Human T-lymphotropic viruses. T-lymphotropic viruses human T lymphotropic virus symptoms

(Deltaretrovirus), causing in humans such malignant neoplasms of lymphoid and hematopoietic tissues as T-cell leukemia and T-cell lymphoma.

Adult T-lymphotropic virus is a strain of the virus that primarily affects adults. Closely related is the bovine leukemia virus. It is likely that this virus is involved in the pathogenesis of some demyelinating diseases, for example, tropical spastic paraparesis.

Classification

HTLV I

Human T-lymphotropic virus type 1(HTLV-I), also known as adult T-cell lymphoma virus(HTLV-1), causes diseases such as HTLV-I associated myelopathy, roundworm hyperinfection Strongyloides stercoralis, as well as viral leukemia. According to some reports, 4-5% of those infected will develop malignant tumors as a result of the activity of these viruses.

HTLV-II

Human T-lymphotropic virus type 2(HTLV-2, HTLV-II) is closely related to human T-lymphotropic virus type 1, HTLV-II has a genome homology of about 70% compared to HTLV-I.

HTLV-III and IV

The terms HTLV-III and HTLV-IV are used to refer to viruses that have been described relatively recently.

These viruses were discovered in 2005 in rural Cameroon, and were likely transmitted from monkeys to hunters through bites and scratches.

HTLV-III is similar to Simian T-lymphotropic virus 3, STLV-III. Numerous strains have been identified.

For these types of T-lymphotropic viruses, transmission between people has not been shown and their pathogenicity in relation to humans has not been proven. The name HTLV-III was previously used to refer to HIV, and HTLV-IV to refer to HIV-2, but these names have now fallen out of use.

Notes

1. Taxonomy of viruses (English) on the website of the International Committee on Taxonomy of Viruses (ICTV).
2. According to Primate T-lymphotropic virus 1(English) on the website of the National Center for Biotechnology Information (NCBI).
3. Mahieux R., Gessain A. (2005). "New human retroviruses: HTLV-3 and HTLV-4". Med Trop (Mars) 65 (6): 525-528.

Robert C. Gallo, Anthony S. Fauci

Biology of retroviruses. Retroviruses were first isolated from chickens at the beginning of this century. Later, in the 50s, a mammalian retrovirus was isolated from mice with leukemia. It is now well known that these viruses are associated with the occurrence of both malignant and non-malignant diseases in many animal species. Retroviruses, depending on the forms of diseases they cause, can be divided into malignant, non-malignant, both malignant and non-malignant and non-pathogenic. Non-pathogenic viruses are often inherited as normal genetic Mendelian elements. This mode of inheritance is unique; these viruses are called endogenous. An example of a virus that has both malignant and non-malignant properties is a virus that can cause leukemia in cats. It causes T-cell leukemia, but is more often responsible for disorders resembling human acquired immunodeficiency syndrome (see Chapter 257). Retroviruses that cause non-malignant diseases, such as encephalitis and other neurological diseases, arthritis, and lung diseases, are slow-acting and are referred to as lentiviruses. They are isolated from ungulates, humans (human T-lymphotropic virus type III, or HTLV-III), and non-human apes (simian T-lymphotropic virus type III, or STLV-III).

Retroviruses have an outer envelope budded from the cell membrane and contain an electron-dense core surrounding the viral genome. Sine qua pop of a retrovirus is a DNA polymerase, which is called reverse transcriptase and which, together with RNA, is part of the core. Reverse transcriptase catalyzes the translation of genetic information from RNA to DNA form (provirus). The provirus then usually migrates from the cytoplasm to the nucleus and, after changing to a circular double-stranded form, integrates with the DNA of the host cell, in which it remains throughout the life of the cell (Fig. 293-1). Since the provirus doubles during the S-phase of the cell cycle along with the cellular DNA itself, the daughter cells inherit the viral genome. Thus, the body becomes infected throughout its entire life. When a virus is expressed, its RNA and proteins can be found in the cytoplasm of the cell and also in association with the inner surface of the cell membrane, where budding and release of the virus complete its life cycle. Sometimes deletions of a provirus occur, as a result of which the resulting virus acquires some properties that distinguish it from the original version.

The molecular mechanisms of cell damage by a virus are determined by the structural features of its genome. The most indicative in this regard are chronic leukemia viruses, which contain only three genes responsible for viral replication: gag, pol and env (Fig. 293-2; see Chapter 59). The first (gag) encodes the synthesis of internal structural proteins, pol - reverse transcriptase, and env - envelope glycoproteins. The properties of a virus's envelope are critical in determining the types of cells it can infect, which can inform the requirements for new antiviral vaccines to produce antibodies that target the virus's envelope. The viral gene chain is bounded at both ends by a nucleotide sequence called the long terminal repeat (LTR), which contains regulatory elements that influence the expression of viral genes and sometimes also nearby host cell genes. The long terminal repeat contains signals that determine the integration of the provirus into the DNA of the host cell and forms the reading termination regions of the integrated proviral nucleotide sequence. Examples of viruses that cause chronic leukemia include FeLV, murine leukemia virus, and avian leukemia virus. Before induction of leukemia, these viruses replicate intensively in host cells. It has been proven that these viruses cause leukemia by integrating into a specific region of the chromosome, thus the associated DCTs stimulate the constant expression of cellular genes involved in cell growth processes. The most demonstrative example of this mechanism of action is the development of leukemia in chickens caused by the avian leukemia virus. Its long terminal repeat stimulates cellular oncogene expression, which appears to be the first step in the induction of leukemia. Integration of the virus is random, however, the high rate of replication favors the integration of the virus into precisely those parts of the chromosome that are located close enough to the cellular oncogene, and thus DCT has the opportunity to activate it. All this allows us to explain the completely obvious need for long-term reproduction of the virus before the development of a malignant process.

