Increased level of arginase activity correlates with disease severity in HIV-seropositive patients.

Infection with human immunodeficiency virus (HIV) results in a chronic infection that progressively impairs the immune system. Although depletion of CD4(+) T cells is frequently used to explain immunosuppression, chronicity of infection and progressive loss of CD4(+) T cells are not sufficient to fully account for immune dysregulation. Arginase-induced l-arginine deprivation is emerging as a key mechanism for the down-regulation of immune responses. Here, we hypothesized that the level of arginase activity increases with disease severity in HIV-seropositive patients. We determined the levels of arginase activity in peripheral blood mononuclear cells from HIV-seropositive patients and uninfected control participants. Our results show that peripheral blood mononuclear cells from HIV-seropositive patients with low CD4(+) T cell counts expressed statistically significantly higher levels of arginase activity, compared with patients with high CD4(+) T cell counts or uninfected control participants. Furthermore, we found a statistically significant correlation between high level of arginase activity and high viral load in HIV-seropositive patients.

Long-term persistence of activated cytotoxic T lymphocytes after viral infection of the central nervous system.

Mice intranasally inoculated with influenza A/X-31 are protected against a subsequent intracerebral challenge with the neurovirulent influenza A/WSN and this heterotypic protection is mediated by CD8(+) cytotoxic T lymphocytes. We have studied the kinetics of this secondary immune response and found that despite the elimination of replication-competent virus by day 10, we were able to recover activated influenza-specific cytotoxic T lymphocytes (CTLs) that killed freshly ex vivo from the brains of mice for at least 320 d after the intracerebral inoculation. The activated antiviral CTLs expressed high levels of the early activation marker CD69, suggesting continuing TCR signaling despite a lack of viral protein and major histocompatibility complex staining by immunohistochemistry in the brain parenchyma and barely detectable levels of viral nucleic acid by single and two-step reverse transcription PCR. Local persistence of activated lymphocytes may be important for efficient long-term responses to viruses prone to recrudesce in sites of relative immune privilege.

Selection forces and constraints on retroviral sequence variation.

All retroviruses possess a highly error-prone reverse transcriptase, but the extent of the consequent sequence diversity and the rate of evolution differ greatly among retroviruses. Because of the high mutability of retroviruses, it is not the generation of new viral variants that limits the extent of diversity and the rate of evolution of retroviruses, but rather the selection forces that act on these variants. Here, we suggest that two selection forces--the immune response and the limited availability of appropriate target cells during transmission and persistence--are chiefly responsible for the observed sequence diversity in untreated retroviral infections. We illustrate these aspects of positive selection by reference to specific lentiviruses [human and simian immunodeficiency viruses (HIV and SIV)] and oncoviruses [feline leukemia virus (FeLV) and human T cell leukemia virus (HTLV)] that differ in their extent of variation and in disease outcomes.

Population dynamics of immune responses to persistent viruses.

Mathematical models, which are based on a firm understanding of biological interactions, can provide nonintuitive insights into the dynamics of host responses to infectious agents and can suggest new avenues for experimentation. Here, a simple mathematical approach is developed to explore the relation between antiviral immune responses, virus load, and virus diversity. The model results are compared to data on cytotoxic T cell responses and viral diversity in infections with the human T cell leukemia virus (HTLV-1) and the human immunodeficiency virus (HIV-1).

The immune response to HTLV-I.

A strong cytotoxic T lymphocyte response to HTLV-I protects against the associated inflammatory disease of the central nervous system, HAM/TSP (HTLV-I-associated myelopathy/tropical spastic paraparesis), by reducing the proviral load of HTLV-I; however, when the proviral load exceeds a threshold level, HTLV-I-specific cytotoxic T lymphocytes could contribute to inflammation.

Human T-cell leukaemia virus type I and neurological disease.

Tropical spastic paraparesis is thought to be caused either directly by human T-cell leukaemia virus type I (HTLV-1), or by the immune response to the virus. Recent work has identified differences between tropical spastic paraparesis patients and healthy carriers of HTLV-I, both in the virus and in the host's T-cell response to the virus. These differences may provide clues to the pathogenesis of tropical spastic paraparesis.

Defective interfering particles and virus evolution.

Almost all viruses produce replication-defective mutants that have complex effects on the growth and evolution of the virus in culture. These effects can be explained qualitatively by a simple mathematical model. However, the model shows that the quantitative effects of these mutants are intrinsically unpredictable.

Immune Compromise in HIV-1/HTLV-1 Coinfection With Paradoxical Resolution of CD4 Lymphocytosis During Antiretroviral Therapy: A Case Report.

