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Charles R Rinaldo

Publications and source records attributed to Charles R Rinaldo.

31 records · Page 2Linked to original sources
PubMed2003

Association of polymorphisms in human leukocyte antigen class I and transporter associated with antigen processing genes with resistance to human immunodeficiency virus type 1 infection.

To examine the relationship of human leukocyte antigen (HLA) class I and transporter associated with antigen processing (TAP) genes with resistance to human immunodeficiency virus type 1 (HIV-1) infection, 100 HIV-seronegative men who had been exposed repeatedly to HIV-1 were compared with 184 men who had seroconverted to HIV positive and had lower risk. In the univariate analysis, the HLA-A2 supertype, excluding A*0201 (HLA-A2/6802 supertype; odds ratio [OR], 4.45; 95% confidence interval [CI], 1.33-4.84; P=.009) was associated with resistance to HIV-1 infection; the effect was the result of the presence of the A*0205 subgroup alleles. Susceptibility was associated in univariate analysis with the B*35 Px alleles (OR, 0.29; 95% CI, 0.08-0.99; P=.037), which suggests that differential preferences for amino acids at the C terminus may influence peptide-binding capacity. TAP2 Ala665 was also associated with resistance (OR, 2.26; 95% CI, 1.35-3.79; P=.002), perhaps because of its higher efficiency in transporting peptides, thus eliciting a greater CD8(+) T cell response, or because of linkage disequilibrium. In multivariate logistic analysis, only the A*0205 subgroup (OR, 5.56; 95% CI, 1.34-23.10; P=.018) and the TAP2 Ala665 (OR, 2.22; 95% CI, 1.28-3.84; P=.005) were associated with resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

When to initiate highly active antiretroviral therapy: a cohort approach.

The appropriate immunologic stage of human immunodeficiency virus infection at which to initiate highly active antiretroviral therapy (HAART) among asymptomatic persons is a core question. A cohort approach using longitudinal data from the US Multicenter AIDS Cohort Study was used to mimic a clinical trial to assess the risk of acquired immunodeficiency syndrome (AIDS) by timing of therapy. Three treatment groups were defined according to CD4(+) count (cells/microl) at HAART initiation between July 1995 and January 2000: <200 (deferral to <200, n = 127), 200-349 (deferral to 200-349, n = 130), and 350-499 (immediate treatment, n = 92). Survival analysis was used to compare time to AIDS between groups from the index visit until July 2000. The index visit for the immediate group was the one prior to HAART initiation. For the deferral groups, the index visit was a randomly selected, pre-HAART, AIDS-free visit after July 1990 at which CD4(+) counts were 350-499 cells/microl. This strategy accounted for lead time bias. Compared with immediate treatment, the relative hazards of AIDS were 2.68 (p = 0.003) and 1.05 (p = 0.897) for deferral to <200 cells/microl and 200-349 cells/ micro l, respectively. These results support recent US public health guidelines for deferring HAART initiation until a count of <350 cells/microl. Furthermore, results suggest a potential threshold for HAART initiation in the neighborhood of 275 cells/microl.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Non-Hodgkin's B cell lymphoma in persons with acquired immunodeficiency syndrome is associated with increased serum levels of IL10, or the IL10 promoter -592 C/C genotype.

Interleukin-10 (IL10) may contribute to the development of non-Hodgkin's B cell lymphoma, especially in the context of acquired immunodeficiency syndrome (AIDS), where lymphoma incidence is greatly increased. Utilizing specimens from the Multicenter AIDS Cohort Study (MACS) obtained prior to diagnosis of AIDS-associated lymphoma, detectable serum human IL10 was seen much more frequently in lymphoma cases (n = 61, 26%) compared to CD4-matched AIDS controls (5%, P = 0.004), or to HIV-infected (2%, P = 0.002) or HIV uninfected subjects (0%, P = 0.0003). In longitudinal studies, detectable IL10 occurred at times closest to but preceding lymphoma diagnosis (P = 0.01). In an independent genetic analysis of single-nucleotide polymorphisms within the promoter region of the IL10 gene in 1157 MACS subjects, a high IL10-expressing genotype (-592 C/C) was overrepresented among lymphoma subjects (P = 0.009), even when controlling for race (P = 0.006). These results suggest that elevated serum IL10 or the IL10 promoter -592 C/C genotype are associated with development of AIDS lymphoma.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Priming of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cell responses by dendritic cells loaded with HIV-1 proteins.

