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A M Geretti

Publications and source records attributed to A M Geretti.

27 records · Page 2Linked to original sources
PubMed1997

Human immunodeficiency virus type 1 Rev- and Tat-specific cytotoxic T lymphocyte frequencies inversely correlate with rapid progression to AIDS.

Immunological correlates of AIDS-free survival after human immunodeficiency virus type 1 (HIV-1) infection are largely unknown. Cytotoxic T lymphocyte (CTL) responses are generally believed to be a major component of protective immunity against viral infections. However, the relationship between HIV-1-specific CTL responses and disease progression rate is presently unclear. Here we show in twelve HIV-1-infected individuals that detection of Rev-specific CTL precursors (CTLp) early in the asymptomatic stage, as well as detection of Rev- and Tat-specific CTLp later during follow-up, inversely correlate with rapid disease progression. No such correlation was found for detection of CTLp against Gag, RT or Nef. Further studies are required to determine whether a protective mechanism is indeed the basis of the observed correlation. The data presented are in agreement with the hypothesis that CTL against proteins that are important for early viral transcription and translation are of particular importance in protection from rapid disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Human immunodeficiency virus type 1 (HIV-1)--and Epstein-Barr virus--specific cytotoxic T lymphocyte precursors exhibit different kinetics in HIV-1--infected persons.

The frequencies of human immunodeficiency virus type 1 (HIV-1) Gag- and Epstein-Barr virus (EBV)-specific cytotoxic T lymphocyte precursors (CTLp) were studied longitudinally in peripheral blood mononuclear cells from 9 HIV-1-infected persons. By antigen-specific stimulation, HIV-1 Gag-specific CTLp were detected in vitro throughout the course of HIV-1 infection, even after the onset of overt disease. In 4 patients, however, HIV-1 Gag-specific CTLp frequencies declined over time in the presence of maintained EBV-specific CTLp. This decline was correlated with decreasing CD4 (r = .38; P < .05) and CD8 (r = .75; P < .001) cell numbers. The maintenance of EBV-specific CTLp in patients with low CD4 cell numbers indicated that EBV-specific CTL-mediated immunity may remain longer unaffected by HIV-1-induced immune dysfunction. Consistent with this observation, the growth of EBV-specific CTL could be supported in vitro by EBV-infected lymphoblastoid B cell lines, independent of both CD4 cells and exogenous cytokines.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Fine-specificity of cytotoxic T lymphocytes which recognize conserved epitopes of the Gag protein of human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 (HIV-1) Gag-specific cytotoxic T lymphocyte (CTL) responses were studied in seven seropositive long-term asymptomatic individuals (CDC A1) with stable CD4 counts for more than 8 years. Using a set of partially overlapping peptides covering the whole Gag, five 15-20-mer peptides were found to contain CTL epitopes. Further characterization of these epitopes revealed a new HLA-A25-restricted CTL epitope in p24, p24(203-212) ETINEEAAEW. This region of Gag is highly conserved in clades B and D of HIV-1. Naturally occurring amino acid sequences, containing p24(203)D (consensus HIV-1 clades A, C, F, G and H) or p24(204)I (HIV-2ROD) were not recognized by CTL recognizing the index peptide. No virus variants with mutations in this sequence were found in peripheral blood mononuclear cells from the HIV-1-infected individual concerned during the 8 year observation period, indicating that the virus had not escaped from the observed CTL response.

Amino Acid Sequence↗
PubMed1995

Vaccine-induced virus-neutralizing antibodies and cytotoxic T cells do not protect macaques from experimental infection with simian immunodeficiency virus SIVmac32H (J5).

To gain further insight into the ability of subunit vaccines to protect monkeys from experimental infection with simian immunodeficiency virus (SIV), two groups of cynomolgus macaques were immunized with either recombinant SIVmac32H-derived envelope glycoproteins (Env) incorporated into immune-stimulating complexes (iscoms) (group A) or with these SIV Env iscoms in combination with p27gag iscoms and three Nef lipopeptides (group B). Four monkeys immunized with recombinant feline immunodeficiency virus Env iscoms served as controls (group C). Animals were immunized intramuscularly at weeks 0, 4, 10, and 16. Two weeks after the last immunization, monkeys were challenged intravenously with 50 monkey 50% infectious doses of virus derived from the J5 molecular clone of SIVmac32H propagated in monkey peripheral blood mononuclear cells. High titers of SIV-neutralizing antibodies were induced in the monkeys of groups A and B. In addition, p27gag-specific antibodies were detected in the monkeys of group B. Vaccine-induced cytotoxic-T-lymphocyte precursors against Env, Gag, and Nef were detected on the day of challenge in the monkeys of group B. Env-specific cytotoxic-T-lymphocyte precursors were detected in one monkey from group A. In spite of the observed antibody and T-cell responses, none of the monkeys was protected from experimental infection. In addition, longitudinal determination of cell-associated virus loads at weeks 2, 4, 6, 9, and 12 postchallenge revealed no significant differences between vaccinated and control monkeys. These findings illustrate the need to clarify the roles of the different arms of the immune system in conferring protection against primate lentivirus infections.

