Felipe Garcia

Publications of Felipe Garcia

• The reconstitution of the thymus in immunosuppressed individuals restores CD4-specific cellular and humoral immune responses.

  Authors: Montserrat Plana, Felipe Garcia, Laila Darwich, Joan Romeu, Anna López, Cecilia Cabrera, Marta Massanella, Esther Canto, Raul Ruiz-Hernandez, Julià Blanco, Marcelo Sánchez, Josep M Gatell, Bonaventura Clotet, Lidia Ruiz, Margarita Bofill

  Immunology. 07/2011; 133(3):318-28.

  Infection with HIV-1 frequently results in the loss of specific cellular immune responses and an associated lack of antibodies. Recombinant growth hormone (rGH) administration reconstitutes thymicInfection with HIV-1 frequently results in the loss of specific cellular immune responses and an associated lack of antibodies. Recombinant growth hormone (rGH) administration reconstitutes thymic tissue and boosts the levels of peripheral T cells, so rGH therapy may be an effective adjuvant through promoting the recovery of lost cellular and T-cell-dependent humoral immune responses in immunosuppressed individuals. To test this concept, we administered rGH to a clinically defined group of HIV-1-infected subjects with defective cellular and serological immune responses to at least one of three commonly employed vaccines (hepatitis A, hepatitis B or tetanus toxoid). Of the original 278 HIV-1-infected patients entering the trial, only 20 conformed to these immunological criteria and were randomized into three groups: Group A (n = 8) receiving rGH and challenged with the same vaccine to which they were unresponsive and Groups B (n = 5) and C (n = 7) who received either rGH or vaccination alone, respectively. Of the eight subjects in Group A, five recovered CD4 cellular responses to vaccine antigen and four of these produced the corresponding antibodies. In the controls, three of the five in group B recovered cellular responses with two producing antibodies, whereas three of the seven in Group C recovered CD4 responses, with only two producing antibodies. Significantly, whereas seven of ten patients receiving rGH treatment in Group A (six patients) and B (one patient) recovered T-cell responses to HIVp24, only two of six in Group C responded similarly. In conclusion, reconstitution of the thymus in immunosuppressed adults through rGH hormone treatment restored both specific antibody and CD4 T-cell responses.

• Evaluation of the Roche COBAS® TaqMan® HIV-1 test for quantifying HIV-1 RNA in infected cells and lymphoid tissue.

  Authors: Cristina Gil, M Teresa Garcia, Felipe Garcia, José M Miró, Fernando Agüero, Lucía Alós, Laura Zamora, Alicia Capón, Josep Costa, Tomás Pumarola, José M Gatell

  Journal of virological methods. 03/2011; 174(1-2):69-76.

  Lymphoid tissue is the main reservoir of HIV-1 in infected individuals. In this study the COBAS® TaqMan® HIV-1 test was evaluated for use with the High Pure System (HPS), for quantifying HIV-1 RNA inLymphoid tissue is the main reservoir of HIV-1 in infected individuals. In this study the COBAS® TaqMan® HIV-1 test was evaluated for use with the High Pure System (HPS), for quantifying HIV-1 RNA in infected cells and lymphoid tissue specimens. Serial dilutions of 8E5-LAV1 infected T-cells into SUP-T1 cells and 44 tonsil specimens were examined. Some modifications of the test were required, such as the removal of residual DNA and the HIV-1 RNA output copies were adjusted to the sample input and expressed as HIV-1 RNA copies/μg of total RNA. The Roche COBAS® TaqMan HIV-1® (HPS) test proved to be a robust, sensitive, specific and reproducible method for quantifying HIV-1 RNA in infected cells and lymphoid tissue. Linearity and reproducibility were observed in serial dilutions of 8E5-LAV1 infected T-cells (R²>0.86). High reproducibility was found in clinical tonsil specimens (Wilcoxon test p > 0.05). rDNase I treatment was essential to avoid false positives caused by residual HIV-1 DNA, mainly in tonsil specimens obtained from infected patients receiving effective antiretroviral treatment. Probit analysis determined the limit of detection as 22HIV-1 RNA copies/μg of total RNA. The Roche COBAS® TaqMan® HIV-1 (HPS) test thereby proved to be a helpful tool for measuring the HIV-1 viral load in infected cells and lymphoid tissue reservoirs.

