paralyzes the antiviral defense mechanism that confronts AIDS in its full development.

The characteristic of PHase L is shown in patients with RSC-AIDS, in whom the signs of HIV in the peripheral blood quickly disappear as a result of dzRNA treatment (registered trademark AMPLIGEN ^R , NEM Research Inc., Roville, Md., USA). The absence or presence of activated PHase L in cytoplasmic extracts of peripheral blood mononuclear cells (PBMCs) of patients is concluded by the ability to form specific cleavage products (SPR) from 28S and 18S rRNA according to the methods of K. Kariko and J. Ludwig, Biochem Biophys - Research Communication, t. 128, p. 695, 1985; DHWreschner et al., Nucleic Acid Research, vol. 9, p. 1571, 1981. Ribosomal RNA (containing two molecular species, designated as 28S and 18S) behaves similarly to viral RNA (e.g. HIV) in its ability to cleave under the action of activated PHases, but not deactivated PHases. Activated PHase is characterized in that in its molecular structure it is bound predominantly to 2-5 A oligomers and is very little, if any, bound to the inhibitor. Table 1 summarizes the treatment data for 10 patients with Ampligen.

 HL 929 cell extracts (PHase L minus), used as a source of ribosomal RNA, are incubated for 1 h in the absence or presence of cytoplasmic extracts of MCPC from a healthy control object or patients with CSC and AIDS (each of which receives its own coding number) before treatment with Ampligen.

Before treatment, extracts from all RNA-AIDS patients also give a lack of activation (lack of CHP) even with the addition of exogenous bioactive oligoadenylates / 2'-5'-p ₃ A ₃ (10 ^-8 M) /, which confirmed the impossibility of even the presence of traces of functional molecules PHase L in the lymphocytes of patients before taking Ampligen. Conversely, in parallel with Ampligen treatment, progressive activation of in vivo PHase L is observed; patient 6; patient 7 (AIDS), as well as various patients according to table 1. Only patient number 5 failed to activate PHase L as a result of dzRNA intake and, as expected, he died from all kinds of secondary infections.

 Experimental data. For the first time, the presence in significant concentrations of 2-5 A-oligomers in lymphocytes that have not received treatment of patients throughout the clinical spectrum of AIDS is observed. However, unlike normal individuals, PHase L is inactive in patients with RSKom and AIDS who have not received treatment. It was also noted that if PHase L preparations obtained from patients with RSK-AIDS were initially rinsed intensively (before the test), including trichloroacetic acid (TCA), as a result, these PHase L preparations restore their functionality, i.e. they are able to catalyze specific cleavage or macromolecular RNA, and should be considered active. It was decided by a series of restoration experiments that the PHase L inhibitor is washed out or terminated, but if it is added again, it interrupts again, in other words, inhibits the reactions of PHase L.

 The data accumulated to date indicate that the status of PNase L (active or inactive) provides an important prognostic parameter for HIV and that specific treatment with the participation of double-stranded RNA can correct HIV-specific disorders. The clinical spectrum of individuals from asymptomatic HIV carriers (e.g., patient 8, Table 1) to early diseases (e.g., RSK or SZL, patients 2, 3, 9, 10, 1, and 4) and AIDS in full bloom is exposed to dzRNA to determine whether the inhibitor can be forced to release PHase L, and it was expected that such an event at the molecular level could lead to a decrease in HIV levels and promising clinical improvements. Individuals (with an approximate weight of 60 kg) took twice a week 50-250 mg of a specific dzRNA called Ampligen. It is known that 2'-5'-oligo A synthetase is a dzRNA dependent enzyme, and it was considered reasonable that the inhibitor can be replaced in P Nase L by gradually increasing the concentration of specific bioactive 2'-5'-oligomers inside the cell using artificial (synthetic) dsRNA.

 Table 1 shows how the use of unpaired dzRNA actually leads to a striking decrease in the level of HIV in the blood serum of the treated patients.

 Activation of PHase L has been found to correlate with HIV content and with clinical improvements. Paired dzRNAs may be acceptable and dosages can be low enough to avoid undesired reactions such as poly I. Poly C (zsRNA prepared by Lampson). Where higher dosages are possible, the need for dzRNA will be much greater.

