ISSN:0892-6638    

DOI:10.1096/fasebj.5.10.2065884

出版商:Wiley    

年代:1991

数据来源: WILEY

ISSN:0892-6638    

DOI:10.1096/fasebj.5.10.1676687

出版商:Wiley    

年代:1991

数据来源: WILEY

ISSN:0892-6638    

DOI:10.1096/fasebj.5.10.1676688

出版商:Wiley    

年代:1991

数据来源: WILEY

ISSN:0892-6638    

DOI:10.1096/fasebj.5.10.2065885

出版商:Wiley    

年代:1991

数据来源: WILEY

摘要:

The worldwide pandemic of acquired immunodeficiency syndrome (AIDS) has the potential to cause catastrophic medical and social effects that will influence world health well into the 21st century. The causative agent, a lentiretrovirus called human immunodeficiency virus (HIV‐1), is spread by intimate exposure to blood and bodily fluids through sexual, parenteral, and mother‐to‐infant exposure. The natural history from exposure to disease has a median incubation period of 8–10 years and is characterized by progressive depletion of CD‐4 positive T lymphocytes as well as effects on other immune and central nervous system cell populations. The World Health Organization (WHO) estimates that between 8 and 10 million persons are currently infected with the virus worldwide, with 8 to 10 times this level projected by some estimates into the 21st century. Recent leveling off of AIDS incidence in the U.S. appears to represent the positive benefits of antiretroviral therapy, and considerable benefit could be seen if such therapies were made more widely available to medically under‐served populations. With prolonged survival, however, other long‐term sequelae such as cancer and lymphoma may emerge as significant complications of prolonged immunodeficiency. Furthermore, the large pool of already infected persons and continued spread of the virus make the development of additional therapies and an effective anti‐HIV vaccine priorities of medical research.—Blattner, W. A. HIV epidemiology: past, present, and future.FASEB J.5: 2340–2348; 1991.

ISSN:0892-6638    

DOI:10.1096/fasebj.5.10.2065886

出版商:Wiley    

年代:1991

数据来源: WILEY

摘要:

The immunodeficiency virus type 1 is a complex retrovirus. In addition to genes that specify the proteins of the virus particle and the replicative enzymes common to all retroviruses, HIV‐1 specifies at least six additional proteins that regulate the virus life cycle. Two of these regulatory genes,tatand rev, specify proteins essential for replication. These proteins bind to specific sequences of newly synthesized virus RNA and profoundly affect virus protein expression. Tat and rev appear to be prototypes of novel eukaryotic regulatory proteins. These two genes may play a central role in regulating the rate of virus replication. Three other viral genes,vif, vpu, andvpr, affect the assembly and replication capacity of newly made virus particles. These genes may play a critical role in spread of the virus from tissue to tissue and from person to person. Our understanding of the contribution of each of the virus structural proteins and regulatory genes to the complex life cycle of the virus in natural infections is incomplete. However, enough insight has been gained into the structure and function of each of these components to provide a firm basis for rational antiviral drug development.—Haseltine, W. A. Molecular biology of the human immunodeficiency virus type 1.FASEB J.5: 2349–2360; 1991.

ISSN:0892-6638    

DOI:10.1096/fasebj.5.10.1829694

出版商:Wiley    

年代:1991

数据来源: WILEY

摘要:

The quantity and quality of HIV‐1 gene expression is temporally controlled by a cascade of sequential regulatory interactions. Basal HIV‐1 transcription is determined by interaction of cellular regulatory proteins with specific DNA target sequences within the HIV‐1 long‐terminal repeat. The most notable of these protein: DNA interactions involves NF‐xB, a transcription factor that plays a pivotal role in the activation of genes important for cellular responses to infection and inflammation. A second level of control involves the virally encoded Tattrans‐activator. Tat, in combination with as yet unidentified cellular proteins, activates HIV‐1 gene expression through a specific interaction with the viral TAR RNA stem‐loop target sequence. A final level of regulation is mediated by the viral Rev protein. Rev acts posttranscriptionally to induce the expression of HIV‐1 structural proteins and thereby commits HIV‐1 to the late, cytopathic phase of the viral replication cycle. Rev activity appears to require a critical, threshold level of Rev protein expression, thus preventing entry into this late phase in cells that are unable to support efficient HIV‐1 gene expression. In total, this cascade of regulatory levels allows the HIV‐1 provirus to respond appropriately to the intracellular milieu present in each infected cell. In activated cells, the combination of Tat and Rev can stimulate a very high level of viral gene expression and replication. In quiescent or resting cells, in contrast, these same regulatory proteins are predicted to maintain the HIV‐1 provirus in a latent or nonproductive state.—Cullen, B. R. Regulation of HIV‐1 gene expression.FASEB J.5: 2361–2368; 1991.

