Immunopathogenesis of HIV infection.

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 that 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.

Immunopathogenic mechanisms of HIV infection: cytokine induction of HIV expression.

In this paper Zeda Rosenberg and Anthony Fauci review the prevailing hypotheses on the mechanisms by which human immunodeficiency virus (HIV) progressively and relentlessly destroys immune function in infected individuals. Although HIV can directly kill CD4+ T cells in vitro, the protracted course of HIV infection in vivo suggests that other pathogenic mechanisms are also involved. As a member of the lentivirus family, HIV can remain latent within the genome of the infected cell. Activation of HIV expression from a latent or low-level state of replication is dependent, in part, on the state of activation of the host cell. As a result, activation of HIV-infected CD4+ T cells or monocyte/macrophages during normal immune responses may ultimately result in the activation of HIV expression and spread of the infection. Thus, HIV may have developed the ability to use normal immune processes to its own reproductive advantage.

Immunology of AIDS: approaches to understanding the immunopathogenesis of HIV infection.

Infection with human immunodeficiency virus (HIV) causes an extensive array of immunologic abnormalities which ultimately lead to severe immunosuppression, opportunistic disease, and death. Many of the immunologic defects can be attributable to the quantitative and qualitative deficiencies of T4 lymphocytes caused by HIV. Other abnormalities may reflect chronic HIV exposure to or infection of other immunologic cells including B cells and monocyte/macrophages. A summary of the potential mechanisms of pathogenesis of HIV infection is shown in fig. 2. One of the most puzzling aspects of infection with HIV is the length and variability of time between initial infection and disease. It appears that activation of latent or chronic, smoldering infection into active disease may be the result of a variety of factors, including heterologous viruses and cytokines, whose common denominator is the ability to induce the production of DNA-binding proteins that interact with the HIV-LTR and induce transcription of virus.

Immunopathogenic mechanisms of HIV infection.

The acquired immunodeficiency syndrome (AIDS) follows infection with the human immunodeficiency virus (HIV) after a long and variable period of time. Although HIV can be rapidly cytopathic in vitro for T4 cells, during early in vivo infection, T4 cell numbers are normal and few infected T4 cells can be found. There is increasing evidence that cells of the monocyte/macrophage lineage, including bone marrow precursor cells, can be infected by HIV and are relatively resistant to the cytopathic effects of the virus. As in other lentivirus infections, the monocyte/macrophage may serve as a reservoir of HIV in the body and may play a major role in the pathogenesis of AIDS. In vitro induction of HIV from a latent or low level chronic infection to an active state results from exposure to physiologic cellular inductive signals that might be encountered during normal immune responses.

Immunopathogenic mechanisms in human immunodeficiency virus (HIV) infections.

Infection with HIV can result in a complex array of immunopathogenic effects. HIV infection involves both a direct quantitative depletion of T4 lymphocytes as well as an indirect qualitative effect on the function of several types of immune effector cells. The combination of T4-cell destruction and functional abnormalities contributes to the broad scope of immunologic aberrations and opportunistic diseases seen in HIV-infected individuals. In addition, HIV infection of monocyte/macrophages may play an important role as a reservoir or sanctuary of infection in the host and contribute to the characteristically long incubation period between HIV infection and disease. The activation of HIV from latent or chronically infected cells in vitro by mitogens, antigens, heterologous viruses, and cytokines represents a potential mechanism whereby HIV infection in individuals progresses from an asymptomatic carrier state to clinical AIDS. The release of virus from activated cells can lead to the spread of the virus to other target cells and result in both a qualitative or quantitative defect in immunocompetent cells and subsequent immunosuppression. It is also clear that HIV infection can result in the modulation of expression of certain cellular genes, thereby potentially compounding immunoregulatory abnormalities. Further knowledge of the complex relation between HIV and its target cells will be essential to our understanding of the myriad of potential pathogenic mechanisms of HIV infection and may lead to ways of interrupting the progression of HIV-induced disease.

Biochemical characterization of cells transformed via transfection by feline sarcoma virus proviral DNA.

Murine fibroblasts transformed by transfection with DNA from mink cells infected with the Snyder-Theilen strain of feline sarcoma virus and subgroup B feline leukemia virus were analyzed for the presence of integrated proviral DNA and the expression of feline leukemia virus- and feline sarcoma virus-specific proteins. The transformed murine cells harbored at least one intact feline sarcoma virus provirus, but did not contain feline leukemia virus provirus. The transformed murine cells expressed an 85,000-dalton protein that was precipitated by antisera directed against feline leukemia virus p12, p15, and p30 proteins. No feline oncornavirus-associated cell membrane antigen reactivity was detected on the surfaces of the transformed murine cells by indirect membrane immunofluorescence techniques. The 85,000-dalton feline sarcoma virus-specific protein was also found in feline cells transformed by transfection. However, these cells also contained env gene products. The results of this study demonstrate that the feline sarcoma virus genome is sufficient to transform murine cells and that expression of the 85,000-dalton gag-x protein is associated with transformation of both murine and feline cells transformed by transfection.

Comparative analysis of the genomes of feline leukemia viruses.

The genomes of several strains of feline leukemia virus (FeLV) were compared by two-dimensional polyacrylamide gel electrophoresis of the large RNase T1-resistant oligonucleotides of the 70S RNA. Differences between each strain of FeLV tested were detected by this method. We estimate that the degree of sequence identity between the viruses is: FeLV A (Glasgow-1) to FeLV B (Snyder-Theilen), 52%; FeLV A (Glasgow-1) to FeLV C(Sarma), 66%; FeLV B(Snyder-Theilen) to FeLV C (Sarma), 37%. The fingerprints of two independent isolates of FeLV strains of subgroup A (Glasgow-1 and Rickard) were detectably different. We conclude that the RNase T1 oligonucleotide fingerprint pattern provides a useful tool for identification of FeLV strains.