Cellular and humoral immunity in the pathogenesis of recurrent herpes viral infections in patients with lymphoma.

86 patients with lymphoma were evaluated prospectively for clinical and laboratory evidence of recurrent varicella-zoster, herpes simplex, and cytomegalovirus infections during the first 16 mo of treatment. Cellular immunity to the viral antigens was measured by in vitro lymphocyte transformation and interferon production. Antibody titers and nonspecific measures of cellular immunity, including T-cell quantitation and transformation to phytohemagglutinin, were also assessed. The patients treated with radiation and chemotherapy had the highest incidence of reactivation of each of the viruses (15-19%). Greater susceptibility to herpes viral reactivation in these patients correlated with suppression of cell-mediated immunity to the specific virus. In individual patients, suppression of cellular immunity to the specific herpes viral antigen preceded each episode of reactivation, but recurrent infection did not occur in all patients with diminished specific lymphocyte transformation. Absence of the response appears to be a necessary but not a sufficient condition for the recrudescence of latent infection. Better preservation of cellular immunity to herpes simplex antigen during treatment was associated with infrequent reactivation of herpes simplex. In 25 patients with acute herpes zoster, uncomplicated recovery from the infection was accompanied by the development of lymphocyte transformation and interferon production to varicella-zoster antigen. Quantitation of T-cell numbers and phytohemagglutinin transformation did not correlate with the presence of viral cellular immunity in treated patients. Responses returned while T-cell numbers were low, and the recovery of phytohemagglutinin transformation often preceded recovery of the responses to viral antigens. Although some patients had deficiencies in viral cellular immunity at diagnosis, the duration of the suppression of specific antiviral responses resulting from treatment appears to be the most important factor predisposing to the recurrence of herpes infections in lymphoma patients.

Human cytomegalovirus-induced immunosuppression. Relationship to tumor necrosis factor-dependent release of arachidonic acid and prostaglandin E2 in human monocytes.

Cytomegalovirus (CMV) has been associated with immunosuppression. Previously CMV was reported to interfere with signal transduction pathways in T cells. In this report the mechanisms underlying CMV-mediated immunosuppression were examined. Supernatants of CMV (Strains C-87, AD-169)-infected primary human monocyte (MO) cultures inhibited mitogenic T cell proliferative responses by > 95%. The inhibitory activity was observed 24 h through day 7 postinfection. The infection of MO was associated with a sustained elevation of intracellular levels of cAMP and the release of arachidonic acid (AA) and its metabolite PGE2 (activator of adenylate cyclase) in culture supernatants. The AA release was incidentally associated with TNF-alpha production. Monoclonal antibodies to TNF-alpha and pentoxyphylline (inhibitor of TNF synthesis) inhibited both AA and PGE2 release. The release of AA required protein synthesis and occurred under conditions consistent with the expression of CMV immediate early genes. Treatment of MO cultures at time of infection with 100 microM indomethacin or 1 microg of TNF-alpha mAb abolished the CMV-induced T cell inhibitory activity of the supernatants by 100%. These data suggest that TNF dependent release of AA and PGE2 contributes to CMV-induced immunosuppression.

Importance of Lyt 1+ T-cells in the antitumor activity of an immunomodulator, SSM, extracted from human-type Tubercle bacilli.

An arabinomannan lipid extracted from Mycobacterium tuberculosis strain Aoyama B (SSM) is an immunopotentiating agent with interferon-inducing and antitumor activities. In the present study, the possible role(s) of various immunocompetent cells on the antitumor effect of SSM was investigated in mice bearing syngeneic (RL male 1 leukemia) and allogeneic (Ehrlich carcinoma) ascites tumors. When Thy 1+ T-cells were depleted from tumor-bearing mice by the administration of monoclonal anti-Thy 1.2 antibody, the protective effect of SSM was eliminated. However, when macrophage (M phi) and natural killer (NK) cell activities were depleted by treatment with M phi blockers (trypan blue and carrageenan) or a blocker for NK cells (anti-asialo GM1 antiserum), no alteration of the antitumor activity of SSM was observed. Therefore, T-lymphocytes, but not M phi or NK cells, were required for the expression of the antitumor efficacy of SSM. The antitumor activity of SSM was also abrogated by Lyt 1+ T-cells being depleted by treatment with monoclonal anti-Lyt 1.2 antibody, whereas the administration of monoclonal anti-Lyt 2.2 antibody had no effect on the antitumor activity. Independent of M phi, NK cells, or Lyt 2+ T-cells, Lyt 1+ T-lymphocytes appear to play an important role in the expression of the antitumor effects of SSM.