Human immunodeficiency virus type-1 (HIV-1) and human T lymphotropic virus type-1 (HTLV-1) infections have complex effects on adaptive immunity, with specific tropism for, but contrasting effects on, CD4 T lymphocytes: depletion with HIV-1, proliferation with HTLV-1. Impaired T lymphocyte function occurs early in HIV-1 infection but opportunistic infections (OIs) rarely occur in the absence of CD4 lymphopenia. In the unusual case where a HIV-1 infected individual with a high CD4 count presents with recurrent OIs, a clinician is faced with the possibility of a second underlying comorbidity. We present a case of pseudo-adult T cell leukemia/lymphoma (ATLL) in HIV-1/HTLV-1 coinfection where the individual fulfilled Shimoyama criteria for chronic ATLL and had pulmonary Mycobacterium kansasii, despite a high CD4 lymphocyte count. However, there was no evidence of clonal T-cell proliferation by T-cell receptor gene rearrangement studies nor of monoclonal HTLV-1 integration by high-throughput sequencing. Mutually beneficial interplay between HIV-1 and HTLV-1, maintaining high level HIV-1 and HTLV-1 viremia and proliferation of poorly functional CD4 cells despite chronicity of infection is a postulated mechanism. Despite good microbiological response to antimycobacterial therapy, the patient remained systemically unwell with refractory anemia. Subsequent initiation of combined antiretroviral therapy led to paradoxical resolution of CD4 T lymphocytosis as well as HIV-1 viral suppression and decreased HTLV-1 proviral load. This is proposed to be the result of attenuation of immune activation post-HIV virological control. This case illustrates the importance of screening for HTLV-1 in HIV-1 patients with appropriate clinical presentation and epidemiological risk factors and explores mechanisms for the complex interactions on HIV-1/HTLV-1 adaptive immunity.

Do infectious diseases drive MHC diversity?

The primary function of the major histocompatibility complex (MHC) is to allow the immune system to identify infectious pathogens and eliminate them. Infectious diseases are now thought to be the main selection force that drives and maintains the extraordinary diversity of the MHC.

Cytotoxic T-cell abundance and virus load in human immunodeficiency virus type 1 and human T-cell leukaemia virus type 1.

The correlation between virus load and specific cytotoxic T-lymphocyte (CTL) frequency during the chronic phase in human immunodeficiency virus type 1 (HIV-1) infection has been found to be negative in cross-sectional studies. We report here that, in infection with the related retrovirus human T-cell leukaemia virus type 1 (HTLV-1), the correlation is positive in asymptomatic carriers and zero in patients with the associated inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We demonstrate that the direction of the correlation may depend on the efficacy of the CTL response using mathematical models. We conclude that the CTL response is effective in asymptomatic carriers of HTLV-1, but ineffective in patients with HAM/TSP. Virus-mediated impairment of specific CTL production in HIV-1 infection can account for the negative correlation observed.

An interactive computer program for the analysis of HLA class II restriction fragment patterns.

There is considerable current interest in the application of Southern blotting and hybridization, with locus-specific HLA class II probes, to HLA typing. The work of several laboratories has shown that, under suitable conditions, restriction fragment patterns that correlate with DR and DQ serology and with DP cellular reactivities can be obtained from homozygous cell lines. Although the identification of class II specificities from restriction fragment patterns is relatively straightforward in homozygotes, the increased complexity of the patterns obtained from heterozygotes makes the interpretation considerably more difficult; this difficulty is compounded by even slight variation between and within gels. We have developed an interactive computer program that allows HLA-DR and DQ typing by the visual matching of restriction fragment pattern data with standard data derived from a panel of well-characterized homozygous cell lines. The program also uses a simple algorithm (after Southern) to estimate the fragment sizes in the unknown track. The screen display can be printed out to give a convenient record of the match; a numerical measure is also given of the goodness of fit of the new data.

High frequency of viral protein expression in human T cell lymphotropic virus type 1-infected peripheral blood mononuclear cells.

Most human T cell lymphotropic virus type (HTLV)-1-infected individuals mount a strong and persistently activated cytotoxic T lymphocyte (CTL) response to the virus, which implies that there is abundant chronic transcription of HTLV-1 genes. On the other hand, several observations suggest that HTLV-1 might be latent in vivo and therefore not detectable by CTLs. To clarify these discrepancies, we quantified the frequency of provirus-positive peripheral blood mononuclear cells (PBMCs) that were capable of expressing the HTLV-1 Tax protein, which is known to be the immunodominant target antigen recognized by HTLV-1-specific CTLs. The analysis showed that a significant proportion of HTLV-1-infected cells (from 14 to 100%) starts to express the Tax protein within a few hours of culture ex vivo. Phenotypic analysis confirmed that the main cell subpopulation expressing the Tax protein is CD4 positive. Frequent Tax expression in CD4(+) T lymphocytes in vivo might account for the chronic activation of the cytotoxic immune response observed in the majority of HTLV-1-infected patients and might contribute to the pathogenesis of HTLV-1-associated diseases.

HTLV-1 infections.