• Adenosine deaminase potentiates the generation of effector, memory, and regulatory CD4+ T cells.

  Authors: José M Martinez-Navio, Víctor Casanova, Rodrigo Pacheco, Isaac Naval-Macabuhay, Núria Climent, Felipe Garcia, José M Gatell, Josefa Mallol, Teresa Gallart, Carme Lluis, Rafael Franco

  Journal of leukocyte biology. 10/2010; 89(1):127-36.

  By interacting with CD26 on the CD4+ T cell surface and with the AdoR A(₂B) on the DC surface, ADA triggers a costimulatory signal for human T cells. The aim of this study was to know whetherBy interacting with CD26 on the CD4+ T cell surface and with the AdoR A(₂B) on the DC surface, ADA triggers a costimulatory signal for human T cells. The aim of this study was to know whether ADA-mediated costimulation plays a role in the differentiation of T cells. The results show that irrespective of its enzymatic activity and dependent on TNF-α, IFN-γ, and IL-6 action, ADA enhanced the differentiation of CD4+CD45RA+CD45RO⁻ naïve T cells toward CD4+CD25+CD45RO+ Teffs and CD4+CD45RA⁻CD45RO+ memory T cells. Furthermore, ADA potentiated generation of CD4+CD25(high)Foxp3+ Tregs by a mechanism that seems to be mainly dependent on the enzymatic activity of ADA. Interestingly, an ADA-mediated increase on Teff, memory T cell, and Treg generation occurred, not only in cocultures from healthy individuals but also from HIV-infected patients. These data suggest that ADA is a relevant modulator of CD4+ T cell differentiation, even in cells from immunologically compromised individuals.

• Immunological dysfunction in HIV-1-infected individuals caused by impairment of adenosine deaminase-induced costimulation of T-cell activation.

  Authors: José M Martinez-Navio, Núria Climent, Rodrigo Pacheco, Felipe Garcia, Montserrat Plana, Meritxell Nomdedeu, Harold Oliva, Cristina Rovira, Laia Miralles, José M Gatell, Teresa Gallart, Josefa Mallol, Carme Lluis, Rafael Franco

  Immunology. 11/2009; 128(3):393-404.

  The cell surface association between CD26 and adenosine deaminase (ADA) has a costimulatory function during T-cell activation. Several studies have revealed correlations among CD4(+) CD26(+) T-cellThe cell surface association between CD26 and adenosine deaminase (ADA) has a costimulatory function during T-cell activation. Several studies have revealed correlations among CD4(+) CD26(+) T-cell depletion, increased serum levels of ADA, and the evolution of human immunodeficiency virus (HIV) infection, implicating CD26 and ADA in HIV disease progression. In this context, we aimed to determine whether ADA costimulation could be altered during HIV infection. ADA costimulation was investigated in cells from HIV-infected patients (n = 36) in terms of proliferation and cytokine secretion. An effect of ADA on T-cell proliferation was found in HIV-1-infected patients and correlated positively with the CD4(+) percentage and the nadir CD4 count and negatively with viral load, demonstrating that the response depends on the immunological status of the patient. The robust ADA-induced increase in cytokine production [interferon (IFN)-gamma, interleukin (IL)-6 and IL-10] was markedly reduced in T cells from HIV-1-infected subjects. To eliminate some of the variables associated with immunological defects in HIV-1-infected patients, anti-CD3 plus ADA assays with T cells from healthy volunteers were performed in the presence of recombinant glycoprotein 120 (gp120). It was found that gp120 was responsible for the impairment of the ADA-CD26 interaction and consequently of the ADA-induced effect on both costimulation and cytokine production. The gp120-mediated disruption of the CD26-ADA interaction is a novel mechanism that might explain, at least in part, the altered immunological features observed in HIV-1-infected patients and may have significant relevance in AIDS pathogenesis.