Induction of interleukin 3 and tumor resistance by SSM, a cancer immunotherapeutic agent extracted from Mycobacterium tuberculosis.

Interleukin 3 (IL-3) activity was demonstrated when inguinal lymph node cells obtained from Bacillus Calmette-Guérin-sensitized mice (BCG-ILNC) were stimulated in vitro with SSM, an immunomodulator extracted from Mycobacterium tuberculosis. The IL-3 activity was first detected on Day 1 in culture fluids of BCG-ILNC stimulated with SSM, reached a peak on Day 3, and then gradually decreased. The activity was completely neutralized by treatment with anti-murine IL-3 monoclonal antibody (mAb). When BCG-ILNC were treated with anti-Thy 1.2 or anti-Lyt 1.2 mAb followed by complement, IL-3 was not produced in the culture fluids. However, IL-3 in the culture fluids was detected when BCG-ILNC were treated with anti-Lyt 2.2 mAb, anti-asialo-GM1, or anti-mouse immunoglobulin antiserum followed by complement. These results suggested that Lyt 1+ T-cells appeared to be required for the production of IL-3 from BCG-ILNC stimulated with SSM. In addition, low but significant IL-3 activity was also observed in sera of mice treated with SSM. However, serum IL-3 activity was not detected in mice treated with both SSM and Thy 1.2 or Lyt 1.2 mAb, whereas the activity was induced by SSM in mice treated with anti-Lyt 2.2 mAb or anti-asialo-GM1 antiserum. On the other hand, the in vivo growth of IMC tumors inoculated in BALB/c x DBA/2 F1 mice was significantly decreased by intralesional injection of culture fluids containing IL-3, as well as by SSM itself. This antitumor activity of the culture fluids was not altered when it was treated with mAbs for interleukin 1, interleukin 2, or anti-mouse gamma-interferon antiserum. The antitumor activity of the fluid was only eliminated when it was treated with anti-mouse IL-3 mAb. Since nonspecific resistance to tumors in mice stimulated with SSM appears to require Lyt 1+ T-cells, these results suggest that, in part, nonspecific resistance to tumors of mice stimulated with SSM may be developed through IL-3, which was produced by Lyt 1+ T-cells after SSM stimulation.

Role of natural killer cells and macrophages in the nonspecific resistance to tumors in mice stimulated with SMANCS, a polymer-conjugated derivative of neocarzinostatin.

Copoly(styrene-maleic acid)-conjugated neocarzinostatin (SMANCS), a lipophilic derivative of the proteinaceous antitumor antibiotic neocarzinostatin, has been reported to stimulate a nonspecific resistance to tumors (NSRT) in solid tumor-bearing mice, in addition to its chemotherapeutic antitumor effect through the arrest of DNA synthesis by direct DNA strand scission. In the present study, splenic or peritoneal effector cells were used to investigate the ability of SMANCS to augment natural killer (NK) cell activity and to generate cytostatic macrophages (A-M phi). Splenic NK cell activity augmented by SMANCS was characterized by cytotoxicity to various target cells, nylon wool nonadherence, and sensitivity to treatment with anti-asialo-GM1 antiserum or monoclonal anti-Thy-1.2 antibody followed by complement. The A-M phi generated by SMANCS stimulation were characterized by their adherence to a plastic surface coated with fetal calf serum and their ability to phagocytize carbonyl-iron. The maximum level of NK cell activity in the spleens of mice was detected 3 days after i.v. injection of SMANCS, and the highest activity of the peritoneal A-M phi was demonstrated in mice 4 days after SMANCS treatment. On the other hand, the NSRT of mice stimulated with SMANCS was not detectable in mice treated with carrageenan or trypan blue, whereas SMANCS-stimulated NSRT was observed in mice treated with anti-asialo-GM1 antiserum. The NSRT that was stimulated with SMANCS was also demonstrated in mice homozygous for the beige mutation and their non-beige littermates, when NK cell-resistant EL-4 thymoma was used as a tumor target. These results suggest that the expression of NSRT of mice stimulated with SMANCS may require the function of A-M phi, although NK cell activity was also augmented in spleens of mice by administration of SMANCS.

