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Biomedical subjects

Jean-Pierre Routy

Publications and source records attributed to Jean-Pierre Routy.

28 records · Page 2Linked to original sources
PubMed2003

HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity.

CD4+ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester-based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4+ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA- CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA- CCR7- effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-gamma. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-gamma. Longitudinal analysis of HIV epitope-specific CD4+ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-gamma-producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4+ T cell memory depends on IL-2-producing CD4+ T cells and that IFN-gamma only-producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-gamma only-producing cells that lack self-renewal capacity.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Clinical features of acute retroviral syndrome differ by route of infection but not by gender and age.

The rate of HIV disease progression is associated with the severity of the acute retroviral syndrome (ARS). We explored the clinical features of ARS by gender, age and route of infection among 378 individuals with documented ARS enrolled in 5 prospective cohort studies with similar enrollment criteria. No major differences were detected by gender or by age. Several symptoms were reported less frequently in the injecting drug users as compared with infection acquired through sexual contacts (either heterosexual or homosexual). This was observed in particular for fever (50% vs. 77%, p=.001), skin rash (21% vs. 51%, p=.001), pharyngitis (18% vs. 43%, p=.004), and myalgia (29% vs. 52%, p=.01). Genital ulcerations were present only in cases of sexual exposure to HIV. Injecting drug users had or reported symptoms associated with the ARS less frequently than persons acquiring HIV via sexual transmission.

Acute Disease↗
PubMed2002

Antiretroviral-drug resistance among patients recently infected with HIV.

BACKGROUND: Among persons in North America who are newly infected with the human immunodeficiency virus (HIV), the prevalence of transmitted resistance to antiretroviral drugs has been estimated at 1 to 11 percent. METHODS: We performed a retrospective analysis of susceptibility to antiretroviral drugs before treatment and drug-resistance mutations in HIV in plasma samples from 377 subjects with primary HIV infection who had not yet received treatment and who were identified between May 1995 and June 2000 in 10 North American cities. Responses to treatment could be evaluated in 202 subjects. RESULTS: Over the five-year period, the frequency of transmitted drug resistance increased significantly. The frequency of high-level resistance to one or more drugs (indicated by a value of more than 10 for the ratio of the 50 percent inhibitory concentration [IC50] for the subject's virus to the IC50 for a drug-sensitive reference virus) increased from 3.4 percent during the period from 1995 to 1998 to 12.4 percent during the period from 1999 to 2000 (P=0.002), and the frequency of multidrug resistance increased from 1.1 percent to 6.2 percent (P=0.01). The frequency of resistance mutations detected by sequence analysis increased from 8.0 percent to 22.7 percent (P<0.001), and the frequency of multidrug resistance detected by sequence analysis increased from 3.8 percent to 10.2 percent (P=0.05). Among subjects infected with drug-resistant virus, the time to viral suppression after the initiation of antiretroviral therapy was longer (P=0.05), and the time to virologic failure was shorter (P=0.05). CONCLUSIONS: The proportion of new HIV infections that involve drug-resistant virus is increasing in North America. Initial antiretroviral therapy is more likely to fail in patients who are infected with drug-resistant virus. Testing for resistance to drugs before therapy begins is now indicated even for recently infected patients.

Adolescent↗
PubMed2002

Human immunodeficiency virus (HIV)-specific effector CD8 T cell activity in patients with primary HIV infection.

The interferon-gamma ELISPOT assay was used to assess and compare the magnitude and breadth of human immunodeficiency virus (HIV)-specific CD8 T cell responses in treatment-naive subjects during the first year of HIV primary infection and during the chronic phase of infection. Twenty-five subjects tested within a year of exposure to HIV resulting in seroconversion and 20 subjects with chronic infection were screened for HIV peptide-specific activity by stimulating peripheral blood mononuclear cells with a panel of 5-21 HLA class I-restricted HIV peptides (mean, 11.2 +/- 3.5 HIV peptides). There was a significant correlation between the magnitude and breadth of HIV-specific effector responses and time elapsed from exposure (r=0.63 for magnitude vs. time and r=0.64 for breadth vs. time; P<.02, paired t test). Maximal breadth of the HIV gene product reactivity was achieved within 2 months of exposure for Nef-specific responses and by 4 months of exposure for responses directed to Env, Gag, and reverse transcriptase.

