Elena Pinter

Long-term evaluation of T-cell subsets and T-cell function after HAART in advanced stage HIV-1 disease.

OBJECTIVES Evaluation of immunological reconstitution after 2 years of highly active antiretroviral therapy (HAART) in AIDS patients. DESIGN Previous data showed the effectiveness of HAART but conflicting evidence of immune reconstitution has been found in severely immunocompromised patients. Therefore, T-cell subsets and functions were analysed during 24 months of HAART in 21 AIDS patients (mean baseline CD4 cell count, 20 x 10(6)/l). METHODS Subjects were tested at baseline and after 4, 12 and 24 months of therapy for clinical symptoms and the following investigations were carried out: plasma HIV RNA, T-cell subsets and lymphoproliferative responses to mitogens (phytohaemagglutinin, anti-CD3), and recall antigens (Candida mannoprotein, tetanus toxoid and recombinant glycoprotein 160). RESULTS Increase in body weight, improvement of Karnofskys score and reduction of opportunistic infections were observed. All patients showed an initial increase in the CD4 memory subset, whereas naive CD4 cells consistently increased only after 1 year. The magnitude of immune recovery was stronger in patients showing a significant reduction in viral load. However seven out of 21 patients who did not reach a sustained suppression of viral load showed also an increase in T-cell subsets. The majority of patients recovered lymphoproliferative responses to mitogens, whereas only four subjects showed a functional response to Candida mannoprotein. No patients showed a response to HIV recombinant glycoprotein 160 or tetanus toxoid. CONCLUSIONS The immune recovery observed is slower and not complete in severely immunocompromised patients. Our data suggest that HAART may be continued also in the absence of a significant HIV RNA decrease if alternative drugs are not available.

Human Infection with Cryptosporidium felis: Case Report and Literature Review

An infection with Cryptosporidium felis in an HIV-positive man from Italy was successfully treated with paromomycin, despite the patient’s having a CD4+ cell count of 31/mL. Fourteen cases of human infection with C. felis have been described, all in the past 3 years, emphasizing the public health importance of Cryptosporidium parasites other than C. parvum.

Clinical and Immunologic Response without Decrease in Virus Load in Patients with AIDS after 24 Months of Highly Active Antiretroviral Therapy

This study reports an analysis of clinical, virological, and immunologic outcomes in a cohort of 77 multidrug-experienced AIDS patients during 24 months of highly active antiretroviral therapy (HAART). Our results have shown a reduced risk of AIDS complications, prolonged survival, and immunologic benefit even in the absence of sustained virus suppression. The degree of immunodepression, the risk factors for HIV-1 infection, the use of 2 drugs instead of 3, and a change in protease inhibitor were independently correlated with virological failure. In the majority of studied patients, an increase in CD4+ T cells was observed after HAART. However, the increase was more pronounced in patients who showed a decrease in virus load than in those who did not. Moreover, we observed an absence of relapses among patients who permanently discontinued prophylaxis for Cytomegalovirus retinitis and atypical mycobacterial infections. Peripheral lipodystrophy developed in the majority of patients, regardless of treatment used and virological outcome.

NK cell activity controls human herpesvirus 8 latent infection and is restored upon highly active antiretroviral therapy in AIDS patients with regressing Kaposi's sarcoma.

Kaposis sarcoma (KS) develops upon reactivation of human herpesvirus 8 (HHV8) infection and virus dissemination to blood and tissue cells, including endothelial and KS spindle cells where the virus is mostly present in a latent form. However, this may likely require the presence of compromised host immune responses and/or the evasion of infected cells from the host immune response.In this regard, mechanisms of evasion of productively infected cells from both CTL and NK cell responses, and resistance of latently infected cells from specific CTL, have already been shown. Here we show that cells which are latently infected by HHV8 are indeed efficiently lysed by NK cells from individuals with a normal immune response. Notably, NK cell‐mediated immunity was found to be significantly reduced in AIDS patients with progressing KS as compared to both HIV‐negative patients with indolent classic KS or normal blood donors. However, it was restored after treatment with the highly active antiretroviral therapy (HAART) in AIDS‐KS patients, that showed regression and clearance of HHV8 from PBMC. By contrast, AIDS‐KS patients with a more aggressive disease and no clinicalresponse had persistent HHV8 viremia associated with reduced NK cell cytotoxicity. These results suggest a key role for NK cells in the control of HHV8 latent infection, KS development, and in disease remission upon HAART.

