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S Rusconi,
P Vitiello,
F Adorni,
B Bruzzone,
A De Luca,
V Micheli,
P Meraviglia,
R Maserati,
M Di Pietro,
G Colao,
G Penco,
A Di Biagio,
G Punzi,
L Monno,
M Zazzi
[show abstract]
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ABSTRACT: Raltegravir (RAL) is the only licensed human immunodeficiency virus (HIV) integrase inhibitor. The factors associated with the virological response to RAL-containing regimens and the prevalence of integrase mutations associated with RAL failure deserve further investigation. From the Antiretroviral Resistance Cohort Analysis database, we selected triple-class-experienced subjects failing their current treatment with complete treatment history available. Selection criteria included HIV-RNA, CD4 count and HIV genotype within 3 months of RAL initiation. Factors associated with 24-week response were analysed; genotypic sensitivity scores (GSS) and weighted-GSS were evaluated. Virological response was achieved in 74.3% of 105 subjects. Mutations associated with RAL failure were detected in 12/24 subjects with an integrase genotype, with the prevalence of Q148H + G140S. Each extra unit of GSS (p 0.05, OR 2.62; 95% CI 1.00-6.87). was found to be a associated with response. Weighted-GSS had borderline statistical significance (p 0.063, OR 2.04; 95% CI 0.96-4.33) When stratifying for different cut-offs (<1 as reference, 1-1.49, ≥1.5), a borderline significant increase in the probability of response appeared for GSS ≥1.5 (p 0.053, OR 4.00; 95% CI 0.98-16.25). GSS ≥1 showed the highest sensitivity, 82.6%. Receiver operating characteristic curves depicted the widest area under the curve (0.663, p 0.054) of GSS ≥1. Unresponsiveness to RAL-containing regimens among triple-class-experienced subjects was low. The activity of the background regimen was strongly associated with response. Although few integrase genotypes were available at failure, half of these were without integrase resistance mutations. The substantial rate of RAL failure in the absence of known RAL-resistance mutations may be associated with adherence issues and this issue warrants further analysis in longer observations.
Clinical Microbiology and Infection 01/2013; · 4.54 Impact Factor
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A. Antinori,
A. Ammassari,
C. Torti,
P. Marconi,
M. Andreoni,
G. Angarano,
S. Bonora,
A. Castagna,
R. Cauda,
M. Clerici, [......],
S. Lo Caputo,
F. Mazzotta,
F. Montella,
C. Mussini,
C. F Perno,
M. Puoti,
G. Rizzardini, S. Rusconi,
V. Vullo,
G. Carosi
[show abstract]
[hide abstract]
ABSTRACT: Background:
Individuals with advanced HIV infection naïve to antiretroviral therapy represent a special population of patients frequently
encountered in clinical practice. They are at high risk of disease progression and death, and their viroimmunologic response
following the initiation of highly active antiretroviral therapy may be more incomplete or slower than that of other patients.
Infection management in such patients can also be complicated by underlying conditions, comorbidities, and the need for concomitant
medications.
Aim:
To provide practical guidelines to those clinicians providing care to HIV-infected patients in terms of diagnostic assessment,
monitoring, and treatment.
Conclusions:
The principals of antiretroviral treatment in asymptomatic naïve patients with advanced HIV infection are the same as those
applicable to the general population with asymptomatic HIV infection. Naïve patients with advanced HIV infection and a history
of AIDS-defining illnesses urgently need antiretroviral treatment, with the choice of antiretroviral regimen and timetable
based on such factors as concomitant treatment and prophylaxis, drug interactions, and potential concomitant drug toxicity.
Finally, an adequate counseling program – both before and after HIV-testing – that includes aspects other than treatment adherence
monitoring is a crucial step in disease management.