Phase II study of recombinant alpha-2 interferon in resistant multiple myeloma.

A multicenter phase II study of INTRON, recombinant alpha-2 interferon (Schering Corp, Kenilworth, NJ), in patients with relapsing or refractory myeloma was initiated. Patients received either intravenous therapy for two weeks followed by subcutaneous therapy or subcutaneous dosing from initiation of treatment. Of 38 evaluable patients, 19 were refractory and 19 had relapsed at entry. Twenty-five of 38 had received prior treatment with multiple drugs. Responses were seen among 2/19 refractory patients and 5/19 relapsing patients. Three of seven responders continue to respond for more than one year while receiving maintenance therapy. Most patients experienced improvement in bone pain, and one patient, with a complete response, had healing of bone lesions. Survival curves show a statistically significant improvement in survival for responders v nonresponders. INTRON was well-tolerated with only four patients discontinuing treatment due to adverse effects. Thirty-two percent of patients had hematologic toxicity requiring dose adjustment; however, there was no evidence of cumulative hematologic toxicity. No patients developed serum neutralizing factors to interferon. Additional trials are warranted to study the activity of INTRON in previously untreated patients.

Lowering the dose of hydroxyurea minimizes toxicity and maximizes anti-HIV potency.

The goal of this study was to optimize the hydroxyurea dosage in HIV-infected patients, and to minimize the toxicity and maximize the antiviral efficacy of the hydroxyurea-didanosine combination. In a randomized, open-label study (RIGHT 702, a multicenter trial performed in private and institutional practices), three daily doses (600 microg, 800-900 microg, and 1200 microg) of hydroxyurea were administered in combination with didanosine and stavudine to 115 chronically HIV-infected patients, one-third antiretroviral drug naive, with viremia between 5000 and 200,000 copies/ml regardless of CD4+ cell count. The primary efficacy end point was the proportion of patients with plasma HIV-1 RNA levels below 400 copies/ml after 24 weeks of therapy. In the RIGHT 702 intent-to-treat population the lowest (600 mg) dose of hydroxyurea was better tolerated, associated with fewer adverse events, and more potent by all efficacy parameters, including the primary end point (76 versus 60% patients with viremia<400 copies/ml at week 24 for the 600-mg and 800- to 900-mg dose groups, respectively; p=0.027), the mean area under the curve (60.3 versus 65.8; p=0.016), and the mean log10 decrease (-1.95 versus -0.77; p=0.001). Patients receiving 600 mg of hydroxyurea daily also had the highest CD4+ cell count, CD4+/CD8+ cell ratio, and lowest CD8+ cell count and percentage (p=0.035). The RIGHT 702 trial provides an explanation for the increased toxicity and decreased efficacy of hydroxyurea when it was used at high dosage (1200 mg daily). At the optimal dosage of 600 mg daily, hydroxyurea, in combination with didanosine, deserves reevaluation for the long-term management of HIV/AIDS worldwide, because of its excellent resistance profile, durability, and affordability.

Influence of type 2 T cell responses on the severity of encephalitis associated with influenza virus infection.