 It is recommended that dzRNA be able to produce the necessary high concentrations of 2'-5 'A origigomers to displace the PHase L inhibitor without toxic effects, for example, due to the accelerated bioavailability of a structure adapted to activate the production of 2'-5'-oligomers without side effects, or due to a relatively short half-life after administration.

 Unpaired double-stranded RNA is a known form of macromolecular RNA in which double helix is not destabilized by basic welding. Unpaired RNA is well known for its ability to induce interferon, which indicates a mechanism unrelated to the induction of interferon per se.

A typical therapeutic embodiment of unpaired double-stranded RNA is synthetic dzRNA formed by a complex of polyriboinosinic and polyribocytidyl uric acid, such as rInr (C _x ; V or G), where x takes values from 4 to 29, for example, rIn. (C ₁₂ V) _n , hereinafter referred to as "Ampligen". Many polymeric dzRNAs, similar in their behavior to Ampligen, have been studied. The key therapeutic advantage of unpaired RNAs over other forms of natural and / or synthetic RNAs is their low toxicity to animals and humans.

 DzRNA complexes are known in the early stages of formation that are capable of triggering various interferon-related effects, however, the toxicity of such compounds precludes any clinical use for treating cancer or similar disorders.

 The inventor has fully described the known types of activity of various interferons, interferon inducers, and dzRNAs in recently published reference books devoted to this issue (see, for example, the chapter written in the book by the inventor in the book Anticancer and interferon drugs, pp. 301-319, edited by RM Ottenbrite and GBButler, Marcel Deccar, New York, 1984; see also Handbook of Experimental Pharmacology on Interferons, edited by PECome and WACarter 1984, Springer-Ferlag, New York and Heidelberg , pp. 533-555, where the well-known properties of dzRN are fully described ).

 As it is now known, dzRNA, for example Ampligen, have therapeutic activity against certain human tumors, in particular, kidney cancer. Although the current opinion assigns only "interferon inducers" to dzRNAs, nonetheless, dzRNAs are active against certain human tumors that are completely resistant to interferon.

 The inventor also describes the inhibition of HIV in human cell culture using dzRNA using Ampligen as a prototype dzRNA.

 The term “unpaired dzRNA” implies that hydrogen bonds (laying of the bases) between opposing strands (dzRNA remain relatively intact, that is, they are interrupted by less than one pair of bases for every 29 consecutive base residues. This is how the term “unpaired dzRNA” is understood .

 dzRNA can be a complex of polyinosinate and polycytidylate, with a specific ratio of uracil bases or guanidine bases, for example, from 1 to 5 to 1 in 30 such bases (poly I. poly (C4-29x> V or G). dzRNA can correspond to the Poly formula I. Poly C, where the ratio of C and V is about 13 to 1 and the deposition coefficients for both Poly I and Poly C are less than 9 and within 2 units of each other, preferably for both about 0.5-7.5 .

dzRNA may correspond to the general formula rIn. (C ₁₂ xV) _n . Other suitable examples of dsRNA are discussed below.

 The composition may include dzRNA and an agent to help inhibit HIV, such as lymphonin, for example, interferon or interleukin, such as IL-3. Table 2 shows the various combinations of compositions. A deficiency of PHase L or a deficiency of another similar dzRNA dependent enzyme will be seen in various cells of AIDS patients, including T cells, EU cells, ALU cells, lymphocytes and monocytes (see Table 2).

 As explained in the present description, dzRNA can be considered as a basic biological agent for the treatment and correction of certain HIV-related disorders. Table 2 lists seven HIV-specific defects or abnormalities that are given in combination with the corresponding potential therapeutic combinations of dzRNA in admixture with another therapeutic agent or agents.

