Achieving sustained virologic response after interferon-free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis.

Chronic hepatitis C virus (HCV) infection can now be treated with oral directly acting antiviral agents, either with or without ribavirin (RBV). Virologic relapse after treatment can occur, and in some studies was more common in cirrhotic subjects. We previously observed changes in hepatic immunity during interferon (IFN)-free therapy that correlated with favourable outcome in subjects with early liver disease. Here, we compared changes in endogenous IFN pathways during IFN-free, RBV-free therapy between cirrhotic and noncirrhotic subjects. mRNA and microRNA (miRNA) expression analyses were performed on paired pre- and post-treatment liver biopsies from genotype-1 HCV subjects treated with sofosbuvir/ledipasvir (SOF/LDV) for 12 weeks (n = 4, 3 cirrhotics) or SOF/LDV combined with GS-9669 or GS-9451 for 6 weeks (n = 6, 0 cirrhotics). Nine of ten subjects achieved a sustained virologic response (SVR), while one noncirrhotic subject relapsed. Hepatic IFN-stimulated gene expression decreased with treatment in the liver of all subjects, with no observable impact of cirrhosis. Hepatic gene expression of type III IFNs (IFNL1, IFNL3, IFNL4-ΔG) similarly decreased with treatment, while IFNA2 expression, undetectable in all subjects pretreatment, was detected post-treatment in three subjects who achieved a SVR. Only the subject who relapsed had detectable IFNL4-ΔG expression in post-treatment liver. Other IFNs had no change in gene expression (IFNG, IFNB1, IFNA5) or could not be detected. Although expression of multiple hepatic miRNAs changed with treatment, many miRNAs previously implicated in HCV replication and IFN signalling had unchanged expression. In conclusion, favourable treatment outcome during IFN-free HCV therapy is associated with changes in the host IFN response regardless of cirrhosis.

Hepatic compartmentalization of exhausted and regulatory cells in HIV/HCV-coinfected patients.

Accelerated intrahepatic hepatitis C virus (HCV) pathogenesis is likely the result of dysregulation within both the innate and adaptive immune compartments, but the exact contribution of peripheral blood and liver lymphocyte subsets remains unclear. Prolonged activation and expansion of immunoregulatory cells have been thought to play a role. We determined immune cell subset frequency in contemporaneous liver and peripheral blood samples from chronic HCV-infected and HIV/HCV-coinfected individuals. Peripheral blood mononuclear cells (PBMC) and biopsy-derived liver-infiltrating lymphocytes from 26 HIV/HCV-coinfected, 10 chronic HCV-infected and 10 HIV-infected individuals were assessed for various subsets of T and B lymphocytes, dendritic cell, natural killer (NK) cell and NK T-cell frequency by flow cytometry. CD8(+) T cells expressing the exhaustion marker PD-1 were increased in HCV-infected individuals compared with uninfected individuals (P = 0.02), and HIV coinfection enhanced this effect (P = 0.005). In the liver, regulatory CD4(+) CD25(+) Foxp3(+) T cells, as well as CD4(+) CD25(+) PD1(+) T cells, were more frequent in HIV/HCV-coinfected than in HCV-monoinfected samples (P < 0.001). HCV was associated with increased regulatory T cells, PD-1(+) T cells and decreased memory B cells, regardless of HIV infection (P ≤ 0.005 for all). Low CD8(+) expression was observed only in PD-1(+) CD8(+) T cells from HCV-infected individuals and healthy controls (P = 0.002) and was associated with enhanced expansion of exhausted CD8(+) T cells when exposed in vitro to PHA or CMV peptides. In conclusion, in HIV/HCV coinfection, ongoing HCV replication is associated with increased regulatory and exhausted T cells in the periphery and liver that may impact control of HCV. Simultaneous characterization of liver and peripheral blood highlights the disproportionate intrahepatic compartmentalization of immunoregulatory T cells, which may contribute to establishment of chronicity and hepatic fibrogenesis in HIV coinfection.

Effect of HIV on liver fibrosis among HCV-infected African Americans.

Degree of liver fibrosis largely determines treatment urgency for hepatitis C virus (HCV). This retrospective study examined fibrosis stages and predictive factors in African Americans with HCV monoinfection and human immunodeficiency virus (HIV)/HCV coinfection. Nearly 50% of patients had early-stage fibrosis in the study, despite the long duration of infection in many patients. HIV was associated with the early fibrosis group. These results indicate that a large proportion of patients with HCV infection, including those with HIV, could possibly await more-effective and better-tolerated treatment.