Infection 04/2012; 37(3):270-282. · 2.66 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Since recent observations demonstrated that extended resistance to protease inhibitors, nucleosidic and non - nucleosidic retrotranscriptase inhibitors (PI, NRTI, NNRTI) is a marker of disease progression and death, it is a matter of the greatest importance that experienced human immunodeficiency virus (HIV) - infected patients with limited therapeutic options receive a suppressive therapy pending the availability of at least two new antiretroviral drugs. Aim of the present study is to evaluate if the GSS score, calculated by analyzing the resistance to historical antiretroviral drugs and drug classes, is still relevant since several new potent drugs and drug classes entered the current clinical use.
Taking into account patients without suppression of HIV replication for ≥ 6 months from October 2008 and October 2009, we analyzed viroimmunological and resistance data of 38 outpatients starting their last antiretroviral regimen including at least one of the following: maraviroc, enfuvirtide, raltegravir, etravirine, darunavir/ritonavir or tipranavir/ritonavir. Mutations present in all available genotypic resistance tests were recorded for each patient and then correlated to GSS value, assessed using the last genotypic ribonucleic acid (RNA) resistance test. GSS was studied as predictor of virological treatment outcome by univariate and multivariate logistic regression.
At 48 weeks, undetectable viral load was obtained in 80% of patients without difference between GSS classes (HIV-RNA median < 50 copies/ml); 95.8% of patients with baseline HIV-RNA < 50,000 copies/ml obtained virological suppression (p=0.003). 48 weeks CD4+ median value was 412 cells/μl considering GSS1 and 300 cells/μl for combined GSS2 and GSS3 scores. Data also showed a > 60% recurrence of specific mutations for NRTI: M41L, M184IV, L210W, T215FY, K219EQ and 75% for D67N. K103N and Y181CIV mutations for NNRTI persisted in 35% of cases and their prevalence incresed in parallel with the number of GRTs. About 60% of tests reported L10FIRVC, M36ILV, M46IL, I54VLAMTS, V82AFTSLI, and L90M mutations in the protease region. 63P mutation was found in a total number of GRTs close to 80%. This percentages, when correlated to GSS, revealed a distinct pattern for most mutations, that showed a greater prevalence for GSS = 2. Conversely, only NNRTI 181CIV and NRTI 210W showed larger numbers in GSS1 and GSS3.
Single drugs belonging to new antiretroviral classes did not correlate to viroimmunological success for any GSS. High frequency and recurrence over GRTs for specific mutations confirm their key role following the exposure to ARVs classes. A baseline HIV-RNA < 50,000 cp/ml is a predictor of therapeutic success and a carefully selected HAART based upon the evaluation of GRTs can favorably influence the immunovirologic response.
Current HIV research 12/2011; 9(8):625-9. · 1.98 Impact Factor
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P Di Vincenzo, S Rusconi,
F Adorni,
P Vitiello,
F Maggiolo,
D Francisci,
A Di Biagio,
L Monno,
A Antinori,
E Boeri,
G Punzi,
C-F Perno,
A Callegaro,
B Bruzzone,
M Zazzi
[show abstract]
[hide abstract]
ABSTRACT: To evaluate whether etravirine (TMC125) might be effective in patients failing therapy with current nonnucleoside reverse transcriptase inhibitors (NNRTIs), we analysed the prevalence of TMC125 mutations and the possible determinants of genotypic resistance to this drug among sequences reported to a large database in Italy [Antiretroviral Resistance Cohort Analysis (ARCA)].
We analysed the prevalence of TMC125 resistance-associated mutations (RAMs) and the TMC125 weighted genotypic score (WGS) together with the determinants of genotypic resistance. A total of 5011 sequences from 2955 patients failing NNRTI therapy were evaluated.
Among the sequences in ARCA, 68% had at least one and 9.8% at least three TMC125 RAMs, whereas 31% had a WGS>2. Frequent RAMs were Y181C, G190A, K101E and A98G, whereas V179F, Y181V and G190S appeared in <5% of sequences. Multivariate analysis revealed a higher risk of developing at least three TMC125 RAMs associated with both nevirapine and efavirenz exposure, whereas CD4 counts > or = 200 cells/microL retained their protective effect. An increased risk of WGS>2 was linked to higher HIV RNA values (maximum risk at >5 log(10) copies/mL) and nevirapine exposure; CD4 counts > or = 200 cells/microL were protective.