Unmatched dsRNAs recommended for use in the invention are based on copolyinucleotides selected from poly (C _x , V) and poly (C _x , G), where x is a digital metric ranging from 4 to 29, and are unpaired analogues of polyriboinosine complexes and polyribocytilinic acids formed by the modification of rIn-rCn by the introduction of unpaired bases (uracil or guanidine) along the thread of polyribocytidylate (rCn). Alternatively, dzRNA can be derived from poly (I), poly (C) dzRNA by modifying the ribosyl skeleton of polyriboinosinic acid (rIn), for example, by including 2'-0-methylribosyl residues. Such unpaired rIn analogues. rCn, of which those corresponding to the general formula rI are preferred. (C ₁₂ , V) _n , the descriptions of which are given as references. The dzRNAs described in these references are generally suitable for use in accordance with the invention.

Specific examples of unmatched dsRNAs for use in the invention include:
poly (I). poly (C ₄ , V)
poly (I). poly (C ₇ , V)
poly (I). poly (C ₁₃ , V)
poly (I). poly (C ₂₂ , V)
poly (I). poly (C ₂₀ , G)
poly (I). poly (C ₂₉ , C) and
poly (I). poly (C _p ) 23G> p.

 The pharmaceutical compositions of the invention include unpaired dzRNA, possibly also interferon or other immune modulators (limfonin) in admixture with a pharmaceutically acceptable carrier or diluent. Pharmaceutical compositions contemplated by the invention include compositions adapted for parenteral administration in an acceptable pharmaceutical carrier.

 For example, parenteral solutions, suspensions or dispersions can be prepared according to known pharmaceutical methods with sterile water or pyrogen-free water as a diluent solvent, possibly also in a mixture with physiologically acceptable salts.

 The amount of unpaired dzRNA administered is preferably sufficient to achieve a peak blood concentration from 0.01 μg per 1 ml of dzRNA to 1000 μg per 1 ml in the systemic circulatory system at a point remote from the injection site immediately after administration. With the concomitant administration of interferon, it is preferably included in an amount that leads to a level of 0.1-100000 IRV per milliliter of body fluid. Typically, the amount administered depends on the severity of the symptoms, in particular, the level of available intracellular bioactive dsRNA, 2'-5'-oligo A or 2'-5'-A synthetase molecules, and the relative level of inhibition of PHase L. As used herein, the term body fluid means a solution of serum, vitamins, etc., which circulates in the body and flushes tissues. The expected fluid volumes of the patient’s body, of course, are known to practitioners and published in the form of diagrams and tables, which are available in the usual manner. The average volume of fluid in the body is approximately 5-6 liters.

 The invention is illustrated by the following examples of the use of dsRNA.

 Unpaired dzRNA, for example Ampligen, is prepared in the form of an aqueous solution so that when added to various human cells, transient liquid concentrations (for washing the cells) are obtained in 0.01-250 μg per 1 ml. Used a number of cells - potential targets for HIV infection.

 The following describes a typical experiment with H-9 human lymphoid cells that can be acutely or chronically infected with HIV. Cells are grown under standard conditions (see, for example, Mitsuya et al., Science, T. 226, p. 172, 1984) and analyzed for several weeks for the presence of HIV enzymes or HIV-specific proteins. Ampligen is added in various concentrations before, after or simultaneously with the addition of the virus, thereby simulating various clinical conditions. Most importantly, a thorough analysis of cell number, morphology, etc. was carried out. in order to determine whether unpaired dsRNA has a different nonspecific effect on the growth of lymphoid cells, as described by Mitsuya, together with other inhibitors. Cells at various points in the experiment are isolated and examined using HPLC (high performance liquid chromatography) for the presence of 2'-5'-A-oligomers according to the method described by Lee et al. Biochemistry, t.24, p. 551, 1985). Certain A-oligomers present in nature are known to confer virus resistance to cells, however, it has not been previously described or suggested that the test compound (synthesized by humans) can precisely trigger such a natural reaction selectively, thereby enhancing the natural defense mechanism against viruses in general and in particular against HIV. The effect of Ampligen on HIV infectivity is given in Table 3.