Rice. 293-1. Life cycle of a retrovirus.

Intact virions enter the cell after adsorption on specific cellular receptors. Single-stranded viral RNA is stripped of its envelope, and reverse transcriptase synthesizes double-stranded viral DNA, which penetrates the nucleus and integrates into the genome of the host cell. Under certain conditions, proviral DNA is not expressed. In other cases, it is transcribed to form RNA, which encodes viral proteins, and genomic RNA. Then the virion is assembled from viral proteins and genomic RNA, followed by its budding from the cell membrane.

A retrovirus, as a result of genetic recombinations, acquires a host cell gene in its genome, which quickly transforms cells and induces acute malignant processes, is often called acute leukemia or sarcoma virus, and the gene is designated as a viral onc gene (see Fig. 293-2; see chapters 58 and 59).

Rice. 293-2. Gene structure and proposed classification of retroviruses. The synthesis of internal structural proteins is encoded by gag, the synthesis of reverse transcriptase - p1, envelope glycoproteins - env; LTR - long terminal repeat; ?gag, ?env - incomplete genes; sre - one of the oncogenes; BLV - bovine leukemia virus; tat - transcriptional transactivator; sor - short open reading frame; 3"orf-3" - open reading frame. The functions of the last two genes in HTLV-III are unknown.

Viruses containing the onc gene are few in number and have not been found in humans. They are of interest for studying the mechanisms of neoplastic transformation rather than as an etiological factor in the natural development of tumors. Each cell infected with these viruses can be transformed (a polyclonal tumor develops), since the product of the viral onc gene has a direct transforming effect. Thus, tumor development does not require virus integration into any specific region of the host cell chromosome.

General properties of human retroviruses. The third category of retroviruses (transactivation retroviruses) is represented by well-known human viruses: T-lymphotropic viruses types I and II (HTLV-I and HTLV-II) and bovine leukemia virus (BLV). The third known human retrovirus, HTLV-III, or lymphadenopathy virus, is in a special category. The genomes of all these viruses have the following properties: 1) in addition to viral reproduction genes, they contain one or more additional genes; 2) the additional gene (genes) is not homologous to the gene (genes) of mammalian cells, i.e., it does not represent an onc gene; 3) at least one of the accessory genes encodes protein synthesis, which is involved in activating the expression of other viral genes and, possibly, some cellular genes (mainly through binding to regulatory enhancing elements in the cell, which are similar to viral DCPs). The biological effect of these viruses is mediated by this gene, which is designated a transcriptional transactivator (tat). Given that tat encodes the synthesis of a nuclear protein that can activate other genes, it is clear that this virus does not need to integrate into any specific region of the chromosome to induce disease. Consequently, for the development of the tumor process there is no need for prolonged replication of the virus in the body. A similar phenomenon is observed with the development of lymphoma in cows caused by the BLV virus. The HTLV-III virus contains not only three viral replication genes and the tat gene, but at least two other genes whose functions remain unclear.

The HTLV-I and HTLV-II viruses are similar in structure; the mature form of HTLV-III is different and has a cylindrical core with a high density. The first retrovirus identified in humans was HTLV-I, which was isolated in 1978 from a man with an aggressive T-cell malignancy. The virus identification method was based on the detection of reverse transcriptase as a trace left by the retrovirus. This method turned out to be more sensitive than electron microscopy. In addition, with the discovery of T-cell growth factor, now called interleukin-2, it became possible to replicate the virus in vitro in a culture of target T-lymphocytes. The same method was used to isolate the AIDS virus.

The main property of all currently known retroviruses is their tropism for T4 lymphocytes (T-helpers). Although other cells can also be infected by these viruses, in vitro T helper cells are primarily damaged by all three types of human retroviruses; in addition, in all diseases caused by them, it is these cells that are almost always damaged. Since T4 cells are involved in the regulation of many immune processes, as well as some functions of non-lymphoid cells (see Chapter 62), it is not difficult to understand why these viruses cause such serious problems. Human retroviruses also have the ability to imitate in vitro processes occurring in vivo. Infection of T4+ cells with HTLV-I or HTLV-II viruses in vitro is accompanied by transformation of some cells. The properties of the transformed cells are very similar to the properties of primary HTLV-1-positive cells in adult T-cell leukemia (ATCL). Other T4 cells and other types of T cells infected with HTLV-I may not transform, but some of their functions are altered. Infection of T4 cells in vitro with the HTLV-III virus with the expression of viral genes can lead to their premature death, which is reminiscent of the processes occurring in patients with AIDS.

Diseases associated with HTLV-I. In most cases of leukemia and lymphoma induced by HTLV-I, T4+ cells are damaged, the nucleus of which acquires pronounced lobulation or which take on the appearance of giant multinucleated cells. However, in some cases it is not possible to identify any obvious morphological changes. Significant expression and increase in the number of receptors for interleukin-2 are of great importance in the pathogenesis of these leukemias. Receptors for this growth factor are also detected in healthy T cells for a short time, but only after their immune activation. Infection of cultured intact T cells is accompanied by a change or complete loss of their immune functions. Such changes occur in parallel with the development of opportunistic infections that often accompany these viral leukemias. Leukemia/lymphoma caused by HTLV-I usually occurs as a lymphoid neoplasia known as adult T-cell leukemia/lymphoma (ATCL), which is characterized by an aggressive course, frequent hypercalcemia (unknown mechanism), infectious complications, and in half of cases - the formation of leukemic infiltrates in the skin (see Chapter 294).