The prevalence of TMC125 resistance mutations in the ARCA cohort was 68%. The DUET studies showed that at least three TMC125-associated mutations were required to impair the efficacy of the drug and Y181C/V, V179F and G190S had the greatest effect on response. The prevalence of these mutations among the patients examined in our study was low. However, WGS>2 was found for one-third of our sequences. Previous nevirapine exposure was associated with an increased risk of having WGS>2 (adjusted odds ratio 1.76).
HIV Medicine 03/2010; 11(8):530-4. · 3.01 Impact Factor
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Clinical and Experimental Immunology - CLIN EXP IMMUNOL. 01/2008; 102(1):26-30.
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B. Castelnuovo,
E. Chiesa, S. Rusconi,
F. Adorni,
M. Bongiovanni,
S. Melzi,
P. Cicconi,
F. Tordato,
L. Meroni,
T. Bini,
A. d’Arminio Monforte
[show abstract]
[hide abstract]
ABSTRACT: Presented here are the results of a cohort study conducted on 3,483 consecutive HIV/AIDS patients between January 1993 and December 2000 to determine trends in AIDS incidence and presentation. The incidence of AIDS was calculated in the general population and examined further according to gender, age ( or >49 years), and heterosexual behaviour as a risk factor for HIV. Multivariate analysis was used to identify variables associated with AIDS presenters (defined as patients diagnosed with AIDS within 1month of the first HIV-positive test). The numbers of patients with AIDS classified as (i) AIDS presenters, (ii) known HIV-positive patients on antiretroviral treatment, and (iii) known HIV-positive patients not receiving antiretroviral treatment were calculated. The overall incidence of AIDS decreased over time, mainly due to the lower number of patients on antiretroviral treatment developing AIDS. Factors associated with a higher risk of being an AIDS presenter were male gender and year of HIV diagnosis. Among patients with AIDS, the proportion of AIDS presenters increased from 13.8% prior to 1997 (when protease inhibitors were introduced in Italy) to 32.5% after 1997. Variables predictive of being an AIDS presenter were male gender, age at diagnosis, and AIDS diagnosis in the years 1997–2000. Heterosexuals had a higher risk of being AIDS presenters and a lower risk of being HIV-positive and not receiving antiretroviral treatment than intravenous drug users. In Italy, AIDS occurs mainly in subjects unaware of their HIV status (especially males, the elderly, and those infected heterosexually) or in patients refusing antiretroviral therapy (mainly intravenous drug users who do not refer to specialised centres).
European Journal of Clinical Microbiology 10/2003; 22(11):663-669. · 2.86 Impact Factor
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Journal of HIV therapy 09/2001; 6(3):51-5.
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A d' Arminio Monforte,
F Adorni,
L Meroni,
T Bini,
L Testa,
E Chiesa,
S Melzi, S Rusconi,
S Sollima,
M Galli,
M Moroni
[show abstract]
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ABSTRACT: The aim was to evaluate whether the three-month CD4 cell counts are a reliable predictor of the long-term clinical outcome of HAART-treated patients, by an observational study of 585 patients initiating HAART in a clinical setting. Clinical failure was defined as the occurrence of new or recurrent AIDS-defining events or death, and was analysed by means of intention-to-treat, univariate and multivariate analyses. An adjusted Cox regression model was used to evaluate the effect of three-month CD4+ counts on clinical outcome. Clinical failure occurred in 65 patients (11.1%) during a median follow-up of 31 months (1-65) as a result of new AIDS-defining events (ADEs) in 48 patients, ADE recurrence in six, and death in 11. The mean (median; range) CD4+ counts were 156/microL (155; 4--529) in patients with and 362/microL (326; 18--1162) in patients without clinical failure (P < .0001). Moreover, the proportion of patients with mean CD4+ counts < 200 microL was higher in those experiencing subsequent clinical failure (chi2: 41.11; P< .00001). Multivariate analysis showed that baseline CD4+ counts < 50 microL, HIV-RNA > 100,000 copies/mL and AIDS at baseline predicted failure; after adjusting for three-month CD4+ counts, this marker was the only one independently associated with clinical failure (HR 2.93; 95% Cl: 1.16--7.38). The three-month immunologic response is a reliable predictor of long-term clinical outcome.