The role of type 2 T cell responses on the severity of post-infectious encephalitis was investigated in a mouse model of influenza virus infection. When mice were infected intracerebrally with 3.0 LD(50) of A/NWS33 strain of influenza virus, they all showed clinical signs of encephalitis, and 90% of them died within 10 days of the infection. However, the post-infectious encephalitis was not demonstrated in mice exposed to 0.5 LD50 of the same virus. The mortality rates of mice infected with 0.5 LD(50) of the virus were increased to levels observed in mice exposed to 3.0 LD(50) of influenza virus infection, after the administration of a mixture of interleukin (IL)-4 and IL-10 (2 ng/mouse each; immediately, 1 and 2 days after the infection). In contrast, mortality rates of mice exposed to 3.0 LD(50) of influenza virus were substantially decreased when these mice were treated with a mixture of monoclonal antibodies directed against IL-4 and IL-10. A predominance of type 2 T cell responses was demonstrated in splenic T cells of mice infected with 3.0 LD(50) of influenza virus, although these responses were minimal in mice infected with 0.5 LD(50) of the virus. After the treatment with the mixture of type 2 cytokines, an increase in the type 2 T cell responses in mice exposed to 0.5 LD(50) of the virus was shown. These results indicate that type 2 T cell responses associated with the viral infection play an important role in the severity of post-infectious encephalitis induced in mice by the intracerebral infection of influenza A virus.

CD4+ contrasuppressor T cells improve the resistance of thermally injured mice infected with HSV.

Modulation of burn-associated CD8+ CD11b+ T cell receptor gamma/delta+ suppressor T cells (BA2T cells) and improved resistance to herpesvirus infections was studied in thermally injured mice. The susceptibility of thermally injured mice to infection by herpes simplex virus (HSV) was approximately 100 times greater than it was in normal mice. The increased susceptibility of thermally injured mice to HSV infection was transferred to normal mice by BA2T cells, which appeared in spleens of mice 2-9 days after thermal injury. The suppressor cell activity of BA2T cells was effectively counteracted by CD4+ CD28+ T cell receptor alpha/beta+ Vicia villosa lectin adherent antisuppressor cells (designated as burn-induced contrasuppressor T cells; BCS cells), which were generated naturally in spleens of mice after the appearance of BA2T cells. The adoptive transfer of BCS cells to mice just after the injury improved the resistance of thermally injured mice to HSV infection to levels observed in normal mice. These results suggest that the increased susceptibility of thermally injured mice to HSV infection may be affected by BA2T suppressor cells and BCS cells may improve the resistance of thermally injured mice to HSV infection through the inhibition of BA2T suppressor cell activities.

Monocyte chemoattractant protein-1 enhances HSV-induced encephalomyelitis by stimulating Th2 responses.

Monocyte chemoattractant protein (MCP)-1 has a pathogenic role in herpesvirus-induced encephalomyelitis (HSM). Anti-MCP-1 antibody greatly decreased HSM severity in mice infected with herpes simplex virus type 2 (HSM mice), compared with its effect in control HSM mice treated with rabbit immunoglobulin. HSM severity was markedly enhanced in mice previously treated with a mixture of interleukin (IL) 4 and -10. In response to stimulation with antigen, HSM mouse cells isolated from cerebrospinal fluids (CSF cells) produced IL-4 in culture fluids; however, IL-4 production decreased in CSF cells derived from HSM mice previously treated with anti-MCP-1 antibody. A macrophage population isolated in CSF cells from HSM mice (CSF-Mphi) produced MCP-1 in culture fluids. In response to stimulation with herpesvirus antigen, a population of T cells isolated from CSF cells from HSM mice (CSF-T cells) produced IL-4 into their culture fluids, although MCP-1 was not produced by CSF-T cells stimulated by this antigen. IL-4 production by CSF-T cells was markedly enhanced when they were stimulated with viral antigen in the presence of murine recombinant MCP-1 (rMCP-1). Furthermore, IL-4 was produced in naive splenic T cells cocultured with CSF-Mphi. These results indicate that the severity of HSM is influenced by MCP-1, which stimulates Th2 responses.

Interleukin-12 protects thermally injured mice from herpes simplex virus type 1 infection.

