Altered lymphocyte antigen expressions in HIV infection: a study by quantitative flow cytometry

To identify surface antigen changes that may contribute to the immune deficiency in infection with the human immunodeficiency virus (HIV), we quantified, by double-staining flow cytometry, the number of antigens of the main peripheral blood lymphocyte subsets from 30 HIV-positive persons and compared them with those of 19 HIV-negative healthy donors. Standard microbeads with different capacities to bind mouse immunoglobulins were used to convert the mean fluorescence intensity values into numbers of antigen molecules per cell, measured as antibody binding capacity. The level of expression of different lymphocyte antigens in HIV-infected patients differs from that seen in normal blood lymphocytes. Some of these surface markers are decreased, whereas others are increased, and their expression is modulated depending on the specific cell subset considered. The expression of CD3, CD4, and CD8 on T lymphocytes is significantly decreased; moreover, CD3 is down-regulated on activated and nonactivated T lymphocytes and on CD4 and CD8 cells. In contrast, the expression of CD2 on T cells is significantly increased. Natural killer cells exhibit down-regulation of CD7, normal levels of CD8 and CD56, and overexpression of CD2. Our results also identified, for most of these antigens, quantitative differences in membrane expression according to different disease stages, as assessed by the CD4 T-cell count. Quantitative flow cytometry therefore may provide useful insights into the lymphocyte functional defects characterizing HIV infection.     

T lymphocytes and their cytokines in human immunodeficiency virus (HIV) infection: implications for associated neoplasias

Infection with the human immunodeficiency virus (HIV) results in gradual immunosuppression due to the loss of CD4+ T cells. In the wake of immune system breakdown, infected individuals may acquire multiple opportunistic infections and develop certain malignancies which ultimately account for the vast majority of deaths in these persons. A limited number of malignancies are directly associated with HIV infection and suggest a common tie between these tumors. Inappropriate immune surveillance resulting in insufficient inhibition of virus replication and inadequate control of the growth of transformed cells may contribute to the development of malignancies in HIV-infected individuals. Alternatively, malignancies in HIV infection may be the consequence of immune dysregulation. Cellular immune responses mediated by antigen-specific cytotoxic T lymphocytes (CTL) are of particular importance for immunologic control of viral infections and substantial information has been gathered about theses cells in HIV infection. The goal of this review is therefore to summarize recent findings regarding the cellular immune response to HIV with a particular focus on cytokines released by HIV-specific CTL.     

Expression of the alpha 5 beta 1 fibronectin receptor on T lymphocytes of patients with HIV-1 infection

AIMS: To evaluate the expression of the alpha 5 beta 1 integrin fibronectin receptor (FNR), which mediates several processes, including phagocytosis, cell motility and the immune response, on T lymphocytes of patients with HIV-1 infection. METHODS: T lymphocytes were incubated with monoclonal antibody directed against FNR and then with monoclonal antibodies, conjugated with phycoerythrin, directed against CD3, CD4 and CD8 positive cells. Expression of FNR on CD3, CD4 and CD8 positive cells was analysed using flow cytometry. RESULTS: Normal expression of FNR was observed on CD3 positive cells from asymptomatic HIV positive patients and those with AIDS. Increased expression of FNR was observed on CD8 positive cells from asymptomatic HIV positive patients and on CD4 positive cells from patients with AIDS. Increased FNR expression was observed on CD4 positive cells from patients with AIDS, particularly those with opportunistic infections caused by Pneumocystis carinii, Mycobacterium sp, Toxoplasma gondii, and Cryptococcus neoformans. CONCLUSION: Increased expression of FNR on CD8 and CD4 positive cells in asymptomatic HIV positive patients and those with AIDS, respectively, may be an epiphenomenon correlated with lymphocyte activation by HIV-1 or opportunistic infection, Further study is required to determine whether upregulation of FNR expression has a direct role in the pathogenesis of AIDS.     

