Examining a paradox in the pathogenesis of human pulmonary tuberculosis: immune activation and suppression/anergy

Protective immunity against Mycobacterium tuberculosis (MTB) in animal models is based on cell-mediated immunity (CMI), involving bi-directional interactions between T cells and cells of the monocyte/macrophage (MO/MA) lineage. Key factors include MO-derived interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha as well as T cell derived IL-2 and interferon (IFN)-gamma. These cytokines appear particularly crucial in the induction of MA-mediated elimination of mycobacteria. Several lines of evidence indicate that similar mechanisms are operating in humans. During active pulmonary tuberculosis (PTB), signs of both immune depression and immune activation are concomitantly present. Decreased tuberculin skin test reactivity in vivo and deficient IFN-gamma production by MTB-stimulated mononuclear cells in vitro are observed. On the other hand, the serum levels of several cytokines, including TNF, and other inflammatory mediators are increased and circulating MO and T cell show phenotypic and functional evidence of in vivo activation. In this review, we will discuss the evidence for three models, which could explain this apparent paradox: 1. Stimulation of the T cell-suppressive function from MO/MA; 2. Intrinsic T cell refractoriness, possibly associated with tendency to apoptosis (programmed cell death), and 3. Compartmentalization and redistribution of immune responses to the site of disease. The opportunistic behavior of MTB during human immunodeficiency virus (HIV) infection can be explained by suppression of type-1 responses at the level of antigen-presenting cells, CD4 T cells and effector macrophages. The ominous prognostic significance of intercurrent PTB during HIV infection seems primarily due to prolonged activation of HIV replication in macrophages. Supportive immune therapy during PTB could aim at correcting the type-1 deficiency either by IFN-gamma inducers (e.g. IL-12, IL-18) or by neutralizing the suppressive cytokines transforming growth factor beta (TGF-beta) and IL-10. Alternatively, inflammatory over-activity could be reduced by neutralizing TNF. Finally, anti-apoptotic therapies (e.g. IL-15) might be considered.     

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Because CD1-restricted T cells lack CD4 but produce IFN-gamma in response to nonpeptide mycobacterial antigens, they could play a unique role in immunity to tuberculosis. We studied CD1-restricted T cells in the context of HIV infection by expanding CD4(-) T cell lines from 10 HIV-infected patients. Upon stimulation with Mycobacterium tuberculosis antigen or upon exposure to macrophages infected with M. tuberculosis, these T cell lines proliferated, produced IFN-gamma, and showed cytolytic T cell (CTL) activity against macrophages pulsed with mycobacterial antigen, findings consistent with a protective role against M. tuberculosis. Anti-CD1b antibodies abrogated T cell proliferation, IFN-gamma production, and CTL activity, demonstrating that these T cells are CD1 restricted. IFN-gamma production in response to M. tuberculosis was enhanced by antitransforming growth factor-beta in 8/10 lines, and by IL-15 in 2/10 lines. IFN-gamma production was augmented in a nonantigen-specific manner by IL-12 in 4/8 lines. When live HIV was cocultured with CD1-restricted T cell lines, p24 antigen and proviral DNA were not detected, indicating that the T cells were not infectable with HIV. Vaccination strategies aimed at activation and expansion of M. tuberculosis-reactive CD1-restricted T cells in HIV-infected patients may constitute a novel means to provide protection against tuberculosis, while minimizing the risk of enhancing HIV replication through stimulation of CD4(+) cells.     

Role of macrophages in the pathogenesis of human immunodeficiency virus (HIV) infection

There are a number of machanisms by which HIV-infected macrophages contribute to the pathogenesis of the Acquired Immunodeficiency Syndrome (AIDS). Macrophage-tropic strains of HIV are present at the time of infection, and persist throughout the course of infection, despite the emergence of T cell tropic quasispecies. As HIV causes chronic infection of macrophages with only minimal cytopathology, these cells can provide an important viral reservoir in HIV-infected persons. Macrophages are more susceptible to HIV infection than freshly isolated monocytes. HIV-infected macrophages can contribute to CD4 T lymphocyte depletion through a gp120-CD4 dependent fusion process with uninfected CD4-expressing T cells. Increasing data support the role of HIV-infected macrophages and microglia in the pathogenesis of HIV-related encephalopathy and AIDS-related dementia through the production of neurotoxins. HIV infection of macrophages in vitro results in impairment of many aspects of their function. Reduced phagocytic capacity for certain opportunistic pathogens, including Toxoplasma gondii and Candida albicans, may be responsible for reactivation of these pathogens in persons with advanced HIV infection, although the mechanisms underlying reactivation of infections and susceptibility to disease from new infections are likely to be multifactorial. Our studies showing defective phagocytosis and killing provide additional information that contribute to our understanding of the pathogenesis of AIDS. Studies of in vitro efficacy of potential antiretroviral therapies should be performed in both primary lymphocyte and monocyte cultures, given the importance of both of these cell populations to HIV pathogenesis and their differing biology.     