Severe burn injury is associated with increased susceptibility to severe herpesvirus infections. Type 2 cytokines [interleukin (IL)-4 and IL-10] released from burn-associated CD8+ type 2 T cells (BA-type 2 T cells) have been shown to play a role in the increased susceptibility of thermally injured mice (TI-mice) to herpes simplex virus type 1 (HSV-1) infection. Because IL-12 has been shown to inhibit the generation of type 2 T cells, murine rIL-12 was injected into TI-mice exposed to HSV-1 to determine whether IL-12 could influence HSV-1 infections in individuals bearing type 2 T cells. rIL-12 improved the resistance of TI-mice or mice inoculated with T6S cells (a BA-type 2 T cell clone) against HSV-1 infection. Type 2 cytokines were detected in sera of TI-mice or mice inoculated with T6S cells (T6S-mice). However, treatment of TI-mice or T6S-mice with rIL-12 inhibited type 2 cytokine production in the sera of these mice. All TI-mice exposed to a lethal dose of HSV-1 survived when they were treated with a mixture of monoclonal antibodies (mAbs) against type 2 cytokines. Staphylococcal enterotoxin A [an interferon-gamma (IFN-gamma) inducer] stimulated serum IFN-gamma production in TI-mice and T6S-mice treated with rIL-12, whereas no IFN-gamma was produced in mice treated with saline. These results suggest that IL-12 has the potential to protect TI-mice infected with a lethal dose of HSV-1 via a shift to type 1 T cell responses from type 2 T cell responses.

Burn-associated Candida albicans infection caused by CD30+ type 2 T cells.

Burn injury is associated with the greatly increased susceptibility of thermally injured patients to infection from a variety of pathogens. In this study we investigated the role of burn-associated type 2 T cells on the increased susceptibility of burned patients to Candida albicans infection using SCID mice and peripheral blood lymphocytes (PBL) from thermally injured patients. When SCID mice that were inoculated with PBL from healthy donors were resistant to C. albicans infection, the SCID mice that were inoculated with PBL from burned patients did not show any resistance to the infection. All SCID mice exposed to the pathogen, however, survived after inoculation with patient PBL that were previously depleted of CD30+ cells. The predominance of type 2 T cell responses was demonstrated in PBLs of thermally injured patients. As burn-associated type 2 T cells, CD3+ CD8+ CD30+ IL-4 and IL-10-producing cells were demonstrated in burned patient PBL. These results suggest that burn-associated CD30+ type 2 T cells may play a role on the increased susceptibility of burned patients to C. albicans infection.

Didanosine once daily: potential for expanded use.

Factors affecting patient adherence to therapy, such as frequent daily dosing and complex dosing schedules, are widely understood to be key obstacles to the durability of effective anti-HIV therapy. Didanosine, a nucleoside analogue reverse transcriptase inhibitor (NRTI) that is a core component of combination antiretroviral regimens, is currently indicated for twice-daily dosing. However, the active metabolite of didanosine (2',3'-dideoxyadenosine-5'-triphosphate) has a long intracellular half-life that supports the use of didanosine in a more patient-friendly, once-daily dosing schedule. Clinical studies in which didanosine was administered either once or twice daily, as monotherapy or in combination with another NRTI, have demonstrated the equivalence of both dosing schedules, with respect to safety and tolerability, virologic and immunologic endpoints, and short-term clinical effects (e.g., weight gain). Preliminary results from recent studies support the clinical efficacy and utility of once-daily didanosine in combination antiretroviral regimens that provide maximal drug exposure, while allowing for once- or twice-daily dosing of all component drugs.

Virological and immunological responses to once-daily dosing of didanosine in combination with stavudine. AI454-143 Team.