HTLV-I can cause T4+ cell leukemias/lymphomas, which typically have a more chronic course (15-20% of all cases), in addition, they differ from TLV in other manifestations. Pathohistologically or clinically, these forms of the disease may be indistinguishable from T-cell chronic lymphoid leukemias, diffuse histiocytic or large and mixed cell lymphomas, mycosis fungoides or Sézary leukemia. Only a small percentage of people in the United States experience these diseases as HTLV-1-positive, whereas almost all cases of TLV are HTLV-1 positive. In some regions where HTLV-I is endemic, certain B-cell lymphoid tumors and cancers are associated with HTLV-I more often than would be expected based on the prevalence of the virus in the population. Unlike HTLV-1-positive T-cell leukemias, where viral genes are integrated into the DNA of leukemia cells,

HTLV-I is not detected in the DNA of damaged cells in B-cell leukemias. On the contrary, in these cases the virus is detected in intact T cells. Malignant B cells from patients produce a single type of antibody directed against the HTLV-I protein. Thus, tumors of B cell origin are formed (at least in part) due to the indirect influence of HTLV-I, i.e. chronic antigenic stimulation, combined with a decrease in the immune properties of T cells, leads to an increase in the likelihood of neoplastic transformation in an increasing B population -cells.

Origin and epidemiology of HTLV-I. Despite the fact that HTLV-I was initially discovered in two black individuals in the United States with a sporadic T-cell tumor, and the first clusters of this process were identified in residents of Japan and somewhat later in representatives of the black population, natives of the Caribbean islands, this virus, according to -Apparently of African origin. This assumption is supported by: 1) the widespread spread of the virus among the population throughout the African continent; 2) the predominant incidence of TLV on the American continent and in Europe among people of African descent; 3) discovery of a closely related virus (STLV-I) in African primitive monkeys. HTLV-I is also widespread among the populations of two small islands of southwestern Japan (Kyushu and Shikoku), where it may have been introduced by Africans in the 16th century. It has a relatively limited distribution in the United States and Europe, where less than 1% of the Caucasian population is infected, and the virus is practically not found in people living in Asia. Thus, it was not at all difficult to establish an epidemiological connection between the virus and the diseases it causes. The virus is transmitted through sexual contact, transfusions of blood or blood products, and through the placenta. It has been suggested that the virus may be transmitted by blood-sucking insects, but no convincing data in its favor have been obtained. With increased population migration, increased drug abuse (use of blood-contaminated injection needles), changes in sexual behavior, and widespread use of blood transfusions and blood products, HTLV-I infection may increase.

When infected with HTLV-I or HTLV-II, a small proportion of T cells become “immortal,” losing the need for exogenous interleukin-2 to support growth. This process appears to be mediated by the tat gene product, which is believed to bind to T cell regulatory elements that activate the expression of gene(s) involved in the process of T cell proliferation. One of these genes is the receptor for interleukin-2, which, as already noted, is significantly expressed in transformed cells. The reason for such frequent transformation of T4+ cells remains unknown, because not only they are infected, but also other types of cells. Maintenance of the neoplastic process probably requires some additional genetic changes in the cells, since the HTLV-I genes are usually not expressed after the development of TLV.

HTLV-II was originally isolated from a cell culture obtained from a man with T-variant hairy cell leukemia. Subsequently, the virus was detected in two more representatives of the Caucasian population with chronic forms of T-cell tumors. Important information has been obtained regarding the nature of the HTLV-II genome (it is 50% homologous to the HTLV-I genome) and its effects in vitro. These two types of viruses differ only slightly from each other.

Etiology of AIDS. The etiological agent is a retrovirus called HTLV-III. This virus is also called lymphadenopathy (LAV) AIDS-associated retrovirus (ARV). The pathogenesis of the syndrome consists of infection of T4+-inducer/helper lymphocytes by the virus, which leads to the premature death of these cells. The ensuing immune defect contributes to the development of opportunistic infections and some forms of malignant tumors. AIDS is discussed in detail in Chap. 257.

Other diseases caused by HTLV-III. In addition to the characteristic picture. AIDS with opportunistic infections, an increased incidence of Galoshi's sarcoma and a symptom complex consistent with AIDS (see Chapter 257), HTLV-III/LAV infection may be associated with other diseases. The virus can infect the brain, which leads to severe neuropsychiatric processes. There are also cases of lymphoid interstitial pneumonitis associated with HTLV-III/LAV infection. In AIDS, the incidence of certain forms of B-cell lymphomas is increased. Moreover, HTLV-III/LAV infection may increase the incidence of Hodgkin's disease and certain head and neck carcinomas, as well as cloacogenic squamous cell carcinoma. The reason for the increase in these malignant tumors is still unclear. HTLV-III/LAV cannot be the direct cause of their development, since the viral nucleotide sequence cannot be detected in the DNA of most tumor cells. In the mechanism of development of B-cell lymphomas, HTLV-III probably also plays the role of a mediating factor. HTLV-III/LAV infection may also lead to the development of autoimmune thrombocytopenia and hereditary abnormalities.