AIDS Vaccines↗
PubMed2002

Quantification of human herpesvirus 8 by real-time PCR in blood fractions of AIDS patients with Kaposi's sarcoma and multicentric Castleman's disease.

Few studies have assessed human herpesvirus 8 (HHV8) viremia levels in different HHV8-related pathologies, using sensitive and reproducible molecular assays. Our objective was to compare the HHV8 DNA load in serial blood samples (collected every 3 months for 1 year) from acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma (KS) and multicentric Castleman's disease (MCD). The HHV8 viral load was determined in both peripheral blood mononuclear cells (PBMC) and plasma fractions, using a competitive real-time polymerase chain reaction (PCR) assay developed in a LightCycler instrument (Roche Diagnostics). In six subjects with limited or extensive KS while on highly active antiretroviral therapy, the HHV8 DNA load was either undetectable (<50 copies/10(5) cells) or low (</=135 copies) in all PBMC samples. In contrast, the cellular HHV8 load was >1,000 copies in at least one of the samples from the two subjects with both KS and MCD. HHV8 DNA was detected in plasma only when the cellular viral load was >10,000 copies/10(5) cells. After chemotherapy, the HHV8 DNA load became undetectable in the MCD patients despite no changes in CD4 T-cell counts or highly active antiretroviral therapy (HAART) regimens. These results suggest that the pathogenesis of the two HHV8-associated diseases (i.e., KS and MCD) might be different, as only the latter was associated with important viremia in our patients.

AIDS-Related Opportunistic Infections↗
PubMed2002

Persistence and fitness of multidrug-resistant human immunodeficiency virus type 1 acquired in primary infection.

This study examines the persistence and fitness of multidrug-resistant (MDR) viruses acquired during primary human immunodeficiency virus infection (PHI). In four individuals, MDR infections persisted over the entire study period, ranging from 36 weeks to 5 years, in the absence of antiretroviral therapy. In stark contrast, identified source partners in two cases showed expected outgrowth of wild-type (WT) virus within 12 weeks of treatment interruption. In the first PHI case, triple-class MDR resulted in low plasma viremia (1.6 to 3 log copies/ml) over time compared with mean values obtained for an untreated PHI group harboring WT infections (4.1 to 4.3 log copies/ml). Increasing viremia in PHI patient 1 at week 52 was associated with the de novo emergence of a protease inhibitor-resistant variant through a recombination event involving the original MDR virus. MDR infections in two other untreated PHI patients yielded viremia levels typical of the untreated WT group. A fourth patient's MDR infection yielded low viremia (<50 to 500 copies/ml) for 5 years despite his having phenotypic resistance to all antiretroviral drugs in his treatment regimen. In two of these PHI cases, a rebound to higher levels of plasma viremia only occurred when the M184V mutation in reverse transcriptase could no longer be detected and, in a third case, nondetection of M184V was associated with an inability to isolate virus. To further evaluate the fitness of MDR variants acquired in PHI, MDR and corresponding WT viruses were isolated from index and source partners, respectively. Although MDR viral infectivity (50% tissue culture infective dose) was comparable to that observed for WT viruses, MDR infections in each case demonstrated 2-fold and 13- to 23-fold reductions in p24 antigen and reverse transcriptase enzymatic activity, respectively. In dual-infection competition assays, MDR viruses consistently demonstrated a marked replicative disadvantage compared with WT virus. These results indicate that MDR viruses that are generated following PHI can establish persistent infections as dominant quasispecies despite their impaired replicative competence.

Adult↗
PubMedDate not supplied

Virologic and immunologic response to a boosted double-protease inhibitor-based therapy in highly pretreated HIV-1-infected patients.