T cell cytokine responses in persons with tuberculosis and human immunodeficiency virus infection

Tuberculosis causes more extensive and life-threatening disease in patients with HIV infection than in immunocompetent persons. To investigate the hypothesis that these severe manifestations of tuberculosis may be due to alterations in cytokine production, we evaluated cytokine patterns in HIV-infected tuberculosis patients. Upon stimulation with Mycobacterium tuberculosis in vitro, PBMC from HIV-infected tuberculosis patients had reduced proliferative and type 1 responses, compared with HIV-seronegative tuberculosis patients. The reduction in proliferative responses was independent of the CD4 cell count, but the reduced type 1 response was a direct result of CD4 cell depletion. There was no enhancement of type 2 cytokine production in HIV-infected patients, although production of IL-10 was prominent in all tuberculosis patients. In HIV-infected tuberculosis patients, M. tuberculosis-induced proliferative responses were significantly enhanced by neutralizing antibodies to IL-10 but not by antibodies to IL-4 or by recombinant IL-12. The M. tuberculosis-induced type 1 response was augmented both by antibodies to IL-10 and by recombinant IL-12. Tuberculosis in the context of HIV infection is characterized by diminished type 1 responses, probably induced by immunosuppressive cytokines produced by macrophages/monocytes, rather than by type 2 cells.     

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To disclose the impact of human immunodeficiency virus (HIV) infection on the tuberculosis epidemic in Taiwan, we prospectively screened for HIV infection in patients with active pulmonary tuberculosis. A total of 378 patients who were admitted to the Taiwan Provincial Chronic Disease Control Bureau from January through December 1996 were enrolled. HIV serologic testing was performed by enzyme-linked immunosorbent assay (ELISA). A positive ELISA test was confirmed by Western blot analysis. One patient was infected with HIV. We conclude that the impact of HIV infection on the epidemic of tuberculosis in Taiwan is not significant at present.     

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It is not known whether impaired hematopoiesis noted during human immunodeficiency virus (HIV) infection results from infection of stem/progenitor cells or of cells of the bone marrow microenvironment. Normal adherent primary stromal layers were exposed to HIV to determine which of this mixture of endothelial cells, fibroblasts, and macrophages are susceptible to the virus. Viral p24 in supernatants was noted with monocytotropic HIV-1Ada, HIV-1Ba-L, and HIV-1JR-FL but not with lymphotropic HIV-1LAI nor HIV-1MN strain, and only stromal macrophages expressed the viral antigens. Coculture of the layers with PHA-activated normal lymphocytes failed to rescue lymphotropic virus. No p24 was produced when macrophage-depleted stromal cells were exposed to either HIV-1Ba-L or HIV-1LAI; proviral DNA was then amplified by PCR in cells exposed to either virus, though coculture with lymphocytes rescued only HIV-1Ba-L. Altogether, these data indicate that macrophages are the major targets of HIV in cultured stromal layers. As virus replication in macrophages did not affect the profile of major cytokines involved in regulating hematopoiesis, HIV infection could alter hematopoiesis by other as yet unspecified mechanisms.     

