Effect of dietary fat on lymphocyte proliferation and metabolism

Dendritic cells (DC) are bone marrow-derived leukocytes that act as powerful stimulators of primary and secondary immune responses. Langerhans cells (LC), which are immature DC in epidermis and genital mucosa, are generally believed to be the initial cells infected with HIV following mucosal exposure to virus. Interestingly, freshly isolated LC express the HIV coreceptor CCR5, but not CXCR4, on their cell surfaces. This expression pattern would theoretically allow only macrophage-tropic [and not T cell (TC)-tropic] HIV to be transmitted across intact mucosal epithelium. In vitro, it is known that HIV infects LC (and other DC) in a CD4- and HIV coreceptor-dependent manner. In addition, HIV can be captured by prominent stellate processes on the surface of LC/DC. HIV-infected DC, as well as DC that have captured HIV, efficiently transmit virus to TC during antigen-specific TC activation. Thus, DC may be involved in HIV plasma viremia increases observed following antigenic exposure, e.g. immunizations, in chronically HIV-infected individuals by (1) activating latently infected TC or (2) activating and transmitting virus to new target TC. In summary, DC most likely play a major role in primary HIV infection by allowing virus to breach mucosal surfaces, and can act during both initial and chronic phases of HIV disease by facilitating infection and depletion of TC.     

Peripheral blood-derived CD34+ progenitor cells: CXC chemokine receptor 4 and CC chemokine receptor 5 expression and infection by HIV

The present study demonstrates cell surface expression of both CXC chemokine receptor 4 (CXCR4) and CC chemokine receptor 5 (CCR5), major coreceptors for T cell-tropic and macrophage-tropic strains of HIV, respectively, on CD34+ progenitor cells derived from the peripheral blood. CD34+ progenitor cells were susceptible to infection by diverse strains of HIV, and infection could be sustained for prolonged periods in vitro. HIV entry into CD34+ progenitor cells could be modulated by soluble CD4, HIV gp120 third variable loop neutralizing mAb and the cognate ligands for the CXCR4 and CCR5 HIV coreceptors. This study suggests that a significant proportion of the circulating progenitor cell pool may serve as a reservoir for HIV that is capable of trafficking the virus to diverse anatomic compartments. Furthermore, the infection and ultimate destruction of these progenitor cells may explain in part the defective lymphopoiesis in certain HIV-infected individuals despite effective control of virus replication during highly active antiretroviral therapy.     

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.     

Activation of blood T lymphocytes down-regulates CXCR4 expression and interferes with propagation of X4 HIV strains

The chemokine receptor CXCR4 serves as a coreceptor for HIV-1 entry into CD4+ cells, in particular for strains emerging late in the infection. Cell surface expression of CXCR4 has, therefore, important implications for HIV-1 pathogenesis. Using blood lymphocytes cultured under various conditions, we studied the expression and regulation of CXCR4. Flow cytometry showed that only about 20% of freshly isolated lymphocytes expressed CXCR4 on the cell surface whereas in 80% of resting blood lymphocytes CXCR4 was located intracellularly. Within a few hours in culture, the intracellular CXCR4 was translocated to the surface and was expressed in the large majority of both naive and memory lymphocytes. A decrease in surface expression of CXCR4 was found when lymphocytes cultured overnight for maximal receptor expression were stimulated with phytohemagglutinin, anti-CD3 antibodies, phorbol 12-myristate 13-acetate and stromal cell-derived factor-1. The superantigen staphylococcal enterotoxin A, a more selective stimulus, induced a marked decrease in CXCR4 expression preferentially in cells positive for the CD25 activation marker. Confocal laser scanning microscopy demonstrated the presence of CXCR4 in the cytosol and on the surface of resting lymphocytes and also showed CXCR4 redistribution after activation. The number of cells infected by the X4 HIV strain NL4.3 paralleled the expression of CXCR4 in CD4+ T lymphocytes. Sustained reduction of CXCR4 cell surface expression upon activation with phytohemagglutinin correlated with a low number of CD4+ T lymphocytes expressing HIV p24 gag antigen. Our results indicate that activation of CD4+ T lymphocytes reduces surface expression of CXCR4 in part by receptor internalization and that cell activation-dependent CXCR4 down-regulation limits spread of infection by X4 viruses.     