PURPOSE: To assess the virologic and immunologic response to a boosted double-protease inhibitor (PI) regimen of highly pretreated patients infected with HIV-1 and to examine the role of PI resistance and concentration of serum saquinavir. METHOD: In an open-label prospective study, lopinavir/ritonavir, saquinavir-sgc, lamivudine, and other nucleoside analogues were offered to highly pretreated patients who had advanced HIV-1 infection and who had failed at least 2 previous highly active antiretroviral therapy regimens including at least 1 nonnucleoside reverse transcriptase inhibitor. The relationship between baseline drug resistance and steady-state saquinavir serum levels and early (week 4) and sustained (week 48) virologic response was documented. RESULTS: 35 advanced HIV-1 patients were enrolled. The boosted double-PI regimen was well tolerated. Twenty-two (63%) of the 35 patients had a > 0.8 log(10) decrease in HIV viral load at week 4. After 48 weeks of follow-up, the 22 patients who remained on the study therapy had an average decrease in viral load of 1 log(10) and had a median increase in CD4 cells of 60 cell/microL. Multiple logistic regression analysis indicated that genotypic resistance to both PIs and the week-3 trough concentrations of saquinavir were associated with virologic outcome at week 4. The presence of > or = 6 lopinavir mutations [odds ratio (OR) 0.03; 95% CI 0.01 to 0.79] and the 48V mutation (OR 0.01; 95%CI <0.01 to 0.88) was independently associated with lower odds of achieving an early response, whereas a higher saquinavir concentration at week 3 (OR 8.36; 95% CI 1.28 to 54.70) was associated with greater odds of an early response. CONCLUSION: These findings suggest that baseline PI resistance and saquinavir concentration were associated with virologic response and should be considered when planning salvage therapy.

Adult↗
PubMedDate not supplied

Effect of protease inhibitor-based highly active antiretroviral therapy on survival in HIV-associated advanced Kaposi's sarcoma patients treated with chemotherapy.

OBJECTIVE: To determine whether the use of protease inhibitor (PI)-based antiretroviral (ARV) therapy had an impact on the survival of patients with human immunodeficiency virus (HIV) infection-associated Kaposi's sarcoma (KS) who were receiving systemic chemotherapy. METHOD: Records of 48 AIDS patients with extensive KS who received chemotherapy from 1995 to 1999 were reviewed. Analysis by presence or absence of PI treatment was undertaken, and patients who were receiving nonnucleoside reverse transcriptase inhibitors (NNRTIs) were excluded from the analysis. RESULTS: Median age was 38 years, and 47 patients were men having sex with men. Half of the patients (54%) had at least one prior AIDS-defining event. Median CD4 count at diagnosis of KS was 28 cells/microL (range, 1-625). Visceral KS was present in 33 patients (69%), and the remainder of patients had extensive and symptomatic cutaneous and/or mucous membrane involvement. All patients received at least one cycle of chemotherapy, including vincristine/bleomycin or an anthracycline-containing regimen. There was a significant difference in the median survival (MS) between the 28 patients (58%) treated with PI-based antiretroviral therapy (31 months [range, 1.8-48]) and the group not receiving PI (7 months [range, 1-28], p =.0001). In addition, 81% of patients in the PI group were alive at 18 months from initiation of chemotherapy versus 12% in the non-PI group. Twenty patients (71%) in the PI-treated group were able to discontinue chemotherapy for at least 1 month after remission of KS, in comparison to 3 of 20 (15%) patients in the group of patients who did not receive PI (p =.00001). Death due to KS occurred in 6 of 28 (21%) patients (total 9 deaths) in the PI group and 14 of 20 (70%) patients (total 18 deaths) in the non-PI group (p =.001). CONCLUSION: In a nonselected group of patients with advanced and extensive KS in a real-life clinical setting, our results show a survival benefit and a decrease in KS-related death for patients receiving chemotherapy and PI-based ARV therapy when compared to patients not receiving PI-based therapy. Discontinuation of chemotherapy in patients receiving PI-based antiretroviral therapy appears to be feasible in patients who attain remission of KS.

Adult↗