Protection from Mycobacterium avium complex disease in human immunodeficiency virus-infected persons with a history of tuberculosis

Risk of Mycobacterium avium complex disease was examined in human immunodeficiency virus (HIV)-infected patients with and without a history of tuberculosis. Information was obtained by retrospective review of charts of patients in HIV clinics in 10 US cities. Among 1363 patients with <200 CD4 cells/mm3 seen at Grady Memorial Hospital (GMH), 11 (17%) of 66 with a history of a positive purified protein derivative (PPD) skin test acquired M. avium infection, while 29 (16%) of 185 who were PPD-negative (but not anergic) did not (P = .85). Only 4 (8%) of 49 GMH patients with a history of tuberculosis acquired M. avium infection compared with 252 (19%) of 1314 GMH patients without a history of tuberculosis (P = .05). Proportional hazards analysis of risk factors for M. avium infection among 441 persons with and 8702 persons without a history of tuberculosis in 9 other cities confirmed protection from M. avium infection in persons with a history of tuberculosis (relative risk, 0.52; 95% confidence interval, 0.36-0.76; P < .001). Prior tuberculosis provides protection against M. avium infection in HIV-infected persons, possibly by stimulation of antimycobacterial immunity.     

HIV-associated tuberculosis in Africa exemplified by Zimbabwe

In Africa, a rapid increase of human immunodeficiency virus (HIV)-associated tuberculosis cases has been observed; 80% of a worldwide 6 million dually infected persons live in this part of the world. The annual risk of progression to clinically overt tuberculosis in dually infected persons approaches the lifetime risk in persons with tuberculosis but no HIV infection. Zimbabwe is an example which illustrates the rapid increase in notified tuberculosis cases since 1985, accounted for primarily by HIV-associated tuberculosis cases. In sputum-smear positive HIV-associated tuberculosis, classical symptoms are reported with the same frequency as in HIV negative cases. Thus, case-finding activities need not be altered. In sputum-smear negative patients, reliable diagnostic tests are not available. Therapeutic trials are widely used and this causes overdiagnosis of tuberculosis. Extrapulmonary manifestations are common in HIV-associated tuberculosis. A majority of lymph node enlargements, pleurisy and pericarditis in Africa are now due to tuberculosis. If compliance is ensured, response to chemotherapy is excellent, but overall case fatality and relapse rates are increased. The cost-effectiveness of tuberculosis control programmes using directly observed therapy for at least the first 2 months of treatment is well established. With the prominent global significance of tuberculosis and the possibility of cost-effective interventions, a commitment to the fight against the worldwide epidemic is more important than ever before.     

Bacillus Calmette-Guérin infection after vaccination of human immunodeficiency virus-infected children

The use of Mycobacterium bovis/Bacillus Calmette-Guérin (BCG) to vaccinate against tuberculosis remains controversial. The development of tuberculosis in human immunodeficiency virus (HIV)-infected children demands specific evaluation of the risk/benefit ratio of BCG vaccination in this situation. In our institution 9 of 68 HIV-infected children vaccinated with BCG before the diagnosis of HIV infection was suspected developed vaccine-related complications: 7 of these children had a large satellite adenopathy with or without skin fistulae, whereas the other 2 had disseminated BCG infection beyond the satellite ganglion (involvement of the spleen and mesenteric and mediastinal lymph nodes in one case and the liver and lungs in the other). The children were vaccinated soon after birth; no particular problems were observed at that time, but complications appeared 3 to 35 months later. All but one of these children had a rapidly progressive form of HIV disease. The possibility of delayed local or disseminated BCG infection must be considered in analysis of the risk/benefit ratio of vaccination of HIV-infected children. The prognosis of HIV infection must be taken into account, even if the child is asymptomatic when vaccination is being considered.     

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The first case of the human immunodeficiency virus (HIV) infection was detected in Singapore in 1985 and the first case of the acquired immunodeficiency syndrome (AIDS) in 1986. Since then, the number of infections had increased. By the end of 1993, there were 222 residents with HIV infection, including 75 cases of AIDS. In view of the rapidly increasing magnitude of HIV infection, a microcomputer-based surveillance system was designed and developed in 1992 to better monitor epidemiological trends of HIV infection in Singapore. OBJECTIVE--The objective was to define a composite model of a successful HIV and AIDS registry that included: (a) patient data forms, (b) patient's contact data forms, (c) data analysis, and (d) report generation. METHODOLOGY--An IBM-compatible desk-top microcomputer was used for the project. The main software used for computer programming and data analysis were DBase IV (Version 1.5) and Epi Info (Version 5.0), respectively. Security features were incorporated into the programme to ensure confidentiality of information and that only authorized personnel could gain access to the programme. MAIN FINDINGS--The system functioned as the National HIV Notification Registry and was able to track notifications, analyse data and enabled prompt dissemination of information. The system was also linked to another database system for tuberculosis to enhance surveillance of both HIV infection and tuberculosis. CONCLUSION--The authors believe that this system would enhance surveillance and provide timely information for national AIDS control programmes. However, the effectiveness of this computer-based surveillance system is dependent on an established notification structure with notifications of sufficient completeness for both HIV infection and AIDS.     