Proteins may serve as ideal CD8(+) T cell immunogens for human immunodeficiency virus type 1 (HIV-1) if they can be delivered to and processed through the human leukocyte antigen class I pathway. This study shows that human blood monocyte-derived dendritic cells loaded with liposome-complexed HIV-1 proteins and matured with CD40 ligand can prime CD8(+) T cells to HIV-1 in vitro. Whole HIV-1 protein in liposome may be an effective immunogen for HIV-1 vaccine protocols.

AIDS Vaccines↗
PubMed2002

Identification of an HLA A*0201-restricted CD8(+) T-cell epitope for the glycoprotein B homolog of human herpesvirus 8.

Human herpesvirus 8 (HHV-8; Kaposi sarcoma-associated herpesvirus)-specific cytotoxic T-lymphocyte (CTL) and interferon-gamma (IFN-gamma) responses to proteins produced during the lytic cycle of HHV-8 replication are mediated by HLA class I-restricted, CD8(+) T cells. We have characterized the fine specificity of the CD8(+) T-cell response to 25 peptides derived from 5 HHV-8 lytic cycle proteins based on a prediction model for HLA A*0201 binding motifs. One of the 25 HLA A*0201 peptides derived from the glycoprotein B (gB) homolog of Epstein-Barr virus (gB(492-500); LMWYELSKI; single-letter amino acid codes) bound to HLA A*0201 and stimulated IFN-gamma responses in CD8(+) T cells from HHV-8(+), HLA A*0201 persons, but not HHV-8-seronegative or non-HLA A*0201 persons. The peptide also induced IFN-gamma and CTL reactivity to naturally processed gB protein. The peptide was a major immunogenic epitope of HHV-8 as indicated by induction of IFN-gamma responses in peripheral blood mononuclear cells from 5 of 5 HHV-8 seropositive, HLA A*0201 persons when gB(492-500) was presented by autologous dendritic cells. T-cell reactivity to gB(492-500) was not related to detectable HHV-8 DNA in the blood. These data show that CD8(+) T cells recognize an HLA A*0201-restricted epitope for HHV-8 lytic cycle protein gB, particularly when presented by dendritic cells. This epitope may be important in control of HHV-8 infection by CD8(+) T cells.

Amino Acid Sequence↗
PubMed2002

Predictive value of immunologic and virologic markers after long or short duration of HIV-1 infection.

Laboratory markers that predict HIV-1 disease progression include plasma viral burden, CD4+ T-cell count, and CD38 expression on CD8 T cells. To better understand whether the predictive value of these markers is dependent on how long an individual has been infected, we analyzed data from the Multicenter AIDS Cohort Study early (median = 2.8 years) and late (median = 8.7 years) in the course of infection. Overall, we found that HIV RNA and CD38 levels were similarly predictive of AIDS early on compared with a relatively weaker CD4 cell count signal. Later in the course of infection, CD38 level remained the strongest predictive marker and CD4 cell count registered a marked increase in prognostic power. Among untreated individuals, there was little difference in prognosis (median time to AIDS) associated with given marker values regardless of infection duration. The prognosis given a specific viral load level tended to deteriorate late in the course of infection among those undergoing treatment with monotherapy or combination therapy, however. These data provide a unique historical look at the predictive value and prognostic significance of HIV-1 disease markers at different stages of infection in a large cohort, with direct relevance to current patients who are untreated or for whom treatment is ineffective.

ADP-ribosyl Cyclase↗
PubMed2002

CD8+ T-cell immunity to HIV infection.

Fifteen years after the first, definitive reports of HIV-1-specific, CD8+ T cells [147,148], there is ample evidence for the importance of these cells in control of HIV-1 infection. As much is known of their role in the natural history of HIV-1 infection and their cellular and molecular mechanisms of reactivity than of T-cell responses to any other human virus. Indeed, HIV-1-related research has led the scientific field in revealing many new, fundamental principles of cellular immunity in the last 15 years. From these data, there are multiple, posited mechanisms for loss of CD8+ T-cell control of HIV-1 infection. These include both intrinsic defects in T-cell function and loss of T-cell recognition of HIV-1 because of its extraordinary genetic diversity and disruption of antigen presentation. Efforts have begun on devising approaches to reverse these immune defects in infected individuals and develop vaccines that induce T-cell immunity for protection from infection. Combination antiretroviral drug regimens now provide exceptional, long-lasting control of HIV-1 infection, even though they do not restore anti-HIV-1 T-cell immunity fully in persons with chronic HIV-1 infection. Very encouraging results show that such treatment can maintain normal T-cell reactivity specific for this virus in some persons with early HIV-1 infection. Unfortunately, the antiviral treatment does not cure the host of this persistent, latent virus. This has led to new strategies for immunotherapeutic intervention to enhance the level and breadth of the T-cell repertoire specific for the host's residual virus in persons with chronic HIV-1 infection. Although the principles of immunotherapy stem from early in the last century, modern era approaches are integrating highly sophisticated, molecular and cell biology reagents and methods for control of HIV-1 infection. The most promising immunotherapies are autologous virus activated in vivo by STI or administered in autologous DC that have been engineered ex vivo. There are also compelling rationales supported by animal models and early clinical trials for use of cytokines and chemokines as recombinant proteins or DNA to augment anti-HIV-1 T-cell reactivity and trafficking of T cells and APC to tissue sites of infection. For prevention of HIV-1 infection, the discouragingly poor results of vaccine development in the late 1980s and early 1990s have led to very encouraging, recent studies in monkeys that show partially protective and possibly sterilizing immunity. Finally, clinical trials of new-generation DNA and live vector vaccines already have indications of improved induction of HIV-1-specific T-cell responses. Knowledge of HIV-1-specific T-cell immunity and its role in protection from HIV-1 infection and disease must continue to expand until the goal of complete control of HIV-1 infection is accomplished.