Amino Acid Sequence↗
PubMed1994

Kinetics and specificities of the T helper-cell response to gp120 in the asymptomatic stage of HIV-1 infection.

Peripheral blood mononuclear cells from 36 asymptomatic HIV-1 seropositive individuals were tested longitudinally for in vitro T-cell proliferation and IL-2 production in response to synthetic peptides spanning the entire gp120 of HIV-1. At baseline, significant T-cell proliferative to pooled and individual peptides was observed in 15 of the 36 donors. After 12 months, proliferative responses to peptide pools were lost or decreased significantly in most donors. Responses appeared to fluctuate over time: at 12 months new recognition sites were detected in four of 10 donors showing T-cell proliferation at baseline, as well as in five of 15 donors with no previous proliferative responses. IL-2 production appeared to be a more sensitive and longer preserved parameter of T-helper cell function: at baseline the majority of donors with no T-cell proliferation produced IL-2 in response to pooled peptides. This response was not decreased significantly after 12 months. The overall patterns of response to both pooled and individual peptides were heterogeneous among donors. Multiple recognition sites were detected in both variable and conserved regions of gp120, but no pool or individual peptide was recognized by all responders. Functional T-cell responses were not statistically correlated to CD4+ cell percentile and absolute numbers.

Adult↗
PubMed1993

Selective in vitro expansion of HLA class I-restricted HIV-1 Gag-specific CD8+ T cells: cytotoxic T-lymphocyte epitopes and precursor frequencies.

OBJECTIVE: To identify HIV-1 Gag cytotoxic T-lymphocyte (CTL) epitopes and HLA restriction of their recognition, and to define precursor frequencies of HIV-1 Gag-specific CTL in the blood of seropositive individuals. METHODS: B-lymphoblastoid cell lines (B-LCL) infected with recombinant vaccinia viruses (rVV) containing a gene coding for HIV-1 Gag (rVV-Gag) were fixed with paraformaldehyde (PFA) and used as antigen-presenting cells (APC) to stimulate peripheral blood mononuclear cells (PBMC) from asymptomatic HIV-seropositive individuals. Specific CTL activity was determined in 51Cr-release assays using B-LCL as targets after infection with rVV-Gag or after pulsing with partially overlapping peptides spanning the Gag sequence. RESULTS: In vitro stimulation resulted in an increased number of CD8+ T cells and CD45R0+ and HLA-DR+ cells. Gag-specific cytotoxicity, mediated predominantly by HLA class I-restricted CD8+ CTL, was observed in all seven individuals studied. Multiple HLA-restricted CTL epitopes were identified with a single culture from one of the individuals. Gag-expressing APC were successfully used as stimulator cells in limiting dilution analysis to determine CTL precursor (CTLp) frequencies. CONCLUSION: PFA-fixed rVV-Gag-infected autologous B-LCL can be used as stimulator cells in bulk PBMC cultures to identify CTL epitopes and to determine CTLp frequencies. This method will facilitate the analysis of HIV-1-specific CTL responses in HIV-infected and vaccinated individuals.

Antigen-Presenting Cells↗
PubMedDate not supplied

Simian immunodeficiency virus as a model of human HIV disease.

Because of strong clinical, pathological, virological and immunological analogies with HIV infection of humans, infection of macaques with SIV provides a valuable model for exploring crucial issues related to both the pathogenesis and prevention of HIV infection. The model has offered a unique setting for the preclinical evaluation of drugs, vaccines and gene-therapies against HIV, and has helped to identify many virus and host determinants of lentiviral disease. For instance, the importance of an intact nef gene for efficient lentivirus replication and disease induction, and the protective ability of live attenuated, nef-deleted viruses have been first demonstrated in macaques using molecular clones of SIV. More recently, the development of chimeric HIV-SIV vectors able to establish infection and induce disease in macaques has provided new opportunities for the evaluation of vaccination strategies based upon HIV antigens. The aim of this review is to describe the natural course of SIV infection in macaques and to outline how this model has contributed to our understanding of the complex interaction between lentiviruses and host immune system.

Animals↗
PubMedDate not supplied

Towards an HIV-1 vaccine: lessons from studies in macaque models.

The development of a safe and effective vaccine for the prevention of AIDS has thus far proven to be extremely difficult, at least in part due to complexities associated with HIV-1 and its pathogenesis. The recent description of individuals transiently infected with HIV-1, as well as persons who survived HIV-1 infection for more than 15 years, indicates the ability of the immune response of certain individuals to control HIV-1 infection. Moreover, vaccination-challenge experiments in macaques infected with simian immunodeficiency virus have shown that protection against infection or development of disease may be achieved in the absence of sterilizing immunity, suggesting that the goals for AIDS vaccine development may have to be redefined. In addition, evaluation of new lentivirus vaccine strategies may largely benefit from the use of the newly developed chimeric simian-human immunodeficiency viruses, allowing the testing of HIV-1 antigen based vaccines in macaques.

AIDS Vaccines↗