ISSN:0892-6638    

DOI:10.1096/fasebj.5.10.1712325

出版商:Wiley    

年代:1991

数据来源: WILEY

摘要:

Since the discovery of human immunodeficiency virus (HIV) as a pathogenic retrovirus linked to acquired immunodeficiency syndrome (AIDS), a number of potentially useful strategies for antiretroviral therapy of AIDS and its related diseases have emerged. One such strategy involves use of the broad family of 2′,3′‐dideoxynucleosides, to which 3′‐azido‐2′,3′‐dideoxythymidine (AZT) belongs. AZT has been shown to reduce the replication of HIV in vivo and to confer significant clinical benefits in patients in both early and advanced stages of infection. Other members of the family, 2′,3′‐dideoxycytidine (ddC), 2′,3′‐dideoxyinosine (ddI), and 2′,3′‐didehydro‐2′,3′‐dideoxythymidine (d4T), have also been reported to be active against HIV in short‐term clinical trials. The armamentarium of antiretroviral agents is rapidly growing. Various nonnucleoside agents have recently been identified to be active against HIV in vitro. HIV‐1 protease inhibitors are notable as possible new therapies for HIV‐1‐related diseases. However, we have faced several new challenges in the antiretroviral therapy in AIDS. These include long‐term drug‐related toxicities; emergence of drug‐resistant HIV variants; and development of various cancers, particularly as effective therapies prolong survival. Progress in understanding structure‐activity relations and clinical effectiveness will continue with dideoxynucleoside analogs. However, it seems certain that a variety of nonnucleoside analogs affecting multiple steps in viral replication will become available before long, and combination therapies using multiple antiretroviral drugs will be available. Such therapies will exert major effects against the moribidity and mortality caused by HIV.—Mitsuya, H.; Yarchoan, R.; Kageyama, S.; Broder, S. Targeted therapy of human immunodeficiency virus‐related diseases.FASEB J.5: 2369–2381; 1991.

ISSN:0892-6638    

DOI:10.1096/fasebj.5.10.1712326

出版商:Wiley    

年代:1991

数据来源: WILEY

摘要:

The ultimate consequence of infection with HIV is profound immunosuppression that is the result of both quantitative and qualitative abnormalities of the helper/inducer subset of T lymphocytes. The initial pathogenic event in HIV infection is binding of the envelope glycoprotein of HIV to the CD4 receptor molecule present on the surface of CD4+T lymphocytes and monocyte/macrophages. In vivo the reservoir for HIV infection in the peripheral blood is the CD4+T cell, whereas in other tissues the monocyte/macrophage may play a substantial role. As disease progresses in HIV‐infected individuals, the viral burden in the peripheral blood CD4+T cells increases. An understanding of the mechanisms involved in the transition from an initially low viral burden during the asymptomatic phase of HIV infection to the higher levels of virus expression detected in late stage disease is being investigated intensively. A number of potential agents thay may influence regulation of HIV expression have been identified including mitogens, antigens, heterologous viruses, cytokines, and physical factors. The pathogenic mechanisms of HIV‐induced neurologic abnormalities and the potential role of HIV in a number of other clinical manifestations of HIV infection are also discussed.—Rosenberg, Z. F.; Fauci, A. S. Immunopathogenesis of HIV infection.FASEB J.5: 2382–2390; 1991.

ISSN:0892-6638    

DOI:10.1096/fasebj.5.10.1676689

出版商:Wiley    

年代:1991

数据来源: WILEY

摘要:

Hallmarks of central nervous system (GNS) disease in AIDS patients are headaches, fever, subtle cognitive changes, abnormal reflexes, and ataxia. Dementia and severe sensory and motor dysfunction characterize more severe disease. Autoimmune‐like peripheral neuropathies, cerebrovascular disease, and brain tumors are also observed. Histological changes include inflammation, astrocytosis, microglial nodule formation, and diffuse de‐ or dysmyelination. Focal demyelination can also be seen. It is clear that AIDS‐associated neurological diseases are correlated with greater levels of HIV‐1 antigen or genome in tissues. In AIDS dementia, macrophages and microglial cells of the CNS are the predominant cell types infected and producing HIV‐1. However, manifestations of the disease make it unlikely that direct infection by HIV‐1 is responsible. It seems more likely that the effects are mediated through secretion of viral proteins or viral induction of cytokines that bind to glial cells and neurons. HIV‐1 induction of such cytokines as interleukin 1 (IL 1) and tumor necrosis factor‐α (TNFα) may lead to an autocrine feedback loop involving further productive virus replication and induction of other cytokines such as interleukin 6 (IL 6) and granulocyte‐macrophage colony‐stimulating factor (GMCSF). Interleukin 1 and TNFα in combination with IL 6 and GMCSF could account for many clinical and histopathological findings in AIDS nervous system diseases. As HIV‐1 infected patients produce elevated levels of IL 1, TNFα, and IL 6, it will be important to make a formal connection between the presence of these factors in the CNS, which are all products of activated macrophages, astroglia, and microglia, their in vivo induction directly by virus or indirectly by virus‐induced intermediates, and the clinical and pathological conditions seen in the nervous system in this disease.—Merrill, J. E.; Chen, I. S. Y. HIV‐1, macrophages, glial cells, and cytokines in AIDS nervous system disease.FASEB J.5: 2391–2397; 1991.

ISSN:0892-6638    

DOI:10.1096/fasebj.5.10.2065887

出版商:Wiley    

年代:1991

数据来源: WILEY