CD8-Positive T-Lymphocytes↗
PubMed2002

Rapid and sensitive detection of respiratory virus infections for directed antiviral treatment using R-Mix cultures.

BACKGROUND: The development of new anti-influenza drugs has led to concerns regarding the impact on healthcare costs if they are used indiscriminately. Restricting their use to proven influenza virus infections has the potential to overcome costly inappropriate therapy. However, conventional culture (CC) does not generate results quickly enough to facilitate the timely initiation of treatment, and rapid detection tests have suboptimal sensitivity. We therefore investigated a new rapid culture system (R-Mix) that contains a mixture of two cell lines and detects respiratory viruses within 24 h. OBJECTIVES: To compare the analytical sensitivity of R-Mix with CC and rapid detection methods, for the detection of influenza and other respiratory viruses. To compare the clinical sensitivity of R-Mix with CC and direct antigen detection for the detection of respiratory viruses in primary and acute care settings. STUDY DESIGN: Stock cultures of influenza virus were titrated and tested by R-Mix, ZstatFlu and FLU OIA. Stock cultures of adenovirus and parainfluenza virus type 3 were titrated and tested by R-Mix and CC. Specimens, which had previously tested positive for influenza viruses, were titrated and tested by R-Mix and CC. In symptomatic patients, the majority of whom were from primary care settings, 124 sequential specimens were tested for influenza viruses by immunofluorescent direct antigen detection and R-Mix. A separate set of 111 sequential specimens, from various symptomatic patient groups, were tested for influenza viruses by CC and R-Mix. Additionally, in acute care patients being surveillance tested during periods of immunosuppression, 155 specimens were tested for respiratory viruses (influenza A and B, parainfluenza 1-3, adenovirus and respiratory syncytial virus (RSV)) by CC and R-Mix. RESULTS: With titrated stock cultures, R-Mix showed an analytical limit of detection of ten infectious virus particles per vial for influenza A, compared with 100,000 particles per test for FLU OIA and 1,000,000 for ZstatFlu. R-Mix also showed a 100-fold greater sensitivity for the detection of influenza A and equivalent sensitivity for the detection of influenza B when compared with CC in titrated known positive specimens. Further, it showed equivalent sensitivity to CC for the detection of adenovirus and parainfluenza virus type 3 in titrated stock cultures. Among prospective specimens from symptomatic patients, the sensitivity of R-Mix, CC and direct antigen detection tests (DAT) for influenza virus detection, was 100, 67 and 66%, respectively, and the specificity was 100, 100 and 98%, respectively. In surveillance specimens from immunosuppressed patients, the sensitivities of R-Mix and CC for respiratory virus detection were equivalent. Moreover, R-Mix results were available within 24 h, and by altering the antibody staining reagents either influenza viruses, or all seven major respiratory viruses, could be detected and distinguished in a single test. CONCLUSIONS: R-Mix is a simple, rapid and sensitive system for the detection of influenza viruses that facilitates the restriction of antiviral drugs to patients with culture-confirmed infections.

Adenoviridae↗
PubMed2002

Distinguishing cytomegalovirus (CMV) infection and disease with CMV nucleic acid assays.