Human T lymphotropic virus type 1 (HTLV-1) causes disabling and fatal diseases, yet there is no vaccine, no satisfactory treatment, and no means of assessing the risk of disease or prognosis in infected people. Recent research on the molecular virology and immunology of HTLV-1 shows the importance of the host's immune response in reducing the risk of these diseases, and is beginning to explain why some HTLV-1 infected people develop serious illnesses whereas most remain healthy life long carriers of the virus. These findings might be applicable to other persistent virus infections such as human immunodeficiency virus, hepatitis B, and hepatitis C.

Passively acquired antibodies to respiratory syncytial virus impair the secondary cytotoxic T-cell response in the neonatal mouse.

Passively acquired antibody has been known since the 1940s to impair the secondary antibody response to the homologous antigen. However, the effect of passive immunity on the T-cell response is largely unknown. The results presented here demonstrate that monoclonal antibodies (Mabs) to respiratory syncytial virus (RSV), transferred in the mother's milk or injected directly, can reduce the generation of RSV-specific cytotoxic T-cell (Tc) precursors by the neonatal mouse; the development of influenza-specific Tc was unaffected. Both non-neutralizing and neutralizing antibodies, and Mabs directed against either the fusion (F) or G proteins of RSV, can impair the secondary Tc response. The ability of a given antibody to produce this impairment depends on its titre and its subclass, which determines its absorption from the gut by the neonate. These results are of interest in relation to virus infections in humans, such as RSV or measles, which are often contracted in the first 6 months of life, when maternal antibody is still present in high titre.

Retrovirus infections of the nervous system.

Mammalian retroviruses of all three subfamilies infect the nervous system. The leukemia viruses (oncovirinae) and lentiviruses (lentivirinae, eg, human immunodeficiency virus) cause serious disease, while the foamy viruses (spumavirinae) have not yet been shown to cause any disease. This review illustrates these diseases by referring particularly to three viruses: the human and murine leukemia viruses (human T-cell leukemia-lymphoma virus type I and murine leukemia virus), and the human immunodeficiency viruses, HIV-1 and 2. Other lentiviruses cause important encephalitides in other animals, notably cats (feline immunodeficiency virus), sheep (maedi/visna virus), and goats (caprine arthritis/encephalitis virus).

Recognition of respiratory syncytial virus fusion protein by mouse cytotoxic T cell clones and a human cytotoxic T cell line.

Two mouse cytotoxic T cell (Tc) clones, D5 and H11a, with specificity for the respiratory syncytial virus (RSV) fusion protein (F) were derived from BALB/c mice primed intranasally (i.n.) with RSV (A2 strain). These clones possessed essentially the same characteristics, and only clone H11a is described here. Tc clone H11a lysed target cells infected with a recombinant vaccinia virus (VV) expressing the RSV F gene, and similar target cells infected with RSV strains Long, 8/60, or 18537. In addition, two RSV-specific mouse Tc lines are described, from BALB/c mice primed i.n. with RSV A2 (Tc line MJC-A2), or intraperitoneally with a VV-RSV F gene recombinant (Tc line MJC-F). Tc line MJC-A2 was of unknown antigen specificity, failing to lyse targets infected with recombinant VVs expressing the RSV nucleoprotein (N), large glycoprotein, F, 1A, 1C, or partial matrix protein (amino acid residues 88 to 257) genes. MJC-A2 Tc were cross-reactive for all strains of RSV tested. In contrast, the F-specific MJC-F Tc showed a marked degree of RSV strain specificity, efficiently lysing targets infected with RSV Long or A2 strains, but showing greatly reduced lysis of targets infected with RSV 8/60 or 18537 strains. An anti-RSV human Tc line, IH.K2, also recognized the fusion protein. IH.K2 Tc efficiently lysed autologous Epstein-Barr virus-transformed B cells (BCL) persistently infected with RSV A2 and BCL infected with a VV-RSV F gene recombinant. IH.K2 function was not exclusively RSV F-specific, however, as these cells also lysed autologous BCL infected with a VV-RSV N gene recombinant. These data show that the RSV fusion protein is a target antigen for anti-RSV Tc following infection of mice and humans, and that the F-specific Tc repertoire in mice can be influenced by the method and route of priming.

What is required of an HIV vaccine?

Mounting evidence suggests that the early dissemination of HIV in human beings evokes an immune response that is responsible for containment of the infection during the long symptom-free period. Loss of this immune control coincides with a final escalation of the viraemia and the terminal failure of the immune system. Other studies imply that pre-emptive vaccination of monkeys with attenuated forms of simian immunodeficiency virus (SIV) produces a substantial degree of resistance to superinfection with fully virulent viruses. Here we consider how observations from natural and experimental systems might influence thought as to what is required to produce safe induced immunity against HIV. We concentrate on three questions: what is the nature of the immune response that contains the infection? How does this response fail? How could a vaccine enhance protective immunity so that it exceeds the efficacy of this natural response?