Disturbed CD4+ T cell homeostasis and in vitro HIV-1 susceptibility in transgenic mice expressing T cell line-tropic HIV-1 receptors

T cell line-tropic (T-tropic) HIV type 1 strains enter cells by interacting with the cell-surface molecules CD4 and CXCR4. We have generated transgenic mice predominantly expressing human CD4 and CXCR4 on their CD4-positive T lymphocytes (CD4+ T cells). Their primary thymocytes are susceptible to T-tropic but not to macrophage-tropic HIV-1 infection in vitro, albeit with a viral antigen production less efficient than human peripheral blood mononuclear cells. Interestingly, even without HIV infection, transgenic mice display a CD4+ T cell depletion profile of peripheral blood reminiscent of that seen in AIDS patients. We demonstrate that CD4+ T cell trafficking in transgenic mice is biased toward bone marrow essentially due to CXCR4 overexpression, resulting in the severe loss of CD4+ T cells from circulating blood. Our data suggest that CXCR4 plays an important role in lymphocyte trafficking through tissues, especially between peripheral blood and bone marrow, participating in the regulation of lymphocyte homeostasis in these compartments. Based on these findings, we propose a hypothetical model in which the dual function of CXCR4 in HIV-1 infection and in lymphocyte trafficking may cooperatively induce progressive HIV-1 infection and CD4+ T cell decline in patients.     

Early HIV-specific cytotoxic T lymphocytes and disease progression in children born to HIV-infected mothers

The activities of HIV-specific cytotoxic T lymphocytes (CTLs) were evaluated in 10 HIV-infected children, born to infected mothers who did not receive AZT during pregnancy. CTL activities were present as early as 4 months of age. The five children that progressed to AIDS before 1 year of age had reduced in vivo and in vitro CTL activities, when compared with children who remained AIDS free after 1 year of age. The latter children had weak in vivo activated CTL responses but strong memory CTLs. No relation was found between viral load, lymphocyte populations, and CTL responses between birth and 6 months of age. Between 7 and 12 months old, children with broader in vitro activated CTLs had higher absolute numbers of CD4+ and CD8+ T lymphocytes and lower plasma viral load. These data support a beneficial role of CTLs in pediatric HIV infection.     

Intestinal mucosal inflammation associated with human immunodeficiency virus infection

The role of the human immunodeficiency virus type-1 (HIV) in producing intestinal disease was studied prospectively in 74 HIV-infected individuals with (43) or without (31) the acquired immunodeficiency syndrome (AIDS). Thirty-one subjects had enteric infections; all but one had AIDS. Alteration in bowel habits was the most common symptom and occurred independently of enteric infections. Abnormal histopathology was present in 69% of cases, and the finding was associated with altered bowel habits. An HIV-associated protein, p24, was detected in 71% of biopsies by ELISA assay. Tissue p24 contents varied with disease stage and were highest in HIV-infected individuals without AIDS (Walter Reed classes 3 and 4). Tissue p24 detection was associated with both altered bowel habits and histologic mucosal abnormalities. Tissue contents of the cytokines, tumor necrosis factor-alpha and interleukin-1 beta, were higher in HIV-infected individuals than in controls and their elevations were independent of enteric infection. We conclude that HIV reactivation in the intestinal mucosa may be associated with an inflammatory bowel syndrome in the absence of other enteric pathogens.     

Electrocortical and behavioral responses produced by acute electrical stimulation of the human centromedian thalamic nucleus

It is now apparent that HIV infection leads to a gradual collapse of a complex system of lymphoid tissue. This collapse tends to be associated with a change in virus tropism from macrophages to T lymphocytes, and a change in phenotype from nonsyncytium inducing (NSI) to syncytium inducing (SI). An experimental system is required to study the role of this change in HIV pathogenesis in lymphoid tissue. Here we describe such a system. Histocultures of human lymphoid tissue preserve their general cytoarchitecture, including a network of follicular dendritic cells (FDCs). Histocultures of tonsils, adenoids, or lymph nodes support productive infection with various laboratory and primary isolates of HIV-1 of different tropism and phenotype and exhibit isolate-dependent CD4+ T lymphocyte depletion. A strong correlation between the extent of CD4+ T cell depletion and the SI/NSI phenotype of the isolates is demonstrated. AZT was used as a model drug to inhibit viral replication and CD4+ T cell depletion in lymphoid histocultures. HIV pathogenesis and the effect of antivirals can now be studied in human lymphoid tissue under controlled conditions in vitro.     