Dendritic cells express multiple chemokine receptors used as coreceptors for HIV entry

Cells of the dendritic lineage are thought to be among the first cells infected after mucosal exposure to HIV. In this study, we have identified the presence of multiple chemokine receptors on dendritic cells (DC) that may function as coreceptors for HIV entry. DC effectively used CCR5 for entry of macrophage (M)-tropic isolates. CCR3, the eotaxin receptor, initially identified on eosinophils, is expressed on DC and may be used as an entry coreceptor by certain dual-tropic strains. CXCR4 was not expressed on DC, although SDF-1 induced a calcium flux and DC could be infected by T cell line (T)-tropic HIV. Our findings provide evidence for the presence of a non-CXCR4 SDF-1 receptor on DC that is used mainly by T-tropic strains of HIV. DC from individuals homozygous for a 32-bp deletion of the CCR5 gene are also infectable with M-tropic strains of HIV-1, and this infection is inhibited by stromal cell-derived factor (SDF)1, suggesting that this receptor can also be used by M-tropic HIV for entry. Delineation of the spectrum of coreceptor usage on DC may offer new approaches to interfere with the initiation and propagation of HIV infection.     

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.     

Activation of CD8+ T lymphocytes through the T cell receptor turns on CD4 gene expression: implications for HIV pathogenesis

T cell activation through the T cell receptor is necessary to achieve a specific and effective immune response. We report here that stimulation of CD8+ T cells through the T cell receptor complex leads to de novo expression of the CD4 antigen on the cell surface that results in susceptibility of CD8+ T cells to HIV infection. In addition, activation of peripheral blood mononuclear cells from HIV-infected individuals results in the appearance of double-positive CD4+/CD8+ T cells, which become infected by endogenous HIV. HIV DNA sequences could be detected in uncultured and sorted mature CD3+CD8+ T cells from HIV+ individuals. These results suggest a new mechanism by which HIV could attack the immune system and may help to explain the CD8+ T cell defects in AIDS patients.     

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.     

Progressive and persistent downregulation of surface CXCR4 in CD4(+) T cells infected with human herpesvirus 7

We have previously shown that infection of CD4(+) T lymphocytes with the T-lymphotropic human herpesvirus 7 (HHV-7) downregulates surface CD4, which represents the high-affinity receptor for HHV-7. In this study, we report that HHV-7 infection also causes a progressive loss of the surface CXC-chemokine receptor 4 (CXCR4) in CD4(+) T cells, accompanied by a reduced intracellular Ca2+ flux and chemotaxis in response to stromal cell-derived factor-1 (SDF-1), the specific CXCR4 ligand. Moreover, CXCR4 is downregulated from the surface of HHV-7-infected T cells independently of CD4. Because intracellular CXCR4 antigen and mRNA levels are unaffected in productively HHV-7-infected cells, the downregulation of CXCR4 apparently does not involve a transcritional block. Since CXCR4 functions in association with CD4 to permit entry of several human immunodeficiency virus (HIV) isolates, the potential of HHV-7 to persistently downregulate the surface expression of CXCR4 may provide novel strategies for limiting HIV infection.     

CXCR4 utilization is sufficient to trigger CD4+ T cell depletion in HIV-1-infected human lymphoid tissue

The human chemokine receptors CCR5 and CXCR4 have emerged as the predominant cofactors, along with CD4, for cellular entry of HIV-1 in vivo whereas the contribution of other chemokine receptors to HIV disease has not been yet determined. CCR5-specific (R5) viruses predominate during primary HIV-1 infection whereas viruses with specificity for CXCR4 (R5/X4 or X4 viruses) often emerge in late stages of HIV disease. The evolution of X4 viruses is associated with a rapid decline in CD4+ T cells, although a causative relationship between viral tropism and CD4+ T cell depletion has not yet been proven. To rigorously test this relationship, we assessed CD4+ T cell depletion in suspensions of human peripheral blood mononuclear cells and in explants of human lymphoid tissue on exposure to paired viruses that are genetically identical (isogenic) except for select envelope determinants specifying reciprocal tropism for CXCR4 or CCR5. In both systems, X4 HIV-1 massively depleted CD4+ lymphocytes whereas matched R5 viruses depleted such cells only mildly despite comparable viral replication kinetics. These findings demonstrate that the coreceptor specificities of HIV-1 are a causal factor in CD4+ T cell depletion ex vivo and strongly support the hypothesis that the evolution of viral envelope leading to usage of CXCR4 in vivo accelerates loss of CD4+ T cells, causing immunodeficiency.     