• Adenosine deaminase enhances T-cell response elicited by dendritic cells loaded with inactivated HIV.

  Authors: Núria Climent, José M Martinez-Navio, Cristina Gil, Felipe Garcia, Cristina Rovira, Carmen Hurtado, Laia Miralles, José M Gatell, Teresa Gallart, Josefa Mallol, Carme Lluis, Rafael Franco

  Immunology and cell biology. 09/2009;

  As host immunological defenses are impaired during HIV infection, it is difficult to elicit good responses when attempting to develop therapeutic vaccines against HIV. To try to solve this situation,As host immunological defenses are impaired during HIV infection, it is difficult to elicit good responses when attempting to develop therapeutic vaccines against HIV. To try to solve this situation, adjuvants, particularly cytokines, are currently under evaluation. Owing to the fact that adenosine deaminase (ADA) is a member of the family of growth factor with deaminase activity, we tested whether it could improve immune responses in the development of HIV dendritic-cell-based therapeutic vaccines. A co-culture model approach has been used to test the usefulness of ADA as adjuvant. Monocyte-derived dendritic cells from HIV-infected patients were pulsed with inactivated HIV, matured and co-cultured with autologous T cells. Addition of ADA to the co-cultures resulted in enhanced CD4(+) and CD8(+) T-cell proliferation and robust ADA-induced increase in cytokine production (IFN-gamma, TNF-alpha and IL-6). As IFN-gamma, TNF-alpha and IL-6 promote the Th1 versus Th2 phenotype and improve T helper proliferation responses and antigen-specific CTL responses ADA may be considered a promising candidate for therapeutic vaccine adjuvant.Immunology and Cell Biology advance online publication, 11 August 2009; doi:10.1038/icb.2009.53.

• Natural Killer Cells and Expression of KIR Receptors in Chronic HIV Type 1-Infected Patients after Different Strategies of Structured Therapy Interruption.

  Authors: Gabriel Mestre, Felipe Garcia, Esteban Martinez, Ana Milinkovic, Anna Lopez, Agathe León, Borja Mora, Roger Argelich, José Manuel Lozano, José Peña, José M Gatell, Montserrat Plana

  AIDS research and human retroviruses. 12/2008;

  Abstract Few data evaluating the NK cell profile during structured therapy interruption (STI) in chronic HIV-1 infection are available. Changes in NK cell percentages and KIR and NKG2A receptors wereAbstract Few data evaluating the NK cell profile during structured therapy interruption (STI) in chronic HIV-1 infection are available. Changes in NK cell percentages and KIR and NKG2A receptors were analyzed at baseline and after 2 years of follow-up in 121 patients on ART with CD4(+) >450 cells/ml and VL <200 copies/ml randomized in three arms according to the criteria employed to resume ART during STI: virological arm (VA n = 47, VL >30,000 copies/ml or CD4 <350 cells/ml), immunological arm (IA n = 37, CD4< 350 cells/ml), and a control arm (n = 37) in which ART was maintained. After 2 years of follow-up, a decrease in CD3(-)CD56(+) CD16(+) cell percentages in VA and IA patients, but not in CA patients, was observed. Those patients with higher decrease in CD3(-)CD56(+)CD16(+) cells had a higher decrease in CD4(+) cells (r = 0.35, p = 0.001) and higher increase in PVL (r = -0.26, p = 0.02). KIR and NKG2A receptor expression tended to increase in CA and decreased in the other two arms (more in IA than in VA). Patients who displayed a greater decrease in CD4(+) T cells and a greater rise in PVL after 2 years of follow-up had a significantly higher decrease in KIR and NKG2A receptors expressed in CD3(-)CD56(+) cells. Patients who presented the lowest levels of total NK cells and KIR and NKG2A receptor expression after STI showed the poorest virology or immunology outcomes. This finding suggests that STI could decrease the number of NK subsets, which is related to the worst clinical development in these patients.