Cytopathic effect of HTLV-III/LAV on T4" cells. Infection of T4 cells with HTLV-III/LAV leads to their premature death. It is known that the death of an infected cell occurs as a result of the action of one or more HTLV-III/LAV genes after entry into DNA provirus cell. In vitro, it is impossible to induce productive viral infection of T4 cells until they are subjected to immune activation. Upon activation, the same process of gene expression occurs in infected cells as in uninfected cells, but the difference lies in the expression the first are also viral genes. At the same time, a larger percentage of cells than normal undergoes terminal differentiation, the rate of which is higher than that of intact cells. The tat-III gene is apparently responsible for the development of these processes (see Fig. 293- 2) Expression of tat can alternately significantly enhance the transcription of other viral genes or cellular genes responsible for enhancing terminal differentiation.

HTLV-III/LAV heterogeneity. Molecular analysis of a variety of HTLV-III/LAV isolates revealed differences in the nucleotide sequence and in certain regions of the genome, especially in the gene encoding the synthesis of envelope proteins. The viral genome changes as cells are successively infected, but these changes can never be detected in cells cultured for an extended period. In this regard, it can be assumed that they occur during the formation of a DNA transcript of viral RNA and/or the recombination process when provirus DNA is integrated into the DNA of the host cell. Changes in parts of the viral genome can ultimately lead to the viral particle losing its infectious properties.

Prevention of infections caused by HTLV-III/LAV and treatment of patients. There are three challenges in preventing and treating HTLV-III/LAV infections. First, T cells are the main type of cell responsible for antiviral actions, but they are also the first to be damaged by the virus. In general, in all cases where infection occurs through direct cell-to-cell contact, little can be done to enhance protection against the virus. Secondly, the heterogeneity of the viral envelope in different HTLV-III/LAV isolates poses a serious problem, but the results of a recent comparison of the nucleotide sequence responsible for the synthesis of envelope proteins in several virus isolates indicate that they share common conserved regions of this gene, some of which must be immunogenic. Thus, theoretically, the task of creating a vaccine to produce protective antibodies seems completely solvable. Thirdly, since infection means the integration of viral genes into the DNA of cells, these genes are transmitted to the offspring of the damaged cell and, therefore, infection continues continuously. In the United States, more than 1 million individuals are infected with HTLV-III/LAV. It is important that they avoid infection with other agents that could activate already infected T cells, allowing the virus to spread and cause death. A number of antiviral drugs have been developed that inhibit reverse transcriptase or act on the viral envelope. Another approach to treating AIDS patients is based on data from structural and functional studies of the viral genome and consists of creating drugs that suppress the function or expression of the tat-III gene. Treatment, apparently, should be continued throughout the patient's life. To reduce the toxic effect of drugs and reduce the likelihood of developing viral resistance, it is necessary to use their combinations, taking into account differences in the mechanism of action. Another direction of treatment may be to destroy infected cells. Hypothetically, if it were possible to achieve their complete removal, then, accordingly, a complete cure would be achieved. In practice, however, this is not possible because most infected cells do not express viral proteins and are therefore no different from healthy cells.

AIDS is a relatively new human infectious disease and is characterized by the development of severe complications, often leading to the death of the patient. Similar to HTLV-I (and probably HTLV-II) infection, AIDS virus infection in individuals living in Africa has occurred from green monkeys or related monkey species through direct contact or indirectly through intermediate vectors, with subsequent spread to individuals living in other regions . HTLV-III/LAV is also similar to HTLV-I in terms of transmission mechanism, tropism for T4 cells, behavior in vitro and the tat gene. Unlike HTLV-I and HTLV-II, the AIDS virus contains at least two additional genes, has a pronounced cytopathic effect, is distinguished by greater structural similarity to lentiretroviruses and is generally higher infectivity.

Human T-lymphotropic virus (HTLV) is a serotype of T-lymphotropic monkey virus that causes in humans such malignant neoplasms of lymphoid and hematopoietic tissues as T-cell leukemia and tropical spastic paraparesis.

Human T-lymphotropic virus type 1 (HTLV-I) was isolated in 1980 from tumor cells of a patient whose disease was initially regarded as mycosis fungoides. It later became clear that this was a different form of lymphoma, first identified in Japan and called adult T-cell leukemia-lymphoma.

According to serological studies, human T-lymphotropic virus type 1 causes two serious diseases: adult T-cell leukemia-lymphoma and tropical spastic paraparesis (another name is human T-lymphotropic virus type 1 myelopathy).

Human T-lymphotropic virus type 2 was isolated in 1982 from a patient with an unusual form of hairy cell leukemia that affected T-lymphocytes. Early epidemiological studies did not reveal an association of human T-lymphotropic virus type 2 with any disease, but such an association has since been established, especially among injection drug users.

Only human T-lymphotropic virus type 1 is considered here. The molecular biology of human T-lymphotropic virus type 2 is largely similar.

The cellular receptor for human T-lymphotropic virus type 1 has not yet been found, but its gene is mapped to chromosome 17. Usually the virus infects only T-lymphocytes, but sometimes also other cells, such as B-lymphocytes. Most often, carriage of a provirus develops, randomly integrated into various parts of the DNA of CD4 lymphocytes.