IL-4 induces functional cell-surface expression of CXCR4 on human T cells

Here we report that IL-4 specifically enhances cell surface expression of CXCR4 on resting peripheral and cord blood T cells. Whereas polarized Th2 clones express variable levels of CXCR4, expression of this receptor is undetectable on polarized Th1 clones but can be induced on the latter cells as well, following short-term culture in the presence of IL-4. The IL-4-induced CXCR4 is functional since interaction with its ligand, stromal-derived factor (SDF)-1, activates the p42 MAP-kinase ERK-2. In addition, although CXCR4 expression is down-regulated following stimulation of T cells and T cell clones via CD28 or CD3 and CD2 cell surface molecules, respectively, it is re-induced by IL-4. These data indicate an important role for IL-4 in rendering CD4+ T cells susceptible to infection with HIV via CXCR4, as well as in promoting SDF-1-induced migration of these cells.     

Immunization with both T cell-dependent and T cell-independent vaccines augments HIV viral load secondarily to stimulation of tumor necrosis factor alpha

Vaccination of HIV-infected individuals increases HIV viral load, reduces CD4 cell counts, and might influence disease progression. Because these deleterious effects are postulated to be secondary to a direct activation of T lymphocytes induced by the immunogen, we compared immunologic and virologic effects of a T cell-dependent and a T cell-independent vaccine. Seventeen HIV-infected children were immunized with influenza (FLU) (T cell-dependent) or pneumococcal (PNEUMO) (T cell-independent) vaccines. HIV viral load and type 1 (IL-2 and IFN-gamma) and type 2 (IL-4 and IL-10) cytokine production were evaluated before and 7, 14, and 28 days after vaccination. Slopes of CD4 cell counts analyzed 6 months before and 6 months after vaccination were not significantly different. HIV viral load increased in both groups of children despite the fact that type 1 cytokine production and the type 1-to-type 2 ratio increased in FLU-vaccinated but not in PNEUMO-vaccinated patients. Thus, an increase in HIV viral load in the absence of T cell activation (as measured by cytokine production) was observed in PNEUMO-vaccinated children. Because polysaccharides of the bacterial cell wall stimulate TNF-alpha production by monocyte-macrophages and TNF-alpha was shown to stimulate HIV replication directly on activation of NF-kappa b after binding the long terminal repeat (LTR) sequences of HIV, we measured TNF-alpha production and observed a significant increase in both groups of vaccines. These data suggest that an increase in HIV viral load can be observed in vaccinated HIV-infected children even independent of direct antigen-induced activation of T lymphocytes, and that augmented production of TNF-alpha might play a role in this phenomenon.     

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.     

CXCR4 and CCR5 on human thymocytes: biological function and role in HIV-1 infection

Thymocyte infection with HIV-1 is associated with thymic involution and impaired thymopoiesis, particularly in pediatric patients. To define mechanisms of thymocyte infection, we examined human thymocytes for expression and function of CXCR4 and CCR5, the major cell entry coreceptors for T cell line-tropic (T-tropic) and macrophage-tropic (M-tropic) strains of HIV-1, respectively. CXCR4 was detected on the surface of all thymocytes. CXCR4 expression on mature, high level TCR thymocytes was similar to that on peripheral blood T cells, but was much lower than that on immature thymocytes, including CD34+ thymic progenitors. Consistent with this, stroma-derived factor-1 (SDF-1) induced calcium flux primarily in immature thymocytes, with CD34+ progenitors giving the strongest response. In addition, SDF-1 mRNA was detected in thymic-derived stromal cells, and SDF-1 induced chemotaxis of thymocytes, suggesting that CXCR4 may play a role in thymocyte migration. Infection of immature thymocytes by the T-tropic HIV-1 strain LAI was 10-fold more efficient than that in mature thymocytes, consistent with their relative CXCR4 surface expression. Anti-CXCR4 antiserum or SDF-1 blocked fusion of thymocytes with cells expressing the LAI envelope. In contrast to CXCR4, CCR5 was detected at low levels on thymocytes, and CCR5 agonists did not induce calcium flux or chemotaxis in thymocytes. However, CD4+ mature thymocytes were productively infected with the CCR5-tropic strain Ba-L, and this infection was specifically inhibited with the CCR5 agonist, macrophage inflammatory protein-1beta. Our data provide strong evidence that CXCR4 and CCR5 function as coreceptors for HIV-1 infection of human thymocytes.     