Baseline CD4+ T-cell counts predict HBV viral kinetics to adefovir treatment in lamivudine-resistant HBV-infected patients with or without HIV infection.

BACKGROUND: Coinfection with HIV and hepatitis B virus (HBV) substantially alters the course of HBV. Directly acting anti-HBV agents suppress HBV viral levels; however, the kinetics of HBV decline in mono- and coinfected persons have not been evaluated. We investigated the role of baseline CD4+ T-cell counts as a predictor of HBV response to adefovir (ADV) therapy in chronic HBV with and without HIV coinfection. METHODS: We conducted a double-blind, randomized, placebo-controlled study of HIV-infected (n = 12) and uninfected (n = 5) chronic HBV patients treated with ADV. Five HIV uninfected patients received ADV; the HIV+ patients received ADV or placebo for a total of 48 weeks. At the end of 48 weeks, all patients received open-label ADV for an additional 48 weeks. HBV, HIV viral loads, CD4+ T-cell counts, and safety labs were performed on days 0, 1, 3, 5, 7, 10, 14, and 28 and then every 4 weeks. RESULTS: Lower HBV slopes were observed among coinfected compared to monoinfected patients (P = .027 at 4 weeks, P = .019 at 24 weeks, and P = .045 at 48 weeks). Using a mixed model analysis, we found a significant difference between the slopes of the 2 groups at 48 weeks (P = .045). Baseline CD4+ T-cell count was the only independent predictor of HBV decline in all patients. CONCLUSION: HIV coinfection is associated with slower HBV response to ADV. Baseline CD4+ T-cell count and not IL28B genotype is an independent predictor of HBV decline in all patients, emphasizing the role of immune status on clearance of HBV.

Distinct and overlapping genomic profiles and antiviral effects of Interferon-λ and -α on HCV-infected and noninfected hepatoma cells.

Recently, several SNPs in the region of the IL28B (IFN-λ) gene have been associated with spontaneous clearance of hepatitis C virus (HCV) and enhanced cure rates for IFN-alfa-based therapies, suggesting a potential correlation between IFN-λ and the ability to clear HCV. To understand the mechanism of IFN-λ's as compared to IFN-α's antiviral activity, we performed a comprehensive analysis of their anti-HCV effects, whole genome transcriptome profiling with validation, and signalling of IFN-α and IFN-λ using J6/JFH-1 and Huh7.5 cells in vitro. IFN-λ and IFN-α exhibited comparable anti-HCV activity and gene expression profiles in Huh7.5 cells. While the majority of genes induced by IFN-α and IFN-λ were similar, IFN-λ exhibits profound, but delayed kinetics of IFN-stimulated genes (ISG) induction, while IFN-α induced more rapid induction of ISGs. Furthermore, the increased induction of ISG expression by IFN-λ correlated with up-regulation of IFN-λ receptor (IL-28RA) expression and more prolonged activation of the Jak-STAT signalling pathway. The findings from our comparative analysis of IFN-α and IFN-λ in HCV-infected and noninfected cells support the clinical use of IFN-λ as a potential alternative to IFN-α in the treatment of chronic hepatitis C.

HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies.

Changes in CD4+ T-cell surface marker phenotype and antigen receptor (TCR) repertoire were examined during the course of HIV infection and following therapy. A preferential decline in naive CD4+ T cells was noted as disease progressed. Following protease inhibitor therapy, naive CD4+ T cells increased only if they were present before initiation of therapy. Disruptions of the CD4+ TCR repertoire were most prevalent in patients with the lowest CD4+ T-cell counts. Antiviral or IL-12 therapy-induced increases in CD4+ T-cell counts led to only minor changes in previously disrupted repertoires. Thus, CD4+ T-cell death mediated by HIV-1 infection may result in a preferential decline in the number of naive CD4+ T cells and disruptions of the CD4+ T-cell repertoire that are not immediately corrected by antiviral or immune-based therapies.

Peripheral expansion of pre-existing mature T cells is an important means of CD4+ T-cell regeneration HIV-infected adults.