Biomedecine [?] Pharmacotherapy 03/2001; 55(1):16-22. · 2.00 Impact Factor
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[show abstract]
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ABSTRACT: The aim of this study (the RESCUE trial) was to verify the effect of a shift from a lamivudine-containing to a didanosine-containing regimen on viral replication in HIV-1-infected subjects who had experienced prior treatment failure. Sixteen patients (didanosine-experienced in 14/16 cases) were consecutively enrolled: eight patients shifted from lamivudine to didanosine without other changes in their drug regimen. The other eight shifted from lamivudine to didanosine and changed one or more of their other drugs according to their physician's judgement. At the time of the regimen shift, all the subjects exhibited a high-level phenotypic resistance to both zidovudine and lamivudine with changes at codons 70-219 in 100% of cases, at codon 215 in 13 of 16 patients, and the M184V substitution in 13/16 patients. Phenotypic susceptibility to didanosine was maintained in the majority of cases (14/16) despite the high prevalence of changes at codon 184. A statistically significant decrease in viral load (P<0.005) without a significant increase in CD4 lymphocytes (P=0.514) was observed after 3 and 6 months from the introduction of the didanosine-containing regimen. These findings suggest the possibility of achieving a viral load response to didanosine-containing regimens in patients with reverse transcriptase (RT) M184V mutations who were previously treated with this drug and its possible use in salvage combinations.
Antiviral therapy 03/2001; 6(1):41-6. · 3.16 Impact Factor
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International Journal of Antimicrobial Agents 01/2001; 16(4):425-7. · 4.13 Impact Factor
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S Rusconi,
D P Merrill,
S La Seta Catamancio,
P Citterio,
E Bulgheroni,
F Croce,
T C Chou,
O O Yang,
S H Herrmann,
M Galli,
M S Hirsch
[show abstract]
[hide abstract]
ABSTRACT: Compounds that can block the CXCR4 chemokine receptor are a promising new class of antiretroviral agents. In these experiments we studied the effect of a modified form of the native stromal cell-derived factor-1 (SDF-1), Met-SDF-1beta. The in vitro susceptibility of two different CXCR4-tropic HIV-1 strains was determined. Antiviral effect was assessed by the reduction of p24 antigen production in PHA-stimulated peripheral blood mononuclear cells with exposure to the modified SDF-1 molecule. The 50% inhibitory concentrations (IC50) were derived from six separate experiments. The IC50 against the two HIV-1 isolates was in 1.0-2.8 microg/ml range for Met-SDF-1beta. Met-SDF-1beta showed synergy to additivity with either zidovudine or nelfinavir at IC75 IC90 and IC95. Additivity was seen when Met-SDF-1beta was combined with efavirenz. No cellular toxicity was observed at the highest concentrations when these agents were used either singly or in combination. This compound is a promising new candidate in a receptor-based approach to HIV-1 infection in conjunction with currently available combination antiretroviral drug therapies.