Productive infection of neonatal CD8+ T lymphocytes by HIV-1

CD8+ T lymphocytes confer significant but ultimately insufficient protection against HIV infection. Here we report that activated neonatal CD8+ T cells can be productively infected in vitro by macrophage-tropic (M-tropic) HIV-1 isolates, which are responsible for disease transmission, whereas they are resistant to T cell-tropic (T-tropic) HIV strains. Physiological activation of CD8-alpha/beta+ CD4- T cell receptor-alpha/beta+ neonatal T cells, including activation by allogeneic dendritic cells, induces the accumulation of CD4 messenger RNA and the expression of CD4 Ag on the cell surface. The large majority of anti-CD3/B7.1-activated cord blood CD8+ T cells coexpress CD4, the primary HIV receptor, as well as CCR5 and CXCR4, the coreceptors used by M- and T-tropic HIV-1 strains, respectively, to enter target cells. These findings are relevant to the rapid progression of neonatal HIV infection. Infection of primary HIV-specific CD8+ T cells may compromise their survival and thus significantly contribute to the failure of the immune system to control the infection. Furthermore, these results indicate a previously unsuspected level of plasticity in the neonatal immune system in the regulation of CD4 expression by costimulation.     

Role of dendritic cells in immunopathogenesis of human immunodeficiency virus infection

The role of dendritic cells (DC) in the pathogenesis of human immunodeficiency virus (HIV) disease has been a subject of considerable interest for several years. Initial studies focused on the infection, dysfunction, and depletion of DC in HIV-infected individuals. More recent studies have begun to identify the functional role of DC in the initiation and propagation of viral replication in T cells in HIV-infected individuals. This review discusses recent data regarding the role of DC in HIV disease with the aim of delineating basic immunopathogenic principles of infection and the development of therapeutic strategies.     

Protein kinase A type I antagonist restores immune responses of T cells from HIV-infected patients

Cyclic AMP-dependent protein kinase A (PKA) type I has been established as an acute inhibitor of T cell activation. For this reason, we investigated the possible role of PKA type I in HIV-induced T cell dysfunction. T cells from HIV-infected patients have increased levels of cAMP and are more sensitive to inhibition by cAMP analog than are normal T cells. A PKA type I-selective antagonist increases the impaired proliferation of T cells from HIV-infected patients to normal or subnormal levels (up to 2.8-fold). Follow-up of patients after initiation of highly active antiretroviral treatment revealed that a majority of patients have a persistent T cell dysfunction that is normalized by incubation of T cells with Rp-8-Br-cAMPS. These observations imply that increased activation of PKA type I may contribute to the progressive T cell dysfunction in HIV infection and that PKA type I may be a potential target for immunomodulating therapy.     

Spontaneous and ligand-induced trafficking of CXC-chemokine receptor 4

A chimeric protein consisting of CXC-chemokine receptor 4 (CXCR4) and the green fluorescent protein (GFP) was used for studying receptor localization and trafficking in real time in stably transduced HeLa, U-937, CEM, and NIH/3T3 cells. CXCR4-GFP was fully active as a co-receptor in mediating human immunodeficiency virus (HIV) entry. Both CXCR4 and CXCR4-GFP were found to undergo significant spontaneous endocytosis. Only 51.5 +/- 7.8% of receptor molecules were found on the plasma membrane in CD4-positive cells, 43.9 +/- 8.5% were found in CD4-negative HeLa cells, 75.6 +/- 9.7% were found in U-937 cells, 72.5 +/- 7.9 were found in CEM cells, and almost none were found in in NIH/3T3 cells. Stromal cell-derived factor-1alpha induced rapid endocytosis of cell surface receptor molecules. A significant part of CXCR4 was targeted to lysosomes upon binding of the ligands, and recycling of internalized CXCR4 was not efficient. Only about 30% of receptor molecules recycled back to the cell surface in HeLa cells, 5% recycled in U937, and 10% recycled in CEM cells, suggesting that the protective effect of chemokines against HIV infection can be attributed not only to competition for binding but also to depletion of the co-receptor molecules from the cell surface. Envelope glycoprotein gp120 of syncytia-inducing/lymphocyte tropic HIV-1 strains induced rapid internalization of CXCR4 in both CD4-negative and CD4-positive cells, suggesting that gp120 is a high affinity ligand of CXCR4.     