Critical role for CD4(+) T cells in controlling retrovirus replication and spread in persistently infected mice

Reactivations of persistent viral infections pose a significant medical problem in immunocompromised cancer, transplant, and AIDS patients, yet little is known about how persistent viral infections are immunologically controlled. Here we describe a mouse model for investigating the role of the immune response in controlling a persistent retroviral infection. We demonstrate that, following recovery from acute Friend virus infection, a small number of B cells evade immunological destruction and harbor persistent virus. In vivo depletions of T-cell subsets in persistently infected mice revealed a critical role for CD4(+) T cells in controlling virus replication, spread to the erythroid lineage, and induction of erythroleukemia. The CD4(+) T-cell effect was independent of CD8(+) T cells and in some cases was also independent of virus-neutralizing antibody responses. Thus, the CD4(+) T cells may have had a direct antiviral effect. These results may have relevance for human immunodeficiency virus (HIV) infections where loss of CD4(+) T cells is associated with an increase in HIV replication, reactivation of persistent viruses, and a high incidence of virus-associated cancers.     

Increased expression of CD80, CD86 and CD70 on T cells from HIV-infected individuals upon activation in vitro: regulation by CD4+ T cells

T cells express CD28 and CD27 which transduce co-stimulatory signals after interaction with their ligands on antigen-presenting cells (APC). These ligands, CD80, CD86 and CD70, are also expressed to some extent on activated T cells. Here, we show that in human immunodeficiency virus (HIV)-infected individuals, CD28 and CD27 expression is decreased on CD8+ T cells. On the other hand, T cell stimulation in vitro induced high CD80, CD86 and CD70 expression on T cells from HIV-infected individuals. It appeared that an inverted CD4:CD8 T cell ratio could explain this enhanced expression of co-stimulatory ligands. Indeed, high expression levels of CD80, CD86 and CD70 were found on activated CD8+ T cells from HIV- individuals cultured in the absence of CD4+ T cells. Addition of CD4+ T cells prevented this up-regulation. However, in HIV-infected individuals, addition of excess autologous or healthy control CD4+ T cells did not completely counteract up-regulation of co-stimulatory ligand expression on CD8+ T cells. Thus, to some extent, CD8+ T cells in HIV-infected individuals appeared to be refractory to CD4+ T cell-mediated regulation of ligand expression in vitro. Activated T cells from HIV-infected individuals and activated CD8+ T cells from healthy controls were able to act as accessory cells in CD3-induced T cell proliferation, which was dependent on cell-cell contact. Thus, we showed that T cells from HIV-infected individuals express enhanced levels of co-stimulatory ligands upon activation, which provides them with accessory cell properties. Enhanced stimulatory potential of these nonprofessional APC may contribute to persistently high levels of immune activation in HIV infection related to disease progression.     

Crohn's ileitis in a patient with longstanding HIV infection

The differential diagnosis of diarrhea in patients infected with HIV is broad, and includes a variety of bacterial, viral, and parasitic pathogens, as well as malignancies including lymphoma and Kaposi's sarcoma. Idiopathic non-specific inflammatory bowel disease rarely occurs in association with HIV infection. A recent case report described a patient with longstanding Crohn's disease who experienced remission of his bowel disease upon infection with HIV (6). The authors inferred that the remission was secondary to a depressed CD4 (T helper) lymphocyte count. We report the first case of Crohn's ileitis developing in a patient with established HIV infection, depressed CD4 lymphocyte count, and no prior history of inflammatory bowel disease. This case raises questions about the role of CD4 cells in the pathogenesis of Crohn's disease.     

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.     

Musculoskeletal infections in patients with human immunodeficiency virus infection