The effect of simian immunodeficiency virus infection in vitro and in vivo on the cytokine production of isolated microglia and peripheral macrophages from rhesus monkey

Microglia are the major target for human immunodeficiency virus (HIV) infection within the central nervous system. Because only a few cells are productively infected, it has been suggested that an aberrant cytokine production by this cell population may be an indirect mechanism leading to the development of neurological disorders in HIV-infected patients. Therefore we decided to study the secretion pattern of several interleukins (IL) by microglial cells and peripheral blood macrophages isolated from uninfected and simian immunodeficiency virus (SIV)-infected Rhesus monkeys. We found that uninfected, unstimulated primate microglia produce more IL-6 and less TNF alpha than peripheral blood macrophages, but generate comparable levels of IL-1 beta and IL-8. After infection with SIV in vitro, synthesis of all cytokines tested is increased compared to uninfected cultures and to peripheral blood macrophages. Microglia isolated from infected animals produce more IL-8 and TNF alpha than the uninfected cultures and display a strongly increased capacity to secrete TNF alpha upon stimulation with lipopolysaccharide. In addition, production of IL-6 by in vivo-infected microglia increases with time in culture to very high levels despite the fact that only a few cells contained replicating virus. These findings clearly show that the cytokine production of microglia is impaired after SIV infection both in vitro and in vivo and that a low level of viral replication is sufficient for these alterations to occur. In conclusion, the results of this study further support a possible role of cytokines in the pathogenesis of neuro-AIDS.     

Detection of HIV infection in pulmonary tuberculosis patients

Well documented 112 pulmonary tuberculosis patients were studied for the prevalence of human immunodeficiency virus (HIV) seropositivity by using two antibody screening tests along with western blot test. Nineteen of the pulmonary tuberculosis patients were HIV seropositive, 12 were acid-fast bacillus smear positive; 12 patients were tuberculin skin test positive and 15 patients were culture positive. As the incidence of HIV infection is increasing in India, it is observed that patients co-infected with HIV and TB are also on the rise. Recognition of the dual infection and taking adequate steps to deal with this epidemic are needed.     

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Infection by the human immunodeficiency virus (HIV) causes depletion of CD4-positive lymphocytes with consequent immunodeficiency. HIV infection also causes, by direct or indirect mechanisms, both reactive and neoplastic changes in lymphoid tissues. In primary infection reactive changes are a direct response to HIV. Later in the course of the disease there are reactive changes in lymph nodes and extranodal lymphoid tissues which are likely to be largely an indirect effect of HIV infection, being a response to opportunistic infection by other organisms. There is also an increased incidence of autoimmune phenomena in HIV-infected subjects which is likely to be consequent, at least in part, on impaired control of the proliferation of self-reactive B-cell clones. A second mechanism of immune damage of blood cells, probably operating in the case of HIV-related immune thrombocytopenic purpura, is that of cellular damage by immune complexes containing antiviral antibodies. Lymphoid neoplasms associated with HIV infection include non-Hodgkin's lymphoma, Hodgkin's disease and, uncommonly, plasma cell dyscrasias. HIV-associated lymphomas have distinct clinicopathological features and generally a poor prognosis. As for reactive lymphoid lesions, induction of neoplasia is likely, in the majority of cases, to be an indirect rather than a direct effect of the virus. The combination of chronic B-cell stimulation and impaired T-cell function is important, and interaction of lymphoid cells with virus-infected stromal cells may also play a role. Infection by oncogenic viruses such as the Epstein-Barr virus and human herpes virus 8 is also aetiologically important. In rare cases of T-cell lymphoma, HIV may be directly oncogenic.     