OBJECTIVE: To compare the antiviral activity of once-daily didanosine (ddI) and twice-daily ddI in combination with stavudine (d4T). DESIGN: Randomized, double-blind, multicenter study. SETTING: Twenty-one sites in the United States. PATIENTS: Eighty-seven antiretroviral-naive, HIV-1-infected adults with baseline plasma HIV RNA counts of > or = 10,000 copies/ml and CD4 cell counts of > or = 100 cells/mm3 started study therapy. INTERVENTIONS: Patients received once-daily ddI or twice-daily ddI, each combined with twice-daily d4T. MAIN OUTCOME MEASURES: Plasma HIV-1 RNA levels, CD4 cell counts, and adverse events were regularly monitored. The primary efficacy analysis used was the time-averaged difference (TAD) between treatment regimens in change from baseline plasma HIV-1 RNA levels over the first 12 weeks of therapy. RESULTS: At week 12, median log10 HIV-1 RNA changes were -1.83 log10 copies/ml in the once-daily ddI/d4T group and -1.80 log10 copies/ml in the twice-daily ddI/d4T group, and 18 out of 44 patients (41%) and 17 out of 43 patients (40%), respectively, had HIV-1 RNA levels below 400 copies/ml. Similar results were seen at week 24. The TAD between the two treatment groups (once-daily ddI/d4T minus twice-daily ddI/d4T) in change from baseline plasma HIV RNA levels over the first 12 weeks was 0.14 log10 copies/ml (95% CI: -0.11, 0.40). At week 12, subjects averaged an increase in CD4 cell count of over 140 cells/mm3. The TAD between the two treatment groups in change from baseline CD4 cell counts over the first 12 weeks was 2 cells/mm3 (95% CI: -40, 45). CONCLUSION: Once-daily ddI plus d4T and twice-daily ddI plus d4T were similarly effective in reducing plasma HIV-1 RNA levels and increasing CD4 cell counts over 12-24 weeks of therapy.

Chemokine/CD4 receptor density ratios correlate with HIV replication in lymph node and peripheral blood of HIV-infected individuals.

OBJECTIVES: Lymphoid tissue is a major reservoir for virus replication in HIV-infected subjects. The relationship of CCR5 and CXCR4 coreceptor density and HIV replication in peripheral blood mononuclear cells (PBMC) and lymph node (LN) mononuclear cells (LNMC) of HIV-infected subjects was examined. METHODS: PBMC and cervical LNMC from 12 HIV-infected patients were examined for virological and immunological parameters including chemokine receptor density, HIV plasma and cellular viral load, coreceptor usage and CD38/HLA-DR expression. RESULTS: The number of CCR5 and CXCR4 molecules on CD4 lymphocytes in the LN were significantly higher than in PBMC. In contrast the number of CD4 molecules/CD4 T cell was higher in PBMC than in LNMC. The CXCR4/CD4 and CCR5/CD4 ratios in the LN were significantly higher than in the PBMC. This was associated with a cellular viral load in the LN that was approximately 110-fold higher than in PBMC. The absolute number of coreceptor molecules per cell did not correlate with the viral load. However, the CCR5/CD4 and CXCR4/CD4 ratios in the LN positively correlated with HIV cellular and plasma RNA. Characterization of the viral isolates suggested an association between clinical isolates using a distinct coreceptor and the upregulation of the corresponding chemokine receptor. CONCLUSIONS: The ratios of chemokine receptors to CD4 molecules in CD4 T cells from LN is higher than in PBMC and may account for the relative difference in cellular viral load in these compartments. Additionally, the coreceptor/CD4 ratios, particularly in the lymphoid tissue, were highly related to HIV replication.

Magnetic resonance imaging and neuropsychological findings in human immunodeficiency virus infection.

Neurobehavioral functioning and magnetic resonance imaging (MRI) were investigated in 25 patients with various Centers for Disease Control (CDC) stages of human immunodeficiency virus (HIV) infection and in a control group of seven normal subjects. Unequivocal slowing of information processing speed and cerebral atrophy were related to the stage of HIV infection, with patients in CDC group IV exhibiting the most abnormal findings. Slowing of response speed was directly related to the severity of cerebral atrophy.

The use of interferon in the treatment of multiple myeloma.

Almost all patients with multiple myeloma still relapse or become refractory in 2 to 3 years. Interferon (IFN) therapy has clearly influenced the levels of abnormal serum proteins in some patients. A multi-institutional phase II clinical trial used alfa-2b recombinant interferon (Intron A, Schering, Kenilworth, NJ) in 38 evaluable patients with relapsing and refractory multiple myeloma; two thirds of the patient population had received extensive prior treatment. Seven responded, of whom three continued to do so beyond 1 year--one with an ongoing complete remission. An additional 13 had at least a 25% decrease in abnormal paraproteins. Of nine patients who were initially refractory to chemotherapy, two responded to IFN. Of nine relapsing patients returned to chemotherapy following IFN therapy, six then responded. Thirty previously untreated patients with multiple myeloma were treated with IFN followed by melphalan and prednisone; of 24 evaluable patients, 18 responded with a median duration of 10+ months. Alfa-2b IFN apparently does not antagonize melphalan or prednisone, nor does it appear to worsen the response of the two drugs alone. Effectiveness of recombinant alfa-2b IFN in pretreated relapsing patients suggests additional trials are needed to study its effects in previously untreated patients. A significant number of patients who relapsed on their original chemotherapy and subsequent interferon will apparently respond to the reinstitution of chemotherapy.