 Experiment A was performed at a 25-fold excess of the virus (expressed as infectious units) compared to the target cells, while experiment B was performed at a 10-fold excess of the target cells (designated as H-9 cells) compared to the virus . The percentage of positive cells is shown in relation to cells that express the HIV markers indicated at p24 and p19 based on immunofluorescence analysis in a cell centrifuge according to a standard method, and designated as rA / dT. At the same time, cells are counted: the cells multiply with normal growth rates at all tested Ampligen concentrations (up to 300 μg per 1 ml). In experiments A and B, Ampligen (50 μg per 1 ml) was added on day 1. HPLC analysis showed (on days 3-7 in experiments A and B) a specific shift in the distribution of the 2'-5'-oligomer so that oligomers with a higher molecular weight (MB) (less antiviral) are biased toward oligomers with a lower MB (more antiviral) contributing to the selective and potent suppression of HIV. At the same time, the determination of PHase L indicates the restoration of PHase L during sequential processing of DzRNA.

 Similar experiments were carried out with other various human cells, which are potential in vivo targets for HIV. In these experiments, cells functionally defined as KU cells (natural killer cells) were used. Assistant phage T cells, suppressor T cells, mononuclear cells, etc. In all cases, unpaired dzRNA at various concentrations was able to selectively stop and / or prevent the multiplication of HIV without any effect on the growth and maturation of normal cells (see Table 2). T cell proliferation in culture is established by standard addition of IL-2 factor, i.e. well known in cell biology. Selective suppression of HIV using unpaired dzRNA is stably associated with a specific shift or increase in the distribution of the 2'-5'-oligomer, as established by HPLC analysis.

 In the corresponding biochemical processes, dzRNAs are involved in a downward direction or in places remote from places of biochemical disturbances in individuals at risk (actively infected or uninfected with HIV), thereby restoring the normal ability to resist viruses.

 dzRNA is very effectively perceived by cells, and therefore does not require intact interferon receptors. In addition, unpaired dzRNA also exists in the form of bioactive fragments, which accelerates intracellular uptake and distribution. Thus, dzRNA has the potential to easily overcome the barrier between blood and the brain, which can serve as a residual reservoir of HIV in individual individuals.

 As a rule, the dzRNA used in the invention has known molecular sizes, however, lower molecular weight dsRNAs obtained as fragments of related molecules are also effective. Such fragments can be, for example, from half to one tenth of the size of a typical dzRNA material described previously.

dzRNA activates 2'-5 'A polymerases and promotes the synthesis of a 500-fold increase in active antiviral oligonucleotides compared to separately used interferon (dzRNA gives up to 250 nanomoles of 2'-5'-oligo A in 1.6 ˙ 10 ⁸ cells, in while 200 units / ml of interferon give only 0.5 nanomoles of 2'-5'-oligo A).

 The applicant observed a similar phenomenon in EU cells of individuals at risk of developing AIDS or with clear signs of AIDS. A similar situation exists in relation to the activity level of natural killer cells of patients with RSK-AIDS. However, much less is known about the mechanism of regulation of EU cells. Patients with RSK-AIDS and healthy members of the risk group often have poor ability to immune control (functional EU and T-lymphocytes) and cannot be reactivated by interferon. Ampligen acts away from the block of the disease and is able to activate cytotoxic lymphocytes.

Claims (1)

METHOD OF INFLUENCE ON THE DEVELOPMENT OF A DISEASE CAUSED BY HIV-VIRUS OR A VIRUS CAUSING A SIMILAR BIOCHEMICAL OR CLINICAL PICTURE by determining biochemical parameters and administering a drug, characterized by the fact that P, the absence or effectiveness of the method determines the presence of P or the presence of RNA in order to increase the efficiency extract of mononuclear cells of the patient’s peripheral blood by measuring the cleavage products of 28-r RNA and 18-s rRNA and bioactive 2 ¹ - 4 ¹ oligomers, and if activated RNA-azaL is not detected, Ampligen is administered in a dose of 50 - 250 ml with a frequency sufficient to achieve a dzRNA concentration of 0.01 - 1 μg / ml in the blood, and Ampligen is a complex of polyinositol and polycytidylate containing from 1 to 5 to 1 in 30 bases of uracil and guanine, mainly formulas rIn · r (C ₁₂ U) _n and continue its administration until improvement or stabilization of clinical symptoms.

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