Human T-lymphotropic virus type 1 does not contain oncogenes and has no affinity for any specific region of the cellular genome. Its transforming properties are associated with the Tax protein. In vitro infection of human T cell cultures with HTLV-I confirms the ability to induce growth independent of exogenous T cell growth factors. Instead, they alter host cell behavior by uniquely interacting viral regulatory proteins. Most infected cells do not express viral genes. The Tax protein is the only viral protein usually present in tumor cells transformed in vivo, but even this protein is not always detected in patients with T-cell leukemia - adult lymphoma. However, in cells transformed in vitro, active transcription of viral RNA and the formation of new viruses occur. Most transformed cell lines are the result of infection of normal T lymphocytes in vitro. Obtaining cell lines from tumor cells of patients with adult T-cell leukemia-lymphoma is associated with significant difficulties.

Although the Tax protein does not directly bind DNA, it induces the expression of genes encoding transcription factors, cytokines, membrane proteins, and receptors. The Tax protein activates genes normally controlled by transcription factors of the ATF/CREB family. It is not yet clear how changes in the expression level of cellular genes lead to cell transformation. It is assumed that autocrine regulation by cytokines based on the principle of positive feedback plays an important role in cellular transformation. When infected with HTLV-I or HTLV-II, a small proportion of T cells become “immortal,” losing the need for exogenous interleukin-2 to support growth.

Since the Tax protein is not constantly present in tumor cells, it can be assumed that this protein is necessary to trigger transformation, which subsequently develops without its participation. Epidemiological studies have shown that transformation of cells infected with human T-lymphotropic virus type 1 occurs rarely; it may require a combination of several different genetic disorders. In patients with T-cell leukemia - lymphoma of adults, no specific chromosomal abnormalities were found, however, in some cases, mutations of the TP53 gene and translocations affecting the genes of the antigen recognition receptors of T-lymphocytes on chromosome 14 were detected. According to studies, the Tax protein is able to suppress the activity of some DNA repair enzymes, causing the accumulation of mutations. However, the molecular mechanism of the transforming effect of human T-lymphotropic virus type 1 has not been fully elucidated.

Human T-lymphotropic virus belongs to the Oncovirinae subfamily, which is part of the retrovirus family.

There are two types of human T-lymphotropic virus - HTLV-I, HTLV-II. These viruses contain single-stranded RNA that encodes reverse transcriptase, an RNA-dependent DNA polymerase that creates a double-stranded copy of DNA from the single-stranded viral RNA. The circular DNA is then transported to the nucleus where it is integrated into chromosomal DNA to form a provirus, allowing it to evade normal immune surveillance mechanisms and establish a lifelong infection. Both types cause transformation of lymphocytes in vitro, their genomes are approximately 65% ​​homologous. The serological methods used in early epidemiological studies did not distinguish between these two types, in contrast to the later immunoblotting and PCR.

Epidemiology and clinical manifestations

Human T-lymphotropic virus type I was the first human retrovirus to be associated with a malignancy, adult T-cell leukemia/lymphoma. In addition to malignancies, HTLV-I also causes the neurodegenerative disease HTLV-I-associated myelopathy, also known as tropical spastic paraparesis. T-lymphotropic virus I is common in southern Japan (antibodies to it are found in more than 25% of adults), Asia, some areas of the Caribbean, Western, Equatorial and Southern Africa, as well as Central and South America. Within small geographic regions, there are microgroups of strains with marked differences. The prevalence of antibodies to both types of virus among the general population is the same and amounts to 0.01%; it increases with age. Type I virus infection is most strongly associated with being born to someone from the above-mentioned areas of Japan or the Caribbean and having sexual contact with these individuals. This infection is more common in women. T-lymphotropic virus II infection has been correlated with injection drug abuse. In one study of drug users in the United States, the prevalence of this infection was 18%, and it was often associated with T-lymphotropic virus I infection and HIV infection.

T-lymphotropic virus types I and II are transmitted together with cells during sexual intercourse, as well as with blood products, parenterally administered drugs; Perinatal transmission has been proven, usually through breast milk. Studies in Japan have shown that approximately 25% of children born to infected mothers are infected, and that more than 90% of children infected with type I virus have infected mothers. Perinatal infection occurs mainly during breastfeeding; If breastfeeding continues for more than 6 months, the risk of infection triples. Intrauterine and intrapartum infection appears to account for less than 5% of cases of vertical transmission of the virus. The second type of virus can also be transmitted through breast milk, but the transmission rate is lower - approximately 14%.

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Robert C. Gallo, Anton S. Fauci ( Robert S. Gallo, Anthony S. Fauci)

Biology of retroviruses.Retroviruses were first isolated from chickens at the beginning of this century. Later, in the 50s, a mammalian retrovirus was isolated from mice with leukemia. It is now well known that these viruses are associated with the occurrence of both malignant and non-malignant diseases in many animal species. Retroviruses, depending on the forms of diseases they cause, can be divided into malignant, non-malignant, both malignant and non-malignant and non-pathogenic.

Non-pathogenic viruses are often inherited as normal genetic Mendelian elements. This mode of inheritance is unique; these viruses are called endogenous. An example of a virus that has both malignant and non-malignant properties is a virus that can cause leukemia in cats. It causes T-cell leukemia, but is more often responsible for disorders resembling human acquired immunodeficiency syndrome. Retroviruses that cause non-malignant diseases, such as encephalitis and other neurological diseases, arthritis, and lung diseases, are slow-acting and are referred to as lentiviruses. They are isolated from ungulates, humans (T-lymphotropic virus, human type III, or HTLV-III ) and non-human apes (simian T-lymphotropic virus type III, or STLV-III).