Human immunodeficiency virus infection alters antigen-induced cytokine responses in patients with active mycobacterial diseases

Peripheral blood cells from 29 patients with active Mycobacterium avium (MAC) or Mycobacterium tuberculosis diseases were tested for mycobacterial antigen-induced interferon (IFN)-gamma and interleukin (IL)-4 production. Among MAC patients, human immunodeficiency virus (HIV) infection was associated with an 80% decrease in those who produced IFN-gamma, resulting in a predominantly type 2 cytokine profile. HIV infection in patients with tuberculosis correlates with a 37% increase in those producing IL-4 and a type 1 to type 0 profile shift. These qualitative changes were independent of CD4+ or CD8+ cell numbers. The amounts of both IFN-gamma and IL-4 were decreased in the HIV-infected population. Quantitative reduction of IFN-gamma was the result of fewer secreting cells rather than a down-regulation at the single-cell level. Disseminated disease was restricted to 2 of 5 HIV-infected MAC patients with a type 2 cytokine profile and 4 of 5 HIV-infected tuberculosis patients with a type 0 profile. These results demonstrated a shift in mycobacterial antigen-specific cytokine profiles from type 1 to type 0 and to type 2, in parallel with AIDS progression.     

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To explore the possibility of conferring a long-term resistance against human immunodeficiency virus (HIV) by a low continuous production of interferon-beta (IFN-beta) in hematopoietic progenitor cells, we transduced the human CD34(+) TF-1 cells with a retroviral vector ensuring IFN-beta production. The IFN-beta-transduction of TF-1 cells resulted in resistance to infection with HIV-LAI, as shown by the selective survival of IFN-beta-transduced CD4(+) cells and the protection against HIV-induced apoptosis. A similar response against HIV-LAI infection was obtained after pretreatment with 100 U/ml of recombinant IFN-alpha2b or IFN-beta. In contrast, after the addition of macrophage cell tropic (M cell-tropic) HIV strain, a treatment with exogenous IFN-alpha2b resulted in a >==10-fold lower protection compared with exogenous IFN-beta or IFN-beta transduction. This specific effect of IFN-beta on M cell-tropic HIV strains was correlated with a down-regulation of the CCR-5 chemokine receptor expression, corresponding to a novel antiviral effect of IFN-beta.     

Redistribution of HIV outside the lymphoid system with onset of AIDS

The basis for many of the symptoms and pathological changes found in patients with the acquired immunodeficiency syndrome (AIDS) remains poorly understood. We have used a quantitative polymerase chain reaction technique to investigate the extent to which direct infection with human immunodeficiency virus (HIV) produces the disease manifestations of AIDS. In five patients who died with AIDS-defining illnesses (Centers for Disease Control and Prevention class IV), we found variable, but in many cases extensive, infection by HIV at various sites, including brain, lung, colon, and liver. By contrast, in three HIV-positive subjects who died without HIV-related disease (CDC class II), we found no evidence of significant infection of any non-lymphoid organ. In both groups of patients there were high levels of infection in cells of the spleen, lymph nodes, and peripheral blood. Pathological examination of tissues from the AIDS patients revealed many abnormalities, of which some, such as giant-cell encephalitis in the brain, were specifically associated with the presence of high levels of HIV infection. These findings suggest that spread of HIV outside cells of the immune system is a late event in HIV infection and is extremely sensitive to the degree of immunosuppression in the patient.     

Mortality among tuberculosis patients in The Netherlands in the period 1993-1995

This study aimed to estimate excess mortality among tuberculosis patients in The Netherlands and identify risk factors for tuberculosis-associated mortality. The national tuberculosis register provided data on patients diagnosed in the period 1993-1995. Excess mortality in tuberculosis cases, according to age and sex, was determined by comparison with national mortality rates. Risk factors were identified and adjustment for confounders was carried out using Cox's proportional hazard analysis. Of 4,340 patients alive at diagnosis, 258 died within 1 yr while on treatment. The Kaplan-Meier survival probability after 1 yr was 93%. Tuberculosis patients had a standardized mortality ratio of 8.3. Independent risk factors for mortality were: gender; age; presence of a malignancy or human immunodeficiency virus (HIV) infection; addiction to alcohol or drugs; localization of tuberculosis; and the type of medical officer having made the diagnosis. Of all deaths, 83% occurred in two risk groups comprising 21% of tuberculosis patients: those aged > or =65 yrs and those having HIV infection or a malignancy. Tuberculosis patients in The Netherlands are at a considerably increased risk of death. However, the prognosis is very good for those aged less than 65 yrs and without human immunodeficiency virus infection or a malignancy.