Immunologic aspects of hyperimmunoglobulinemia E–like syndrome in patients with AIDS

In this study we describe a series of nine patients affected by acquired immunodeficiency syndrome (AIDS) or AIDS-related complex who had hypereosinophilia and hyperimmunoglobulinemia E (hyper-IgE) with chronic dermatitis and recurrent staphylococcal infections. These patients had features similar to those present in hyper-IgE syndrome, a primary immunodeficiency disease. In addition, immunologic characterization of these patients with human immunodeficiency virus (HIV) infection, compared with 51 HIV-positive patients without hyper-IgE, both atopic and nonatopic, and three patients affected by the primary hyper-IgE syndrome, also revealed an increase in IgA and a severe decrease in B and CD4+ lymphocytes. Spontaneous in vitro synthesis of IgE by peripheral blood mononuclear cells was confirmed in both hyper-IgE conditions, together with increased levels of circulating eosinophil cationic protein. Serum-soluble CD23, usually increased in atopic conditions and hyper-IgE, was similar to that of normal control subjects in the HIV-positive patients with hyper-IgE. On the basis of our findings, we conclude that a hyper-IgE-like syndrome represents a distinct aspect of the clinical manifestations associated with HIV infection and that the immunologic mechanisms in this condition seem to differ from those known in primary hyper-IgE syndrome, because CD4+ TH2 type cells, which are currently believed to have a role in IgE production, are severely depleted in HIV-positive patients.

Lack of evidence for a superantigen in lymphocytes from HIV-discordant monozygotic twins

Objective:An HIV-associated superantigen (SAg) has been hypothesized. Here we test whether an SAg is functionally detectable in peripheral blood mononuclear cells (PBMC) from monozygotic twins discordant for HIV infection. Design and methods:The vβ selective T-cell depletion found in minor lymphocyte stimulation (Mls)-positive mice is caused by an SAg encoded by the mouse mammary tumour virus. Mis is a locus whose gene product stimulates a mixed lymphocyte reaction (MLR) in mice strains identical at the major histocompatibility complex locus. If an SAg is present in PBMC and/or sorted CD4+ cells from one HIV-infected monozygotic twin, it would stimulate PBMC from the corresponding healthy monozygotic twin in an MLR. In addition, if an SAg causes vβ-selective T-cell depletion in AIDS patients, a differential proliferation to a panel of staphylococcal enterotoxins (SE) of T lymphocytes from healthy and HIV-infected monozygotic twins should become measurable. Results:No positive MLR or significant differences in the SE-driven proliferation between the healthy and the HIV-infected twins were observed. Conclusions:Our results suggest that PBMC from the two HIV-infected twins do not express a functionally detectable SAg.

Serum eosinophil cationic protein (ECP) in human immunodeficiency virus (HIV) infection

HIV infection is immunologically characterized by progressive decrease of CD4’ lymphocytes and hypergammaglobulinemia. 1 Clinically, it spans from asymptomatic infection to full-blown AIDS, divided into definite stages by the Center for Disease Control classification.* A high incidence of atopic manifestations has been reported in HIV seropositive individuals3* ’ with increased serum levels of IgE.5 Recently, the rise of serum IgE has been related to the decrease of CD4+ cells.6 We selected 22 HIV seropositive subjects at different stages of disease, who presented allergic symptoms either for the first time or as a reexacerbation of previous atopic disease. In their sera, we measured the levels of total IgE, allergen-specific IgE, and ECP, a basic protein with cytotoxic properties released by EOSs, which is increased in sera and secretions of atopic patients.‘.’ As control subjects, we chose 25 healthy nonatopic subjects, 20 patients with acute recurrent infection (both bacterial and viral), and 29 HIV seropositive cases without history or present symptoms of atopy. Care was taken to match the HIV groups for age, sex, and disease stages. Detailed data on the composition of the groups are reported in Table I. Additional tests in HIV-positive subjects were white blood cell count, EOS count, both by standard methods, CD4’ lymphocyte count, with direct immunofluorescence with monoclonal anti-CD4 (OKT4, Ortho Diagnostic Systems, Raritan, N . J .) and read by flow cytometry (Cytoron, Ortho Diagnostic Systems), and serum levels of IgG, IgA, and IgM by nephelometry with a TDX analyzer (Abbott Diagnostics, Irving, Texas). Results of serum levels of IgE, mea-