Human cytomegalovirus (CMV) continues to be a significant cause of morbidity and mortality among transplant recipients. Molecular assays have been developed for the detection and quantification of CMV nucleic acid. In evaluating the clinical utility of these assays, correlations with clinical outcome are essential. The Amplicor CMV Monitor and NucliSens CMV pp67 tests were compared to the CMV antigenemia assay for 45 transplant recipients and 1 patient with Wegener's granulomatosis. Twenty-three patients remained antigenemia negative throughout the monitoring period, none of whom developed CMV disease. In this patient group, both the Amplicor and NucliSens assays showed very high specificity; only 1 of the 324 specimens assayed by NucliSens and none of the 303 specimens assayed by Amplicor were positive. Twenty-three patients were antigenemia positive during the monitoring period, 12 of whom developed 13 episodes of symptomatic CMV disease. In this patient group, the NucliSens assay was positive at or before the development of symptoms in 12 of the 13 episodes of CMV disease. All eight patients with symptomatic CMV disease who were tested by the Amplicor assay were positive at or before the development of disease. For the 11 asymptomatic patients, the NucliSens assay was positive less frequently than the antigenemia or Amplicor assays. The NucliSens assay was more likely to be positive at higher antigenemia or viral load levels. Both the NucliSens and Amplicor assays appear to have clinical utility in monitoring patients for CMV disease.

Cytomegalovirus↗
PubMed2002

Induction of anti-human immunodeficiency virus type 1 (HIV-1) CD8(+) and CD4(+) T-cell reactivity by dendritic cells loaded with HIV-1 X4-infected apoptotic cells.

T-cell responses to X4 strains of human immunodeficiency virus type 1 (HIV-1) are considered important in controlling progression of HIV-1 infection. We investigated the ability of dendritic cells (DC) and various forms of HIV-1 X4 antigen to induce anti-HIV-1 T-cell responses in autologous peripheral blood mononuclear cells from HIV-1-infected persons. Immature DC loaded with HIV-1 IIIB-infected, autologous, apoptotic CD8(-) cells and matured with CD40 ligand induced gamma interferon production in autologous CD8(+) and CD4(+) T cells. In contrast, mature DC loaded with HIV-1 IIIB-infected, necrotic cells or directly infected with cell-free HIV-1 IIIB were poorly immunogenic. Thus, HIV-1-infected cells undergoing apoptosis serve as a rich source of X4 antigen for CD8(+) and CD4(+) T cells by DC. This may be an important mechanism of HIV-1 immunogenicity and provides a strategy for immunotherapy of HIV-1-infected patients on combination antiretroviral therapy.

Apoptosis↗
PubMed2002

Induction of mucosal protection against primary, heterologous simian immunodeficiency virus by a DNA vaccine.

An effective vaccine against human immunodeficiency virus (HIV) should protect against mucosal transmission of genetically divergent isolates. As a safe alternative to live attenuated vaccines, the immunogenicity and protective efficacy of a DNA vaccine containing simian immunodeficiency virus (SIV) strain 17E-Fr (SIV/17E-Fr) gag-pol-env was analyzed in rhesus macaques. Significant levels of cytotoxic T lymphocytes (CTL), but low to undetectable serum antibody responses, were observed following multiple immunizations. SIV-specific mucosal antibodies and CTL were also detected in rectal washes and gut-associated lymphoid tissues, respectively. Vaccinated and naive control monkeys were challenged intrarectally with SIV strain DeltaB670 (SIV/DeltaB670), a primary isolate whose env is 15% dissimilar to that of the vaccine strain. Four of seven vaccinees were protected from infection as determined by the inability to identify viral RNA or DNA sequences in the peripheral blood and the absence of anamnestic antibody responses postchallenge. This is the first report of mucosal protection against a primary pathogenic, heterologous isolate of SIV by using a commercially viable vaccine approach. These results support further development of a DNA vaccine for protection against HIV.

Amino Acid Sequence↗
PubMedDate not supplied

Proinflammatory cytokines in HIV disease-a review and rationale for new therapeutic approaches.

Antiretroviral drugs currently in use for treating HIV-1 infection are very effective at maintaining low viral loads and clinical stability, but have been limited by their inability to eradicate virus in infected individuals, resulting in the need for indefinite therapy. The inability of antiretroviral drug therapy to eliminate HIV-1 infection is thought to be due to incomplete restoration of host immunity to the virus. New strategies to improve control of HIV-1 infection during antiretroviral therapy should target enhancement of host immunity. Proinflammatory cytokines are the central mediators of both innate and adaptive immunity, and modulation of these cytokines has been shown to alter anti-HIV-1 reactivity in vitro. Modulation of proinflammatory cytokines could therefore be utilized in strategies for immunotherapy of HIV-1 infection. The ultimate goal is to find regimens that could more durably suppress viral replication and potentially eliminate the need for indefinite antiretroviral therapy. This review presents what is known about the dysregulation of proinflammatory cytokines in HIV-1 infection, highlighting newly available immune-based therapies that could augment antiretroviral drug therapies.

Anti-HIV Agents↗