The CD4+ T-cell pool in HIV-infected patients is in a constant state of flux as CD4+ T cells are infected and destroyed by HIV and new cells take their place. To study T-cell survival, we adoptively transferred peripheral blood lymphocytes transduced with the neomycin phosphotransferase gene between syngeneic twin pairs discordant for HIV infection. A stable fraction of marked CD4+ T cells persisted in the circulation for four to eighteen weeks after transfer in all patients. After this time there was a precipitous decline in marked cells in three of the patients. At approximately six months, marked cells were in lymphoid tissues in proportions comparable to those found in peripheral blood. In two patients, the proportion of total signal for the transgene (found by PCR analysis) in the CD4/CD45RA+ T-cell population relative to the CD4/CD45RO+ population increased in the weeks after cell infusion. These findings indicate that genetically-marked CD4+ T cells persist in vivo for weeks to months and that the CD4+ T-cell pool in adults is maintained mostly by the division of mature T cells rather than by differentiation of prethymic stem cells. Thus, after elements of the T-cell repertoire are lost through HIV infection, they may be difficult to replace.

The interaction in vitro of Pneumocystis carinii with macrophages and L-cells.

A model was developed for studying the interaction between Pneumocystis, rat-derived cells, and humoral factors. Pneumocystis were obtained in large quantity by bronchial lavage of steroid-treated rats. The trophozoite was the predominant form obtained, and it could readily be recognized by phase contrast microscopy. Organisms maintained a typical morphology for at least 3 days in culture, and 10-20% took up radiolabeled nucleotides. Pneumocystis readily adhered to cell surfaces in a similar manner in alveolar macrophages from steroid-treated or normal rats, mouse peritoneal macrophages, and L-cells. Adherent organisms were not interiorized to a significant degree in the absence of antipneumocystis serum. After addition of rabbit antipneumocystis serum, rapid interiorization of organisms occurred from the surface of macrophages but not L-cells. Organisms appeared to be promptly destroyed within macrophages after interiorization. Persisting or multiplying intracellular forms were not seen. Antipneumocystis serum did not morphologically alter Pneumocystis. These observations suggest a role for antibody and mononuclear phagocytes during the immune response to Pneumocystis.

Quantitative analysis of mononuclear cells expressing human immunodeficiency virus type 1 RNA in esophageal mucosa.

The mucosa of the gastrointestinal tract is presumably an important reservoir for human immunodeficiency virus type 1 (HIV-1), but the level of virus-expressing cells within the mucosa of infected patients is not known. To study this issue, we identified HIV-1 mRNA-expressing (positive) mononuclear cells by in situ hybridization in specimens of esophageal mucosa from eight patients with acquired immune deficiency syndrome (AIDS) and esophageal infections. Such cells were not found in four patients with AIDS and no esophageal disease. Immunocytochemical staining revealed that the mononuclear cells expressing HIV-1 mRNA were lamina propria macrophages. The prevalence of positive cells was measured by triplicate determinations in each of three experiments using an inverse sampling technique. No significant differences in prevalence were found among patients or among experiments. The overall prevalence of HIV-1 mRNA-expressing cells in the esophageal lamina propria was 0.059 +/- 0.01%. This prevalence of cells expressing HIV-1 mRNA in the mucosa of patients with mucosal infections may reflect the local abundance of stimuli such as bacterial endotoxin and certain cytokines capable of inducing viral transcription.

Activity of antifolates against Pneumocystis carinii dihydrofolate reductase and identification of a potent new agent.

The therapy of Pneumocystis carinii (PC) pneumonia is often unsuccessful, particularly in patients with acquired immune deficiency syndrome (AIDS). Because of difficulties in growing the organism in vitro or obtaining purified organisms, current treatment choices have been made with little information on the metabolic effects of therapeutic agents on PC. This report quantitates the effects of the commonly used antifolates as well as the classic antineoplastic antifolate methotrexate and a lipid-soluble analogue, trimetrexate, on the target enzyme, dihydrofolate reductase (DHFR), in the PC organisms. Trimethoprim and pyrimethamine were found to be weak inhibitors (ID50 = 39,600 and 2,800 nM, respectively), while methotrexate and trimetrexate were potent reductase inhibitors (ID50 = 1.4 and 26.1 nM, respectively). transport studies with radiolabeled compounds showed that compounds with the classic folate structure (methotrexate and leucovorin) were not taken up by the intact PC organisms. In contrast, trimetrexate exhibited rapid uptake. These results suggest a major therapeutic advantage may be gained by combining a potent, readily transported PC DHFR inhibitor such as trimetrexate with the reduced folate leucovorin to achieve a highly potent antiprotozoan effect while preventing toxicity to mammalian cells.

Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV.