Retroviruses have an outer envelope budded from the cell membrane and contain an electron-dense core surrounding the viral genome. Sine qua pop retrovirus is a DNA polymerase, which is called reverse transcriptase and which, together with RNA, is part of the core. Reverse transcriptase catalyzes the translation of genetic information from RNA to DNA form (provirus). The provirus then usually migrates from the cytoplasm to the nucleus and, after changing to a circular double-stranded form, integrates with the DNA of the host cell, where it remains throughout the life of the cell. Because the provirus is in progress S -phase of the cell cycle doubles along with the cellular DNA itself, then the daughter cells inherit the viral genome. Thus, the body becomes infected throughout its entire life. When a virus is expressed, its RNA and proteins can be found in the cytoplasm of the cell and also in association with the inner surface of the cell membrane, where budding and release of the virus complete its life cycle. Sometimes deletions of a provirus occur, as a result of which the resulting virus acquires some properties that distinguish it from the original version.

The molecular mechanisms of cell damage by a virus are determined by the structural features of its genome. The most indicative in this regard are chronic leukemia viruses, which contain only three genes responsible for viral replication: gag, pol and env. First (gag ) encodes the synthesis of internal structural proteins, pol - reverse transcriptase, and env - envelope glycoproteins. The properties of a virus's envelope are critical in determining the types of cells it can infect, which can inform the requirements for new antiviral vaccines to produce antibodies that target the virus's envelope. The viral gene chain is bounded at both ends by a nucleotide sequence called the long terminal repeat (LTR), which contains regulatory elements that influence the expression of viral genes and sometimes also nearby host cell genes. The long terminal repeat contains signals that determine the integration of the provirus into the DNA of the host cell and forms the reading termination regions of the integrated proviral nucleotide sequence. Examples of viruses that cause chronic leukemia include: FeLV , murine leukemia virus, avian leukemia virus. Before induction of leukemia, these viruses replicate intensively in host cells. It has been proven that these viruses cause leukemia by integrating into a specific region of the chromosome, thus the associated DCTs stimulate the constant expression of cellular genes involved in cell growth processes. The most demonstrative example of this mechanism of action is the development of leukemia in chickens caused by the avian leukemia virus. Its long terminal repeat stimulates cellular oncogene expression, which appears to be the first step in the induction of leukemia. Integration of the virus is random, however, the high rate of replication favors the integration of the virus into precisely those parts of the chromosome that are located close enough to the cellular oncogene, and thus DCT has the opportunity to activate it. All this allows us to explain the completely obvious need for long-term reproduction of the virus before the development of a malignant process.

Intact virions enter the cell after adsorption on specific cellular receptors. Single-stranded viral RNA is stripped of its envelope, and reverse transcriptase synthesizes double-stranded viral DNA, which penetrates the nucleus and integrates into the genome of the host cell. Under certain conditions, proviral DNA is not expressed. In other cases, it is transcribed to form RNA, which encodes viral proteins, and genomic RNA. Then the virion is assembled from viral proteins and genomic RNA, followed by its budding from the cell membrane.

A retrovirus, as a result of genetic recombinations, acquires a host cell gene in its genome, which quickly transforms cells and induces acute malignant processes, is often called acute leukemia or sarcoma virus, and the gene is designated as viral onc -gene

Viruses containing onc -gene, are few in number and have not been found in humans. They are of interest for studying the mechanisms of neoplastic transformation rather than as an etiological factor in the natural development of tumors. Each cell infected with these viruses can transform (a polyclonal tumor develops), since the product of the viral onc -gene has a direct transforming effect. Thus, tumor development does not require virus integration into any specific region of the host cell chromosome.

General properties of human retroviruses.The third category of retroviruses (transactivation retroviruses) is represented by well-known human viruses: T-lymphotropic viruses types I and II ( HTLV - I and HTLV - II ) and bovine leukemia virus ( BLV ). Third known human retrovirus HTLV-III , or lymphadenopathy virus, is allocated to a special category. The genomes of all these viruses have the following properties: 1) in addition to viral reproduction genes, they contain one or more additional genes; 2) the additional gene (genes) is not homologous to the gene (genes) of mammalian cells, i.e. it does not represent onc -gene; 3) at least one of the accessory genes encodes protein synthesis, which is involved in activating the expression of other viral genes and, possibly, some cellular genes (mainly through binding to regulatory enhancing elements in the cell, which are similar to viral DCPs). The biological effect of these viruses is mediated precisely by this gene, which is designated as a transcriptional transactivator ( tat ). Considering that tat encodes the synthesis of a nuclear protein that can activate other genes, it becomes clear that this virus does not require integration into any special region of the chromosome to induce disease. Consequently, for the development of the tumor process there is no need for prolonged replication of the virus in the body. A similar phenomenon is observed during the development of lymphoma in cows caused by a virus BLV. HTLV-III virus contains not only three viral replication genes and a gene tat , but at least two other genes whose functions remain unclear.

Viruses HTLV - I and HTLV - II similar in structure, mature form HTLV-III differs from them and has a cylindrical core with high density. The first retrovirus identified in humans was HTLV-I , which in 1978 was isolated from a man with an aggressive T-cell malignancy. The virus identification method was based on the detection of reverse transcriptase as a trace left by the retrovirus. This method turned out to be more sensitive than electron microscopy. In addition, with the discovery of T-cell growth factor, now called interleukin-2, it became possible to replicate the virus in vitro in the culture of target T lymphocytes. The same method was used to isolate the AIDS virus.