Antiviral therapy 10/2000; 5(3):199-204. · 3.16 Impact Factor
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C Balotta,
M Violin,
L Monno,
P Bagnarelli,
C Riva,
G Facchi,
A Berlusconi,
M Lippi, S Rusconi,
M Clementi,
M Galli,
G Angarano,
M Moroni
[show abstract]
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ABSTRACT: We evaluated the prevalence of both Q151M and 6-bp insert at position 69 of RT region responsible for multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 variants in 177 patients who failed to respond to combination therapy. Patients had received protease inhibitors (PI) and/or nonnucleoside reverse transcriptase inhibitors (NNRTIs) after a long-term experience with nucleoside reverse transcriptase inhibitors (NRTIs) (including zidovudine monotherapy). Two of 177 patients (1.1%) showed the specific complex of Q151M mutation, while 4 (2.3%) had the 69 6-bp insert. Mutations that belong to the 151 set in the absence of the pivotal Q151M substitution were detected in as many as 3.9% of the patients. One patient exhibited a 69S [VG] insert that has not been previously phenotypically characterized. This HIV-1 isolate had high levels of resistance to all NRTIs except stavudine. MddNR is an emerging problem after sequential therapy with this class of compounds among HIV-1-infected patients. Either didanosine (ddI) or zidovudine (ZDV) monotherapy allowed the emergence of MddNR variants containing Q151M complex. Monotherapy with ZDV and ddI or subsequent treatments with various NRTI combinations were the common background in the patients with the 69 insert. The overall prevalence of MddNR (3.4%) in Italy is comparable with that observed in several other European countries (3.4%-6.5%). These data suggest that patients failed by NRTI regimens should be analyzed for the presence of both patterns of MddNR.
JAIDS Journal of Acquired Immune Deficiency Syndromes 08/2000; 24(3):232-40. · 4.43 Impact Factor
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Antimicrobial Agents and Chemotherapy 07/2000; 44(6):1767. · 4.84 Impact Factor
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S Menzo, S Rusconi,
A Monachetti,
M C Colombo,
M Violin,
P Bagnarelli,
P E Varaldo,
M Moroni,
M Galli,
C Balotta,
M Clementi
[show abstract]
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ABSTRACT: To develop and optimize a fast and quantitative recombinant strategy for evaluating the HIV-1 phenotype to protease inhibitors (PI).
A non-replicative HIV-1 molecular vector (designated pdelta prodelta env) capable of expressing exogenous HIV-1 protease-encoding sequences was developed in this study. The HIV-1 protease sequences were amplified from either viral isolates or plasma samples (both from 21 HIV-1-infected individuals, 19 of whom were failing different anti-HIV-1 combination treatments) and cloned in the pdelta prodelta env backbone. The HIV-1 recombinant phenotype to PI was determined directly after transfection of viral chimeric clones by measuring protease activity and calculating a percentage sensitivity index (SI%; the ratio between the results from each clone and those from a PI-sensitive reference strain).
The SI% values obtained from the recombinant clones paralleled the IC50 results of the viral isolates and documented different degrees of resistance and cross-resistance to PI, compatible, with few exceptions, with the respective genotype. Interestingly, an inverse correlation between SI% values and the presence of primary mutations for resistance to PI (P = 0.0038 and P = 0.0414, for indinavir and ritonavir, respectively) and a difference in SI% between samples harbouring an increasing number of mutations (indinavir, P = 0.022; ritonavir, P = 0.0466) were observed.
The data substantiate the reliability of the novel strategy for a fast (5 day) quantitative evaluation of HIV-1 phenotype to PI, and indicate that this method may contribute to the understanding of mechanisms of virus resistance to PI.
AIDS 07/2000; 14(9):1101-10. · 6.24 Impact Factor
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ABSTRACT: We report the case of two patients in whom acute hepatitis A was associated with a marked and prolonged increase in human immunodeficiency virus type 1 (HIV-1) viral load. Although in one patient the rise in HIV-1 RNA might also have been related to the interruption of antiretroviral therapy, we also observed a similar pattern in the other patient who had a stable undetectable plasma viraemia prior to acute hepatitis and never received treatment with anti-retrovirals. Our observation supports the hypothesis that immune activation that is induced by acute hepatitis A virus (HAV) infection may trigger HIV-1 replication. This highlights the importance of maintaining antiretroviral therapy throughout the acute phase of hepatitis A and of preventing HAV infection through active immunization.