We examined the effects of human immunodeficiency virus infection on the turnover of CD4 and CD8 T lymphocytes in 17 HIV-infected patients by 30 min in vivo pulse labeling with bromodeoxyuridine (BrdU). The percentage of labeled CD4 and CD8 T lymphocytes was initially higher in lymph nodes than in blood. Labeled cells equilibrated between the two compartments within 24 h. Based on mathematical modeling of the dynamics of BrdU-labeled cells in the blood, we identified rapidly and slowly proliferating subpopulations of CD4 and CD8 T lymphocytes. The percentage, but not the decay rate, of labeled CD4 or CD8 cells in the rapidly proliferating pool correlated significantly with plasma HIV RNA levels for both CD4 (r = 0.77, P < 0.001) and CD8 (r = 0.81, P < 0.001) T cells. In six patients there was a geometric mean decrease of greater than 2 logs in HIV levels within 2 to 6 mo after the initiation of highly active antiretroviral therapy; this was associated with a significant decrease in the percentage (but not the decay rate) of labeled cells in the rapidly proliferating pool for both CD4 (P = 0.03) and CD8 (P < 0.001) T lymphocytes. Neither plasma viral levels nor therapy had an effect on the decay rate constants or the percentage of labeled cells in the slowly proliferating pool. Monocyte production was inversely related to viral load (r = -0.56, P = 0.003) and increased with therapy (P = 0.01). These findings demonstrate that HIV does not impair CD4 T cell production but does increase CD4 and CD8 lymphocyte proliferation and death by inducing entry into a rapidly proliferating subpopulation of cells.

Proviral DNA of a retrovirus, human T-cell leukemia virus, in two patients with AIDS.

The acquired immune deficiency syndrome (AIDS) is characterized by T-lymphocyte dysfunction and is frequently accompanied by opportunistic infections and Kaposi's sarcoma. Human T-cell leukemia virus (HTLV) is associated with T-cell malignancies and can transform T lymphocytes in vitro. In an attempt to find evidence of HTLV infection in patients with AIDS, DNA from samples of peripheral blood lymphocytes from 33 AIDS patients was analyzed by Southern blot-hybridization with a radiolabeled cloned HTLV DNA probe. Analysis of DNA from both the fresh (uncultured) lymphocytes and from T cells cultured with T-cell growth factor revealed the presence of integrated HTLV proviral sequences in lymphocytes from two of the patients, both of whom had antibody to HTLV. The proviral sequences could not be detected in blood samples obtained from these individuals at a later date, consistent with the possibility that the population of infected cells had become depleted.

Transmission of HTLV-III infection from human plasma to chimpanzees: an animal model for AIDS.

Two of three chimpanzees given plasma from patients with acquired immune deficiency syndrome (AIDS) or pre-AIDS showed serum antibodies to type III human T-cell leukemia virus (HTLV-III) 10 to 12 weeks after transfusion. One animal also developed lymphadenopathy, transient depression of the ratio of T4 to T8 lymphocytes, and impaired blastogenic responses. No opportunistic infections occurred. Adenopathy persisted for 32 weeks, and antibody to HTLV-III persisted for at least 48 weeks. This transmission of HTLV-III by lymphocyte-poor plasma confirms the potential risk of such plasma or plasma derivatives to recipients. The susceptibility of the chimpanzee to HTLV-III infection and the ability to simulate the human lymphadenopathy syndrome in this animal makes it a valuable model for further study of AIDS.

Differential antiviral effect of PEG-interferon-alpha-2b on HIV and HCV in the treatment of HIV/HCV co-infected patients.

OBJECTIVE: The major antiviral effect of interferon (IFN)-alpha on hepatitis C virus (HCV) is blocking of virion production from infected cells. We now investigate the previously unknown mechanism of action of IFN-alpha against HIV. METHODS: HIV kinetics in parallel to HCV kinetics and IFN pharmacokinetics during pegylated-IFN-alpha-2b (1.5 microg/Kg q.w., PEG-IFN) and ribavirin (1-1.2 g daily) treatment in nine HIV patients co-infected with HCV genotype 1 were analyzed. In vivo modeling predictions of suppression of HIV replication by PEG-IFN in CD8-depleted peripheral blood mononuclear cells were verified by in vitro experiments. RESULTS: HCV and HIV show different viral decline patterns after administration of PEG-IFN. Unlike the bi-phasic decline shown by HCV, HIV shows a slow continuous decline during the first week, with no rebound when PEG-IFN levels decline. Fitting of HIV kinetics with known half-lives of free virus and infected cells indicates that the major effect of IFN on HIV is to block de novo infection rather than to block virion production. The magnitude of the antiviral effect is similar (mean 1.1 log10 decline at 7 days) to those of direct anti-HIV drugs, but shows an inverse correlation with baseline viremia. In vitro studies show that preincubation with IFN renders a suppression of HIV replication superior to that of treatment postinfection, thus corroborating the mathematical analysis in vivo. CONCLUSION: The complimentary antiviral properties of IFN-alpha and antiretroviral therapy suggest a role for pharmacokinetically improved formulations of IFN as part of salvage therapy for HIV-infected individuals.