Silent HIV infection

The period of latency between infection by the human immunodeficiency virus type-1 (HIV-1) and the production of specific antibodies to viral antigens may be prolonged and, occasionally, may last for years. This condition of seronegative infection could represent a serious risk of viral transmission from subjects who are unaware of their status. However, whether these individuals are actually infectious, especially through body fluids, has not been clarified. We have performed a prospective study in 65 high-risk individuals seronegative for HIV-1 antibodies for a prolonged period of time. Twelve of them (18%) were shown to be carriers of HIV-1 proviral sequences by the polymerase chain reaction (PCR). The virus was isolated from mitogen-stimulated peripheral blood lymphocytes in five out of ten subjects tested since the first positive PCR. In two of them, virus could also be isolated from cell-free plasma, subsequently they remained seronegative during 10 months of follow-up. These data indicate that delayed seroconversions may be associated with productive infection, suggesting that mechanism(s) other than viral latency may be responsible for the absence of antibody responses to HIV-1 proteins. Furthermore, our findings suggest that prolonged seronegative individuals can transmit HIV infection through their body fluids.

Differential course of HIV-1 infection and apolipoprotein E polymorphism

We studied the course of infection with human immunodeficiency virus type 1 (HIV-1) in relation to apolipoprotein E (APOE) polymorphism found for 209 Italians treated at Infectious Disease Clinics in Rome and Modena. Clinically, patients were classified into four groups according to the yearly rate of decline in CD4+ cell count (LTNP: long-term non-progression; SLOW, ’NORMAL’ or RAPID). Patients at both extremes of the clinical spectrum, i.e. those who rapidly progressed to AIDS and those with stable high CD4 cell counts, had few APOE ɛ4 and ɛ2 alleles (P = 0.04). Detailed clinical information was then used to construct four model-based clinical profiles using grade-of-membership analysis (GoM), predictive of APOE genotypic frequencies: 1. The clinical profile associated with good long-term prognosis lacked ɛ2 (P=0.01); 2. Disease progression to AIDS was associated with ɛ4 and ɛ2, most evident for zidovudine-lamivudine regimens without a protease inhibitor (P = 0.03); and, 3. AIDS patients had low ɛ4 and ɛ2 frequencies, consistent with a high mortality rate among ɛ4+ and ɛ2+ AIDS patients. These findings suggest allele-specific immunomodulatory effects involving inherited APOE isoform important enough to alter the clinical course of HIV infection and, possibly, drug efficacy. They imply a connection between lipid metabolism and immunity potentially relevant to common disorders.

Use of Component-Resolved Diagnosis (CRD) for Allergen Immunotherapy (AIT)

Opinion statementAllergen immunotherapy (AIT) is presently the only treatment able to modify the natural history of respiratory allergic disease. The essential condition for AIT to be effective is that the right allergen(s) is/are administered. The proportion of allergic patients showing multiple sensitizations to distinct airborne allergen sources has dramatically increased during the last decades, and this fact, along with the frequent co-recognition of highly cross-reacting pollen panallergens (i.e., profilin and polcalcin), may make a correct diagnosis virtually impossible by using the traditional allergen extracts for diagnosis. Many purified recombinant or natural allergens are currently available for the in vitro diagnosis of respiratory allergy. These represent an invaluable tool to prevent the inclusion of inappropriate allergens in AIT extracts, and the present article provides some suggestions for their rational use in everyday clinical practice.