Antiviral therapy 04/2000; 5(1):15-7. · 3.16 Impact Factor
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C Balotta,
A Berlusconi,
A Pan,
M Violin,
C Riva,
M C Colombo,
A Gori,
L Papagno,
S Corvasce,
R Mazzucchelli,
G Facchi,
R Velleca,
G Saporetti,
M Galli, S Rusconi,
M Moroni
[show abstract]
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ABSTRACT: We retrospectively studied 38 Italian recently HIV-1-infected subjects who seroconverted from 1994 to 1997 to investigate: (i) the prevalence of nucleoside reverse transcriptase inhibitors (NRTI)-related mutations at primary infection; (ii) the proportion of naturally occurring mutations in reverse transcriptase (RT) and protease regions of patients naive for non-nucleoside RT inhibitors (NNRTIs) and protease inhibitors (PIs); (iii) the drug-susceptibility to NRTIs and PIs in subjects with NRTI- and/or PI-related mutations; and (iv) the outcome of seroconverters treated with various NRTIs or NRTI/PI regimens. Baseline HIV-1 plasma viraemia and absolute CD4 count at baseline could not be used to distinguish patients with NRTI- and/or PI-related pre-existing mutations from those with wild-type virus (P = 0.693 and P = 0.542, respectively). The frequency of zidovudine-related mutations was 21% in the study period. The response to treatment was not significantly different in subjects with or without genotypic zidovudine-related mutations at primary infection (P = 0.744 for HIV-1 RNA and P = 0.102 for CD4 cells). Some natural variation (2.6%) was present within regions 98-108 and 179-190 of RT involved in NNRTI resistance. The high natural polymorphism in the protease region present in our patients was similar to that reported by others. In our study some PI-associated substitutions, thought to be compensatory in protease enzymatic function, could confer intermediate to high PI-resistance. As discrepancies between genotypic and phenotypic results may exist in recent seroconverters, our data suggest that the role of transmitted NRTI- and PI-resistant variants remain to be fully elucidated in vivo.
Antiviral therapy 04/2000; 5(1):7-14. · 3.16 Impact Factor
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L Milazzo, S Rusconi,
L Testa,
S La Seta-Catamancio,
M Galazzi,
S Kurtagic,
P Citterio,
M Gianotto,
A Grassini,
F Adorni,
A d'Arminio-Monforte,
M Galli,
M Moroni
JAIDS Journal of Acquired Immune Deficiency Syndromes 10/1999; 22(1):101-3. · 4.43 Impact Factor
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A d'Arminio Monforte,
V Testori,
F Adorni,
B Castelnuovo,
T Bini,
L Testa,
G Moscatelli,
E Chiesa, S Rusconi,
C Abeli,
S Sollima,
M Musicco,
L Meroni,
M Galli,
M Moroni
[show abstract]
[hide abstract]
ABSTRACT: To evaluate the influence of immunological and virological markers on clinical outcome in patients receiving their first highly active antiretroviral therapy (HAART) regimen.
Observational study of 585 patients initiating HAART in a clinical setting. Clinical failure was defined as the occurrence of new or recurrent AIDS-defining events or death, and was analysed by means of intention-to-treat, univariate and multivariate analyses. An adjusted Cox regression model was used to evaluate the effect of 3-month CD4 cell counts on clinical outcome.
Clinical failure occurred in 55 patients (9.4%) during a median follow-up of 483 days (range 33-1334 days): 45 new AIDS-defining events (ADEs) in 38, ADE recurrence in six, and death in 11. Twenty-four of the 45 new ADEs (53.4%) occurred during the first 3 months of HAART, and 11 of 45 (24.4%) in the presence of CD4 cell counts > 200 x 10(6) cells/l. The mean (median, range) CD4 counts were 144 x 10(6) cells/l (128, 4-529) in patients with and 322 x 10(6) cells/l (288, 14-1162) in patients without clinical failure (P < 0.0001). Moreover, the proportion of patients with mean CD4 cell counts < 200 x 10(6) cells/l was higher in those experiencing subsequent clinical failure (X2 test: 26.75; P < 0.00001). Multivariate analysis showed that baseline CD4 cell counts < 50 x 10(6) cells/l and AIDS at enrolment predicted failure; after adjusting for 3-month CD4 cell counts, this marker was the only one independently associated with clinical failure (hazard risk, 4.79; 95% confidence interval, 1.40-16.47).