Potent in vitro and in vivo antitoxoplasma activity of the lipid-soluble antifolate trimetrexate.

Trimetrexate, a highly lipid-soluble quinazoline antifolate now undergoing trials as an anticancer agent, was found to be a potent inhibitor of the dihydrofolate reductase (DHFR) isolated from Toxoplasma gondii. The concentration required for 50% inhibition of protozoal DHFR was 1.4 nM. As an inhibitor of this enzyme, trimetrexate was almost 600-fold (amount of antifolate required to inhibit catalytic reaction by 50%) and 750-fold (inhibition constant) more potent than pyrimethamine, the DHFR inhibitor currently used to treat toxoplasma infection. When the protozoan was incubated with 1 microM trimetrexate, the drug rapidly reached high intracellular concentrations. Since toxoplasma organisms lack a transmembrane transport system for physiologic folates, host toxicity can be prevented by co-administration of the reduced folate, leucovorin, without reversing the antiprotozoal effect. The effectiveness of trimetrexate against toxoplasma was demonstrated both in vitro and vivo. Proliferation of toxoplasma in murine macrophages in vitro was completely inhibited by exposure of these cells to 10(-7) M trimetrexate for 18 h. When used alone, trimetrexate was able to extend the survival of T. gondii-infected mice.

Sera from patients with the acquired immunodeficiency syndrome inhibit production of interleukin-2 by normal lymphocytes.

We studied the effects of sera from patients with the acquired immunodeficiency syndrome (AIDS) on interleukin-2 (IL-2) production to help elucidate the mechanism of immunodeficiency. Compared with sera from healthy controls, sera from AIDS patients suppressed phytohemagglutinin (PHA)-induced IL-2 production by normal blood mononuclear cells. Sera from homosexual contacts of AIDS patients and from adults with acute cytomegalovirus infection generally lacked this suppressive activity. The effect of the AIDS sera could not be attributed to absence of a stimulatory or nutritive factor, to inactivation of IL-2, to inhibition of the IL-2 assay, nor to increased turnover of IL-2. The suppressive effect of the sera was not mediated by radiosensitive or T8 antigen-bearing suppressor cells or by increased prostaglandin production or decreased interleukin-1 production. The sera acted directly on the groups of cells that produce IL-2, T cells and large granular lymphocytes; suppression occurred at an early, probably pretranslational, stage. When cells were incubated with AIDS sera and then washed, the suppressive effect persisted. The sera did not cause direct or complement-mediated cytotoxic effects on normal mononuclear cells nor did they suppress PHA-induced interferon production, nor proliferation of T lymphoblasts or lymphocyte lines. The suppressive effect was not mediated by interferon, cortisol, immunoglobulin G or M, or immune complexes. The activity was stable at pH 3, pH 10, and 60 degrees C; inactivated at 100 degrees C; and not ether extractable. Because IL-2 plays a central role in the development of many immune responses, the serum factor(s) that inhibits IL-2 production could contribute significantly to the immunodeficiency of AIDS.

Monocyte function in the acquired immune deficiency syndrome. Defective chemotaxis.

The ineffective immune response in patients with the acquired immune deficiency syndrome (AIDS) contributes to severe and widespread infections and unrestricted growth by certain tumors. To determine whether monocyte dysfunction contributes to this immunosuppressed condition, we investigated monocyte chemotaxis in patients with AIDS. Using three different chemotactic stimuli, N-formylmethionylleucylphenylalanine, lymphocyte-derived chemotactic factor, and C5a des Arg, we studied the chemotactic responses of monocytes from seven homosexual men with AIDS, three homosexuals with lymphadenopathy and an abnormal immunological profile, seven healthy homosexual men, and 23 heterosexual control individuals. Monocytes from each of the AIDS patients with Kaposi's sarcoma and/or opportunistic infection exhibited a marked reduction in chemotaxis to all stimuli compared with the healthy control subjects. The reduced chemotactic responses were observed over a wide range of concentrations for each stimulus. Monocytes from AIDS patients who had clinically apparent opportunistic infection(s) exhibited a greater reduction in monocyte migration to all three stimuli than monocytes from the AIDS patient with only Kaposi's sarcoma. Monocytes from each of three homosexuals with lymphadenopathy and an abnormal immunological profile exhibited decreased chemotactic responses that were intermediate between those of the AIDS patients and the healthy heterosexual control subjects. In contrast to these findings, monocytes from each of seven healthy homosexuals exhibited normal chemotactic responses to the same stimuli. In addition, monocytes from AIDS patients exhibited reduced chemotaxis to soluble products of Giardia lamblia, one of several protozoan parasites prevalent in AIDS patients. Thus the immune abnormality in AIDS, previously thought to involve only the T-, B-, and natural killer lymphocytes, extends to the monocyte-macrophage. Defective monocyte migratory function may contribute to the depressed inflammatory response to certain organisms and to the apparent unrestricted growth of certain neoplasms in patients with AIDS.