Musculoskeletal infections constitute an unusual clinical manifestation in patients with human immunodeficiency virus (HIV) infection. Available information about patients' characteristics and their clinical course has been obtained mainly from case reports and small retrospective studies. Our retrospective study is the largest in the literature providing detailed information about the clinical and laboratory characteristics of HIV-infected patients with different musculoskeletal infections. We identified 30 patients with various infections of the musculoskeletal system during a 5-year period among a cohort of 3,000-4,000 HIV-infected patients, and we describe them along with all cases of musculoskeletal infections in patients with HIV reported in the literature since 1985. Septic arthritis was the most commonly reported infection of the musculoskeletal system. It usually affects young men with a median CD4 count of 241. The exact contribution of a previous history of intravenous drug abuse in the pathogenesis of septic arthritis is unclear from the present and previous studies. Staphylococcus aureus was the most commonly isolated agent (31.3%). Numerous atypical pathogens were also identified as causes of septic arthritis. Approximately 90% of patients recovered with appropriate antibiotic treatment. Osteomyelitis was a more serious infection which also affected young individuals but with lower CD4 counts (median, 41). Half the cases were due to atypical mycobacteria. The mortality rate in the previously reported cases and in our series was high (20%). Pyomyositis is an increasingly recognized infection of the striated muscles in HIV-infected patients. It affects almost exclusively males with advanced HIV infection (median CD4 count, 24). Most cases are due to Staphylococcus aureus (67%). Drainage of the involved muscle(s) accompanied by proper antibiotic treatment resulted in resolution of the infection in the majority of patients (90%). Although the incidence of musculoskeletal infections in patients with HIV from this and previous studies appears to be low (0.3%-3.5%), these infections add a significant morbidity and mortality in the affected individuals. Better understanding of their pathogenesis and clinical course would aid the proper diagnosis and management of these infections.     

Interrelationship between the duration of HIV infection, viral load and CD4 positive lymphocyte count

BACKGROUND: The decline in CD4+ lymphocytes occurs at different rates in patients with HIV infection. A longer duration of HIV infection and a higher level of viral replication, represented by the viral load, are associated with a lower CD4+ lymphocyte count. However, the interelationship between these variables is still not well known. PATIENTS AND METHODS: 107 HIV-infected patients for whom the date of infection was known, were included in a transversal study, in which the CD4+ lymphocyte count and the plasma viral load were analysed, the last using an isothermal amplification method (NASBA). Patients were not receiving antiretroviral drugs or suffered intercurrent infections at the time of the study. RESULTS: The mean duration of HIV infection was 8.6 +/- 2.9 years. The mean CD4+ lymphocyte count was 366 +/- 264 x 10(6)/l. The mean plasma viraemia was 4.3 +/- 0.9 logs. In a linear regression model, the CD4+ lymphocyte count was explained in 21.7% of cases by the duration of HIV infection, meanwhile the viral load justified up to 36.2 of CD4+ cell variability. When both parameters were combined, up to 58.4% of CD4+ lymphocyte values were explained. In this model, changes of 1 log in viral load had a 4-fold higher effect on the CD4+ cell count than each year of HIV infection. CONCLUSIONS: The duration of HIV infection and, particularly the viral load strongly influences the current CD4+ lymphocyte count, although other variables should exist (virus with syncytium-inducing phenotype, age of the patient and his immunegenetic repertoire) influencing the different decline seen in CD4+ T-cells.     

Demonstration of the Th1 to Th2 cytokine shift during the course of HIV-1 infection using cytoplasmic cytokine detection on single cell level by flow cytometry

OBJECTIVE: To characterize changes of Th1/Th2 cytokine production by peripheral blood mononuclear cells (PBMC) that occur during the course of HIV infection by cytoplasmic cytokine staining on single cell level. DESIGN AND METHODS: Mitogen-stimulated PBMC from 16 healthy donors, 18 HIV-1-infected individuals without AIDS and 14 patients with AIDS were stained intracellularly with fluorescein-labelled MAb against interleukin (IL)-2, IL-4, IL-10 and interferon (IFN)-gamma. Additionally, co-staining of CD4+ T-cell, CD8+ T-cell, natural killer (NK) cell, B-cell and monocytic markers was performed. Fluorescence staining was analysed by three-colour flow-cytometry. RESULTS: A reduced percentage of IL-2 and IFN-gamma (Th1 type)-producing cells among CD4+ T cells from HIV-1-infected individuals could be demonstrated. There was a continuous decrease of IFN-gamma-producing CD4+ T cells in the course of HIV infection and a dramatic reduction of IL-2-expressing cells among CD4+ T cells in patients with AIDS. In contrast to Th1 cytokines, the frequency of Th2 cytokine expressing cells among CD4+ T cells increased in HIV-infected individuals. The maximum frequency of IL-4-expressing cells among CD4+ T cells was seen in HIV-infected individuals without AIDS, whereas the rate of IL-10-producing cells was highest in patients with AIDS. In HIV-infected individuals no significant proportion of Th0 cells expressing both Th1 and Th2 cytokines was detectable. In CD8+ T cells the percentage of IL-2 was expressing cells decreased continuously accompanied by a strong increase of the frequency of IFN-gamma-producing cells. CONCLUSION: The decreased percentage of cells expressing IL-2 and IFN-gamma in conjunction with an increased proportion of IL-4- and IL-10-producing cells among the CD4+ T cells in HIV-1-infected individuals demonstrate a Th1 to Th2 cytokine shift in the course of HIV infection on a single cell level. There was no evidence of a Th1 to Th0 cytokine shift. In addition to the loss of CD4+ T cells in HIV infection, the qualitative changes of Th1/Th2 cytokine expression may serve as a marker for progressive failure of cell-mediated immunity.     