Early reduction of immune activation in lymphoid tissue following highly active HIV therapy

OBJECTIVE: To evaluate immune reconstitution within HIV-infected lymphoid tissue during highly active antiretroviral therapy (HAART). DESIGN AND METHODS: In situ cellular responses were studied in sequential tonsillar biopsies in three asymptomatic HIV-infected (CD4 cells greater than 400 x 10(6)/l) antiretroviral treatment-naive volunteers enrolled in a clinical trial to determine the early effect of HAART. Computerized image analysis was used to study immunohistochemically stained sequential tonsil sections for the patterns of local cytokine production, chemokine receptor expression and cellular distribution. Replicate quantitative assessments of samples before and after 4 weeks of therapy were used for the evaluation of drug effects and compared with four uninfected controls. Tonsillar HIV proviral-DNA was determined by fluorescent in situ 5'-nuclease assay. RESULTS: HIV-infected tonsil tissue was characterized by extensive pro-inflammatory and type 1 cytokine expression. A five- to 15-fold elevation of interleukin (IL)-1 alpha, IL-12, IL-2 and interferon (IFN)-gamma protein expression was found compared with controls, and each encompassed a mean of at least 4.5% of the tissue compartment. This was reduced by 20-90% in all individuals after 4 weeks of HAART. In contrast, type 2 cytokine expression (IL-4, IL-10), plus tumour necrosis factor (TNF)-alpha, remained low throughout the study. HAART reduced, by 40%, the expression of HIV co-receptors, CCR5 and CXCR4, which initially were elevated four to six times over the control values. In addition, the myelomonocytic inflammatory proteins, CD68 and calprotectin, diminished by 26-83% after therapy. The HIV RNA was reduced to undetectable levels in plasma by HAART. However, a large pool of tonsil cells (2-7%), remained HIV DNA positive after 4 weeks of therapy. CONCLUSIONS: Although immune activation may be the direct consequence of HIV replication, HAART-associated reconstitution begins with a reduction in inflammatory cytokine production which precedes the elimination of local proviral reservoirs.     

Immune activation in HIV-infected African individuals. Italian-Ugandan AIDS cooperation program

OBJECTIVE: Immune activation induced by chronic infections, dietary limitations, and poor hygienic conditions is suggested to be present in African HIV infection and is at the basis of the hypothesis that HIV infection in Africa could be prevalently associated with immunopathogenetic mechanisms. Very limited data are nevertheless available supporting this theory, and in particular no data are reported on functional and phenotypic analyses performed on fresh peripheral blood mononuclear cells (PBMC) of African HIV-infected patients living in Africa. DESIGN: Immunological and virological parameters were analysed in fresh PBMC of HIV-infected African and Italian patients with advanced HIV disease and comparable CD4 and CD8 counts, sex, and age. Both functional (antigen- and mitogen-stimulated cytokine production) and phenotypic (activation markers; markers preferentially expressed by T helper (Th) type 2 cells or by memory and naive cells) analyses were performed. Results were compared with those of HIV-seronegative African and Italian controls. HIV plasma viraemia was analysed by competitive polymerase chain reaction (PCR) and branched DNA techniques. RESULTS: (1) The production of mitogen-stimulated IFN-gamma and TNF-alpha as well as the production of env peptide-stimulated IFN-gamma, TNF-alpha, and IL-10 are increased in African HIV infection; (2) the expression of activation and Th2-associated markers is augmented in African HIV infection as is the memory/naive ratio; (3) mitogen-stimulated IFN-gamma and IL-10 production, as well as the expression of activation and Th2-associated markers and the memory/naive ratio, are augmented in African compared with Italian controls; and (4) plasma viraemia is reduced in African compared with Italian HIV-infected individuals. CONCLUSIONS: These results, which are the first to be reported on fresh material from African HIV-infected patients living in Africa, indicate that HIV disease is associated with an abnormal immune hyperactivation and may be accompanied in these patients by lower loads of virus, and show that such activation is present even in HIV-seronegative controls.