Interaction of sulfonamide and sulfone compounds with Toxoplasma gondii dihydropteroate synthase.

Toxoplasma gondii is a common protozoan disease that often causes life-threatening disease, particularly among patients with the acquired immunodeficiency syndrome. This study demonstrates that the dihydropteroate synthase in T. gondii is kinetically distinct from the enzyme characterized from other sources and can be highly purified with a high yield using sequential dye-affinity chromatography. Conditions have been identified that allow for stabilization of the purified enzyme, and its physical characteristics have been elucidated. The molecular weight of the native protein was 125,000 and the protein appeared to contain both dihydropteroate synthase and 6-hydroxymethyl-dihydropterin pyrophosphokinase activities. The sulfonamide class of compounds vary in inhibitory potency by more than three orders of magnitude. Sulfathiazole, sulfamethoxazole, and sulfamethazine, with 50% inhibitory concentrations (IC50's) of 1.7, 2.7, and 5.7 microM, respectively, represent the most potent of this class of inhibitors. Several sulfone analogues, including dapsone, were identified as highly potent inhibitors with IC50's less than 1 microM. The results of these cell-free experiments were corroborated by investigating the metabolic inhibition produced by the various inhibitors in intact organisms. The qualitative and quantitative relations among the inhibitors were preserved in both the cell-free and intact cell assay systems. These studies suggest that the sulfones may be important therapeutic agents for the treatment of toxoplasmosis.

Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immune deficiency syndrome.

The recently described acquired immune deficiency syndrome (AIDS) is characterized by the occurrence of severe opportunistic infections and an aggressive form of Kaposi's sarcoma. A variety of profound defects in cell-mediated immunity have been reported in association with the AIDS, including deficiencies in natural killer (NK) cell activity and cytomegalovirus (CMV)-specific cytotoxicity. In the present study, the in vitro effects of interleukin-2 (IL-2) and interferon beta (IFN Beta) on these abnormalities were examined to assess the potential use of these lymphokines in the immunotherapeutic treatment of this syndrome. The peripheral blood lymphocytes (PBL) from six male homosexuals with AIDS and an active CMV infection exhibited markedly depressed NK cell and CMV-specific cytotoxic lymphocyte responses compared with uninfected, heterosexual control subjects. Incubation of PBL with IFN Beta enhanced the NK cell activity and the CMV-specific cytotoxicity of only one of six and neither of two AIDS patients, respectively, while enhancing the NK cell activity of all six control subjects. In contrast, IL-2 dramatically enhanced both the NK cell and the CMV-specific cytotoxic lymphocyte activities of all of the patients. These results indicate that IL-2 can substantially potentiate the depressed cytotoxic effector functions of PBL from AIDS patients, while IFN Beta has little effect.

Therapeutic approaches to patients with AIDS.

The immune systems of patients with acquired immunodeficiency syndrome are characterized by a profound defect in the number and function of helper/inducer T-lymphocytes, particularly at the level of soluble antigen recognition. Due to this selective yet profound defect in the immune system, these patients are prone to recurrent severe opportunistic infections and Kaposi's sarcoma. While therapies exist for some of these complications of acquired immunodeficiency syndrome, no effective therapies exist for the underlying immune defect of this syndrome. Reviewed here are some of our recent attempts at immune reconstitution in acquired immunodeficiency syndrome, using either whole scale immune reconstitution through the use of lymphocyte transfers and bone marrow transplantation or enhancement of the remaining immune systems with the T-cell-derived lymphokines interleukin-2 or immune gamma-interferon. In addition, recent advances in the therapy of Pneumocystis carinii pneumonia and disseminated cytomegalovirus disease are discussed.