The main property of all currently known retroviruses is their tropism for T4 lymphocytes (T-helpers). Although other cells can also be infected by these viruses, in vitro Helper T cells are primarily damaged by all three types of human retroviruses; in addition, in all diseases caused by them, it is these cells that are almost always damaged. Since T4 cells are involved in the regulation of many immune processes, as well as some functions of non-lymphoid cells, It is not difficult to understand why these viruses cause such serious problems. Human retroviruses also have the ability to mimic in vitro processes occurring in vivo . Infection of T4 + cells by viruses HTLV - I or HTLV - II in vitro accompanied by transformation of some cells. The properties of transformed cells are very close to the properties of the primary cells. HTLV -1-positive cells in adult T-cell leukemia (ATCL). Other T4 cells and other types of T cells infected HTLV-I , may not transform, but some of their functions change. T4 cell infection in vitro with HTLV-III virus with the expression of viral genes can lead to their premature death, which is reminiscent of the processes occurring in patients with AIDS.

Diseases associated with HTLV-I.In most cases of leukemia and lymphoma induced HTLV-I , T4+ cells are damaged, the nucleus of which acquires pronounced lobulation or which take on the appearance of giant multinucleated cells. However, in some cases it is not possible to identify any obvious morphological changes. Significant expression and increase in the number of receptors for interleukin-2 are of great importance in the pathogenesis of these leukemias. Receptors for this growth factor are also detected in healthy T cells for a short time, but only after their immune activation. Infection of cultured intact T cells is accompanied by a change or complete loss of their immune functions. Such changes occur in parallel with the development of opportunistic infections that often accompany these viral leukemias. Leukemia/lymphoma caused by HTLV-I , usually occur in the form of lymphoid neoplasia, known as adult T-cell leukemia/lymphoma (ATL), which is characterized by an aggressive course, frequent development of hypercalcemia (the mechanism is unknown), infectious complications and, in half of the cases, the formation of leukemic infiltrates in the skin.

HTLV-I can cause T4 + -cell leukemia/lymphoma, which typically have a more chronic course (15-20% of all cases); in addition, they differ from TLV in other manifestations. Pathohistologically or clinically, these forms of the disease may be indistinguishable from T-cell chronic lymphoid leukemias, diffuse histiocytic or large and mixed cell lymphomas, mycosis fungoides or Sézary leukemia. Only a small percentage of people in the United States experience these diseases as HTLV -1-positive process, whereas in almost all cases of TLV this virus is detected. In some regions endemic for HTLV-I , certain B-cell lymphoid tumors and cancers are associated with HTLV-I more often than would be expected based on the prevalence of the virus in the population. Unlike HTLV -1-positive T-cell leukemia, when viral genes are integrated into the DNA of leukemic cells,

HTLV-I is not found in the DNA of damaged cells in leukemias of B-cell origin. On the contrary, in these cases the virus is detected in intact T cells. The patients' malignant B cells produce a single type of antibody directed against the protein HTLV-I . Thus, tumors of B cell origin are formed (at least in part) due to the indirect influence HTLV-I , i.e., chronic antigenic stimulation, combined with a decrease in the immune properties of T cells, leads to an increased likelihood of neoplastic transformation in an increasing population of B cells.

Origin and epidemiology HTLV-I.Although HTLV-I was originally discovered in two black individuals in the United States with a sporadic T-cell tumor, and the first clusters of this process were identified in residents of Japan and somewhat later in representatives of the black population, natives of the Caribbean islands, this virus appears to be of African origin. This assumption is supported by: 1) the widespread spread of the virus among the population throughout the African continent; 2) the predominant incidence of TLV on the American continent and in Europe among people of African descent; 3) discovery of a closely related virus in African primitive monkeys ( STLV-I). HTLV-I It is also widespread among the populations of two small islands of southwestern Japan (Kyushu and Shikoku), where it may have been introduced by Africans in the 16th century. It has a relatively limited distribution in the United States and Europe, where less than 1% of the Caucasian population is infected, and the virus is practically not found in people living in Asia. Thus, it was not at all difficult to establish an epidemiological connection between the virus and the diseases it causes. The virus is transmitted through sexual contact, transfusions of blood or blood products, and through the placenta. It has been suggested that the virus may be transmitted by blood-sucking insects, but no convincing data in its favor have been obtained. With increasing population migration, increasing drug abuse (use of blood-contaminated injection needles), changes in sexual behavior and widespread use of blood transfusions and blood products, infection rates HTLV-I may increase.

When infected HTLV - I or HTLV - II a small proportion of T cells become “immortal”, losing the need for exogenous interleukin-2 to support growth. This process appears to be mediated by the gene product tat , which is believed to bind to T cell regulatory elements that activate the expression of gene(s) involved in the process of T cell proliferation. One of these genes is the receptor for interleukin-2, which, as already noted, is significantly expressed in transformed cells. The reason for such frequent transformation of T4+ cells remains unknown, because not only they are infected, but also other types of cells. Maintenance of the neoplastic process probably requires some additional genetic changes in the cells, since genes HTLV-I once developed, TLVs are usually not expressed.

HTLV-II was originally isolated from a culture of cells obtained from a man with T-variant hairy cell leukemia. Subsequently, the virus was detected in two more representatives of the Caucasian population with chronic forms of T-cell tumors. Important information about nature was obtained HTLV-II genome (it is 50% homologous to the genome HTLV-I), its effects in vitro . These two types of viruses differ only slightly from each other.