• Influence of repeated cycles of structured therapy interruption on the rate of recovery of CD4+ T cells after highly active antiretroviral therapy resumption.

  Authors: Agathe León, Esteban Martinez, Ana Milinkovic, Borja Mora, Josep Mallolas, Jose L Blanco, María Larrousse, Montserrat Laguno, Teresa Gallart, Montserrat Plana, José M Gatell, Felipe Garcia

  The Journal of antimicrobial chemotherapy. 11/2008;

  Background CD4+ T cell recovery dynamics were analysed during the 'on treatment' periods in structured therapy interruption (STI) as well as the long-term immune reconstitution with highly activeBackground CD4+ T cell recovery dynamics were analysed during the 'on treatment' periods in structured therapy interruption (STI) as well as the long-term immune reconstitution with highly active antiretroviral therapy (HAART) after finishing STI. Methods One hundred and twenty HIV-1-infected patients on successful HAART were randomized to receive for 2 years continuous HAART (n = 37) or two different strategies of STI (n = 83). After this period, most patients received continuous HAART for 2 years. Results During the STI period, the rate of recovery of CD4+ T cells decreased progressively from the first to the last resumption of HAART {median change of increase: +232 [interquartile range (IQR): +126, +318], +116 (IQR: +10, +471), +87 (IQR: -54, +252) and -26 (IQR: -352, +211) cells/mm(3) after the first, second, third and fourth resumption, respectively}. After the STI period and 2 years of continuous HAART, the median CD4+ count remained significantly lower than at baseline in STI arms, both in the virological arm [559 (IQR: 383, 727) versus 771 (IQR: 625, 913) cells/mm(3), P < 0.0001] and the immunological arm [619 (IQR: 501, 789) versus 787 (IQR: 657, 954) cells/mm(3), P < 0.0001], but not in the control arm [886 (IQR: 564, 1122) versus 780 (IQR: 539, 945) cells/mm(3), P = 0.68]. In a multivariate analysis, the nadir of CD4+ T cells and the baseline value of CD4+ before the STI period independently predicted the level of CD4+ T cells 2 years after resumption of HAART (in both cases, P < 0.0001). Conclusion The drop in CD4+ cell count after a first and a second period of 3 months of interruption of HAART was completely recovered after resuming HAART; conversely, interruptions longer than 6 months were deleterious for the recovery of CD4+. CD4+ cell count did not rebound completely in patients who received 2 years of HAART after 2 years of STIs.

• Redistribution of FOXP3-positive regulatory T cells from lymphoid tissues to peripheral blood in HIV-infected patients.

  Authors: Ana Mozos, Marta Garrido, Joaquim Carreras, Montse Plana, Alba Diaz, Llucia Alos, Elias Campo, Felipe Garcia, Antonio Martinez

  Journal of acquired immune deficiency syndromes (1999). 01/2008; 46(5):529-37.

  OBJECTIVE: Regulatory T (Treg) cells are altered during HIV replication, but their role in chronic infection is controversial and lacks reproducibility between series. FOXP3 is a specific marker ofOBJECTIVE: Regulatory T (Treg) cells are altered during HIV replication, but their role in chronic infection is controversial and lacks reproducibility between series. FOXP3 is a specific marker of Treg cells. We study for the first time FOXP3 expression in a unique series of paired samples at different time points of HIV infection. Design: Paired samples from lymphoid tissue and peripheral blood were simultaneously obtained from 27 HIV-infected patients (before and after highly active antiretroviral therapy [HAART]) and 6 controls. METHODS: We analyzed FOXP3 expression by TaqMan (Universal PCR Master Mix; Applied Biosystems, Foster City, CA) reverse transcriptase polymerase chain reaction in lymphoid tissue and peripheral blood. Treg cells were assessed in lymphoid tissue by immunohistochemistry/computer image analysis and in peripheral blood by flow cytometry. CD4 cell counts and viral loads were obtained. RESULTS: HIV-infected patients had a low FOXP3 copy number and Treg cell frequencies in lymphoid tissue but a high number of Treg cells in peripheral blood. Lymphoid tissue FOXP3 expression decreased after HAART, and it correlated to lymphoid tissue viral load. Patients treated with nonnucleoside HAART had the lowest lymphoid tissue FOXP3 expression. CONCLUSIONS: HIV-infected patients had low FOXP3 expression in lymphoid tissue and redistributed Treg to peripheral blood. HAART reduced even more the proportion of lymphoid tissue Treg in association with the immunologic recovery observed after treatment. The type of HAART may have an impact on the distribution of Treg cells.