Analogy of human immunodeficiency virus to hepatitis C virus: the human immunodeficiency model.

The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) for many years overshadowed hepatitis C, which we now know is in some ways an even bigger problem. Important differences also exist between these two viruses and the diseases they cause, and we must be cautious about drawing too close an analogy. However, there are some striking similarities, and many lessons have been learned from HIV research over the past two decades. Parallels with HIV include persistence of the virus, genetic diversity during replication in the host, and the utility of combination treatment that is just now being appreciated with HCV infection. In the last few years, targeted antiviral drugs, such as protease inhibitors, have had an impressive effect on HIV-related morbidity and mortality. Similarities in the HIV and HCV genomes suggest that such drugs may also be useful in treating hepatitis.

Specific cell-mediated immunity and infections with herpes viruses in cardiac transplant recipients.

Immune responses and infections with herpes viruses were studied prospectively in 36 cardiac transplant recipients. Specific lymphocyte transformation and interferon production in response to viral antigens, viral culture results, antibody levels, responses to phytohemagglutinin, and T-cell numbers were determined. Responses to phytohemagglutinin and T-cell numbers were depressed for six to 12 weeks. Cytomegalovirus infection occurred in 100 percent of seropositive patients and in 62 percent of seronegative patients. Primary infection was more frequently symptomatic. Heart implantation from a seropositive patient wwas significantly correlated with subsequent infection in seronegative patients. Depression of transformation in response to cytomegalovirus correlated with prolonged shedding. Herpes simplex infection occurred in 95 percent of seropositive patients but decreased after 12 weeks. Asymptomatic shedding was rare, and primary infection did not occur. Return of transformation in response to herpes simplex was associated with decreased infection. Herpes zoster occurred in 22 percent during the first year, and transformation responses to varicella-zoster returned thereafter. Depression of interferon production in response to viruses did not correlate with infection as well as did lymphocyte transformation.

A pathogenic role of Th2 responses on the severity of encephalomyelitis induced in mice by herpes simplex virus type 2 infection.

A pathogenic role of Th2 cells and their cytokine products (IL-4 and IL-10, Th2 cytokines) on the development of herpes simplex myelitis (HSM) was studied in mice exposed to footpad injection of herpes simplex virus type 2 (HSV-2). Morbidity and mortality of mice with HSM (HSM mice) increased when they were treated with a mixture of Th2 cytokines. Additionally, survival rates of HSM mice increased when they were treated with a mixture of mAbs for Th2 cytokines. As compared with HSM mice treated with saline, the growth of HSV-2 in spinal cords of HSM mice treated with the mixture of Th2 cytokines increased. Th2 cells (myelitis-associated Th2 cells, MTh2 cells) were demonstrated among cerebrospinal fluid cells from HSM mice. After the stimulation with HSV-2 antigen (Ag), MTh2 cells from HSM mice previously treated with the mixture of Th2 cytokines produced enhanced amounts of Th2 cytokines into their culture fluids, as compared with the amount of Th2 cytokines produced by MTh2 cells. Th2 cells were also demonstrated in mononuclear cells from spleens of HSM mice. When compared with HSM mice inoculated with splenic CD4(+) T cells from normal mice, morbidity and mortality of HSM mice inoculated with MTh2 cells markedly increased. These results indicated that the severity of HSM induced in mice by footpad injection of HSV-2 was influenced by MTh2 cells or Th2 cytokines released from these MTh2 cells. Th2 responses manifested in mice by HSV-2 infection may act as a pathogenic enhancer of HSM severities.