Etiology of AIDS.The etiological agent is a retrovirus called HTLV-III . This virus is also called lymphadenopathy ( LAV ) AIDS-associated retrovirus ( ARV ). The pathogenesis of the syndrome consists of infection of T4+-inducer/helper lymphocytes by the virus, which leads to the premature death of these cells. The ensuing immune defect contributes to the development of opportunistic infections and some forms of malignant tumors.

Other diseases caused by HTLV-III.In addition to the characteristic picture. AIDS with opportunistic infections, increased incidence of Galoshi's sarcoma and symptom complex correlated with AIDS, infection HTLV-III/LAV may be associated with other diseases. The virus can infect the brain, which leads to severe neuropsychiatric processes. There are also cases of lymphoid interstitial pneumonitis associated with infection HTLV-III/LAV . In AIDS, the incidence of certain forms of B-cell lymphomas is increased. Moreover, in case of infection caused by HTLV-III/LAV , there may be an increase in the incidence of Hodgkin's disease and some types of carcinomas with predominant localization in the head and neck region, as well as cloacogenic squamous cell carcinoma. The reason for the increase in these malignant tumors is still unclear. HTLV-III/LAV cannot serve as a direct cause of their development, since the viral nucleotide sequence cannot be detected in the DNA of most tumor cells. In the mechanism of development of B-cell lymphomas HTLV-III , probably also plays a role as a mediating factor. For infection caused by HTLV-III/LAV , it is also possible to develop autoimmune thrombocytopenia and hereditary abnormalities.

Cytopathic effects HTLV-III/LAV to T4 cells. T4 cell infection HTLV-III/LAV leads to their premature death. It is known that the death of an infected cell occurs as a result of the action of one or more genes HTLV-III/LAV after the introduction of a DNA provirus into the cell. In vitro it is impossible to induce productive viral infection of T4 cells until they are subjected to immune activation. When activated, the same process of gene expression occurs in infected cells as in uninfected cells, but the difference lies in the expression of viral genes first. In this case, a larger percentage of cells than normal undergoes terminal differentiation, the rate of which is higher than that of intact cells. The gene is apparently responsible for the development of these processes tat -111. tat expression can alternately significantly enhance the transcription of other viral genes or cellular genes responsible for enhancing terminal differentiation.

Heterogeneity of HTLV-III/LAV.In molecular analysis of a variety of isolates HTLV-III/LAV Differences were identified in the nucleotide sequence and in certain regions of the genome, especially in the gene encoding the synthesis of envelope proteins. The viral genome changes as cells are successively infected, but these changes can never be detected in cells cultured for an extended period. In this regard, it can be assumed that they occur during the formation of a DNA transcript of viral RNA and/or the recombination process when provirus DNA is integrated into the DNA of the host cell. Changes in parts of the viral genome can ultimately lead to the viral particle losing its infectious properties.

Prevention of infections caused by HTLV-III/LAV , and treatment of patients.In preventing infections caused by HTLV-III/LAV , and treatment of patients, there are three problems. First, T cells are the main type of cell responsible for antiviral actions, but they are also the first to be damaged by the virus. In general, in all cases where infection occurs through direct cell-to-cell contact, little can be done to enhance protection against the virus. Secondly, the heterogeneity of the virus envelope in different isolates poses a serious problem. HTLV-III/LAV , however, a recent comparison of the nucleotide sequence responsible for the synthesis of envelope proteins in several virus isolates suggests that they share common conserved regions of this gene, some of which should be immunogenic. Thus, theoretically, the task of creating a vaccine to produce protective antibodies seems completely solvable. Thirdly, since infection means the integration of viral genes into the DNA of cells, these genes are transmitted to the offspring of the damaged cell and, therefore, infection continues continuously. In the US, more than 1 million people are infected HTLV-III/LAV . It is important that they avoid infection with other agents that could activate already infected T cells, allowing the virus to spread and cause death. A number of antiviral drugs have been developed that inhibit reverse transcriptase or act on the viral envelope. Another approach to treating AIDS patients is based on data from structural and functional studies of the viral genome and consists of creating drugs that suppress the function or expression of the gene tat -111. Treatment, apparently, should be continued throughout the patient's life. To reduce the toxic effect of drugs and reduce the likelihood of developing viral resistance, it is necessary to use their combinations, taking into account differences in the mechanism of action. Another direction of treatment may be to destroy infected cells. Hypothetically, if it were possible to achieve their complete removal, then, accordingly, a complete cure would be achieved. In practice, however, this is not possible because most infected cells do not express viral proteins and are therefore no different from healthy cells.

AIDS is a relatively new human infectious disease and is characterized by the development of severe complications, often leading to the death of the patient. Like an infection HTLV - I (and probably HTLV - II ), infection of persons living in Africa with the AIDS virus occurred from green monkeys or related species of monkeys through direct contact or indirectly through intermediate vectors, with subsequent spread to persons living in other regions. HTLV - III / LAV is similar to HTLV - I by transmission mechanism, tropism to T4 cells, behavior in vitro and the tat gene. Unlike HTLV - I and HTLV - II The AIDS virus contains at least two additional genes, has a pronounced cytopathic effect, is characterized by greater structural similarity to lentiretroviruses and is generally higher infectivity.

T.P. Harrison.Principles of internal medicine.Translation by Doctor of Medical Sciences A. V. Suchkova, Ph.D. N. N. Zavadenko, Ph.D. D. G. Katkovsky