Human immunodeficiency virus induction of corticotropin in lymphoid cells

Disruption of the linkage among the immune, nervous, and endocrine systems may contribute to the pathology and symptoms of acquired immunodeficiency syndrome (AIDS). We investigated the role of human immunodeficiency virus (HIV) in altering these linkages via induction of corticotropin (ACTH) by lymphocytes. Cultured T lymphocytes (H9 cell line) were infected with HIV-1, after which ACTH production was measured and characterized at various time intervals by immunofluorescence and Western blotting. We report a coordinate expression of ACTH and p24 HIV core protein in H9 cells. Also, the kinetics of HIV-induced ACTH production by H9 T lymphoma cells are demonstrated using three different strains of HIV as well as UV-inactivated HIV. ACTH production corresponded with the appearance of p24 antigen and was maximal 35 days after infection. UV-inactivated HIV and the viral envelope protein, gp120, were also able to induce ACTH production in these cells, indicating that viral replication was not required for the ACTH induction. The HIV-induced ACTH was synthesized de novo and had the size and biological activity of pituitary ACTH. Inhibition of ACTH in HIV-infected lymphocyte cultures by anti-ACTH antiserum enhanced viral p24 expression. The significance of lymphocyte ACTH in AIDS is not clear, but these results suggest that it may restrict HIV replication and possibly infection.     

The theory and practice of health education applied to nursing: a bi-polar approach

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.     

Amelioration of collagen-induced arthritis and suppression of interferon-gamma, interleukin-12, and tumor necrosis factor alpha production by interferon-beta gene therapy

Human Vgamma9Vdelta2 T cells contribute to immunity against intracellular pathogens and recognize nonpeptidic antigens, such as the mycobacterial phosphoantigen TUBAg. HIV infection is associated with a polyclonal decrease of peripheral Vgamma9Vdelta2 T cells and we previously reported that the remaining cells show a proliferative anergy to stimulation with Mycobacterium tuberculosis in 60% of patients. Because of alterations in the Th1/Th2 cytokine balance reported in HIV infection, we analyzed, at the single-cell level, the influence of exogenous IL-4, IL-10, IL-12 and IL-15 on the response to mycobacterial phosphoantigens of gammadelta T cells from HIV-infected patients and healthy donors. We report that the strong gammadelta T cell response to TUBAg is characterized by the rapid and selective production of the Th1/proinflammatory cytokines IFN-gamma and TNF-alpha in responder HIV-infected donors. In addition, a positive regulation by IL-12 and IL-15 of the production of these cytokines by Vgamma9Vdelta2 T cells in response to nonpeptidic ligands was observed, whereas IL-4 and IL-10 had no effect. In contrast, Vgamma9Vdelta2 T cells from the anergic HIV-infected donors had lost the ability to produce Th1 cytokines and were not shifted towards a Th2 profile. Furthermore, neither IL-12 nor IL-15 could reverse this functional anergy. The consequences of these observations are discussed in the context of HIV pathogenesis.     