The 3-month immunological response is a reliable predictor of long-term clinical outcome.
AIDS 10/1999; 13(13):1669-76. · 6.24 Impact Factor
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[show abstract]
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ABSTRACT: Signaling lymphocytic activation molecule (SLAM) is a transmembrane lymphocytic receptor which gets rapidly upregulated following cell activation. SLAM engagement augments T cell expansion and interferon-gamma (IFN-gamma) production independently of CD28. SLAM signaling is regulated by the SLAM-associated protein. We evaluated the expression and function of SLAM on CD4(+) and CD8(+) lymphocytes in HIV-infected individuals with either recently acquired infection (Group A) or asymptomatic HIV infection (Group B) and in healthy controls (HC). Soluble antigen (HIV env peptides and tetanus toxoid)- and mitogen-stimulated proliferation and IFN-gamma and IL-10 production upon SLAM costimulation were also measured. Results showed that: (1) SLAM-expressing CD4(+) and CD8(+) lymphocytes diminish in group A patients compared to both group B patients and HC; (2) SLAM expression on CD4(+) lymphocytes is preferentially associated with the lack of CD7 on cell surface (CD4(+)CD7(-) produce IL-10 but not IFN-gamma); (3) SLAM engagement increases HIV env peptide-stimulated, but neither tetanus toxoid- nor PHA-stimulated proliferation of peripheral blood mononuclear cells (PBMC) in patients but not in HC; and (4) SLAM engagement augments IFN-gamma and reduces IL-10 production by env peptide-stimulated PBMC of HIV-infected individuals. These results demonstrate that early HIV infection results in an altered SLAM expression which correlates with a time-limited impairment of cell-mediated immunity. Furthermore, they show that triggering via SLAM potentiates HIV-specific proliferative responses with simultaneous downregulation of IL-10 and redirection of the response to TH0/TH1.
Clinical Immunology 10/1999; 92(3):276-84. · 4.05 Impact Factor
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S Rusconi,
S La Seta-Catamancio,
S Kurtagic,
M Galazzi,
D Arienti,
D Trabattoni,
J Wilken,
D A Thompson,
R E Offord,
M Galli,
M Clerici
[show abstract]
[hide abstract]
ABSTRACT: Studies have demonstrated that the beta-chemokines RANTES, MIP-1alpha, and MIP-1beta suppress human immunodeficiency type 1 (HIV-1) replication in vitro. Infection with HIV-1 requires expression of CD4 antigen and the chemokine receptor CXCR4 (X4) or CCR5 (R5) on the surface of target cells. The engagement of these receptors with the viral surface proteins is essential for the membrane fusion process. This study investigated the anti-HIV-1 activity of a derivative of RANTES, the CCR5 antagonist aminooxypentane (AOP)-RANTES, on R5 HIV-1 isolates in peripheral blood mononuclear cells. In drug exposure experiments, AOP-RANTES efficiently inhibited viral replication of HIV-1 R5 strains, with a viral breakthrough observed after the withdrawal of the compound. The HIV-1-specific proliferative capacity was maintained under all conditions when compared with controls. An increase in IFN-gamma production accompanied by a parallel decrease in the generation of IL-10 was observed following the in vitro exposure of cells to AOP-RANTES in the presence of three of four HIV-1 R5 isolates. These experiments confirmed that the chemokine receptor antagonist AOP-RANTES was effective as an inhibitor of HIV-1 R5 strain infectivity in peripheral blood mononuclear cells. The capacity of this compound to maintain HIV-1-specific proliferative activity with a shift toward a type 1 cytokine profile makes this compound a unique molecule, one adopting an immunological pathway to limit HIV-1 infection.
AIDS Research and Human Retroviruses 08/1999; 15(10):861-7. · 2.25 Impact Factor