Seroconversion for human herpesvirus 8 during HIV infection is highly predictive of Kaposi's sarcoma

BACKGROUND: The finding of antibodies against human herpesvirus 8 (HHV-8) is associated with the occurrence of Kaposi's sarcoma in persons infected with HIV. However, the predictive value of HHV-8 antibodies for Kaposi's sarcoma in HIV infection is unknown. METHODS: The Amsterdam Cohort Studies on HIV infection and AIDS started in 1984 for homosexual men and in 1985 for injecting drug users. Serum samples from 1459 homosexual men and 1167 drug users were tested for antibodies to recombinant HHV-8 lytic-phase capsid (ORF65) antigen and latent-phase nuclear (ORF73) antigen. Individuals were retrospectively identified as HHV-8-positive or HHV-8-negative at enrolment or HHV-8 seroconverter during the study. Kaposi's sarcoma-free survival time was compared between HIV-infected men who were positive for HHV-8 at enrolment and those who later seroconverted for HHV-8. Hazard ratios were estimated for Kaposi's sarcoma, lymphoma, and opportunistic infection according to the HHV-8 serostatus. RESULTS: The incidence of HHV-8 seroconversion among drugs users was 0.7 per 100 person-years based on 31 seroconversions, whereas an incidence of 3.6 was found among homosexual men based on 215 seroconversions. The hazard ratio for Kaposi's sarcoma was 3.15 (95% CI: 1.89-5.25) in HIV-infected individuals if HHV-8 antibodies were present either at enrolment or at HIV seroconversion. In HIV-infected persons who later seroconverted to HHV-8, Kaposi's sarcoma developed more rapidly: hazard ratio of 5.04 (95% CI: 2.94-8.64), an additional risk of 1.60 (95% CI: 1.01-2.53; P = 0.04). Time-dependent adjustment for CD4+ cell count and HIV RNA had no impact on the additional risk, although the CD4+ cell count was an independent risk factor for Kaposi's sarcoma. HHV-8 infection did not increase the risk of AIDS-related lymphoma or opportunistic infections. CONCLUSIONS: The incidence of HHV-8 infection is higher in homosexual men than in drug users. The presence of HHV-8 antibodies in HIV-infected persons increases the risk of Kaposi's sarcoma. Among HIV-infected persons, those who subsequently seroconvert for HHV-8 are at highest risk. These results strongly confirm the causal role of HHV-8 in Kaposi's sarcoma and emphasize the clinical relevance of HHV-8 seroconversion before and after the HIV infection.     

Differential effects of human immunodeficiency virus isolates on beta-chemokine and gamma interferon production and on cell proliferation

All human immunodeficiency virus (HIV) isolates can grow readily in primary CD4(+) T cells, but they can be distinguished by their ability to replicate in macrophages and established T-cell lines. The macrophage-tropic viruses are generally non-syncytium inducing (NSI), whereas the T-cell-line-tropic viruses are syncytium inducing (SI) in cultured cells. We now demonstrate that infection of CD4(+) T cells by NSI and SI viruses shows a differential effect on production of beta-chemokines and gamma interferon. Infection by NSI viruses increased production of MIP-1alpha, MIP-1beta, and gamma interferon, whereas infection by SI viruses had no effect or decreased production of these cytokines. Production of RANTES was slightly increased during infection by both virus phenotypes. This differential effect of NSI and SI viruses was observed at the level of beta-chemokine mRNA as well as at the level of protein expression. Infection by NSI viruses also increased CD4(+) cell proliferation. These results may have relevance for a differential role of HIV strains in AIDS pathogenesis.     

Cytokines regulate expression and function of the HIV coreceptor CXCR4 on human mature dendritic cells

HIV-infected dendritic cells (DC) efficiently transmit infection to CD4+ T cells during the process of T cell activation. To further understand interactions between DC and HIV, cytokine regulation of HIV coreceptors on cultured Langerhans cells (cLC, as prototypes of mature DC) was studied. Expression of cell surface CXCR4 on cLC was up-regulated by IL-4 and TGF-beta1 and inhibited by IFN-alpha, IFN-beta, and IFN-gamma, whereas cytokines did not appreciably regulate CCR5. Changes in cell surface CXCR4 expression on cLC correlated with T cell-tropic (X4)-HIV envelope-mediated syncytium formation and X4-HIV infection levels. A relative increase in the ratio of type 2/type 1 cytokine production, which can occur in HIV disease, may up-regulate CXCR4 expression on mature DC and promote infection by X4 viruses. Importantly, these findings suggest that cytokine dysregulation may be linked to the emergence of X4-HIV strains as HIV-infected individuals progress to AIDS.