• Polymorphisms in the 3' untranslated region of the fractalkine (CX3CL1) gene and the risk of HIV-1 infection and disease progression.

  Authors: Joaquim Peraire, Francesc Vidal, Montserrat Plana, Pere Domingo, Blai Coll, Consuelo Viladés, Felipe Garcia, Sergi Veloso, Josep M Gatell, Montserrat Broch

  AIDS (London, England). 05/2007; 21(7):891-3.

• HIV and syphilis: when to perform a lumbar puncture.

  Authors: Agnès Libois, Stéphane De Wit, Bénédicte Poll, Felipe Garcia, Eric Florence, Ana del Rio, Paquita Sanchez, Eugenia Negredo, Marc Vandenbruaene, José M Gatell, Nathan Clumeck

  Sexually transmitted diseases. 03/2007; 34(3):141-4.

  OBJECTIVES: The objectives of this study were to determine predictive factors for neurosyphilis in HIV-infected patients with syphilis and optimize the use of lumbar puncture. STUDY DESIGN: TheOBJECTIVES: The objectives of this study were to determine predictive factors for neurosyphilis in HIV-infected patients with syphilis and optimize the use of lumbar puncture. STUDY DESIGN: The authors reviewed 112 cases of HIV-infected patients with syphilis who underwent a lumbar puncture. Diagnosis of neurosyphilis was based on a cerebrospinal fluid white blood cells count > or =20/microL, and/or a reactive cerebrospinal fluid-Venereal Disease Research Laboratory, and/or a positive intrathecal T. pallidum antibody (ITPA) index. RESULTS: Twenty-six of 112 had neurosyphilis. Neurologic manifestations and serum rapid plasma reagin (RPR) were associated with neurosyphilis (P = 0.036, P = 0.018, respectively). In multivariate analysis, log(2)RPR was still associated with neurosyphilis (P = 0.005). In patients without neurologic manifestations, the risk of neurosyphilis increases gradually with log(2)RPR. A serum RPR of 1/32 seems to be the best cutoff point to decide the performance or not of a lumbar puncture (sensitivity 100%, specificity 40%). CONCLUSION: In HIV-infected patients with syphilis, lumbar puncture could be restricted to those with neurologic manifestations or a serum RPR > or =1/32.

• Effect of genetic variants of CCR2 and CCL2 on the natural history of HIV-1 infection: CCL2-2518GG is overrepresented in a cohort of Spanish HIV-1-infected subjects.

  Authors: Consuelo Viladés, Montserrat Broch, Montserrat Plana, Pere Domingo, Carlos Alonso-Villaverde, Enric Pedrol, Hernando Knobel, David Dalmau, Joaquim Peraire, Cristina Gutiérrez, Anna López, Maria Antònia Sambeat, Montserrat Olona, Felipe Garcia, Cristóbal Richart, Josep Maria Gatell, Francesc Vidal

  Journal of acquired immune deficiency syndromes (1999). 03/2007; 44(2):132-8.

  BACKGROUND AND OBJECTIVES: Polymorphisms in the genes that encode for the CCR2 chemokine receptor and its natural ligand CCL2 have been shown to influence the natural history of HIV-1 infection,BACKGROUND AND OBJECTIVES: Polymorphisms in the genes that encode for the CCR2 chemokine receptor and its natural ligand CCL2 have been shown to influence the natural history of HIV-1 infection, although data are inconsistent. Our aim was to determine whether functionally active CCR2 and CCL2 genetic variants influence the risk of infection and disease progression in a cohort of white Spaniards. PATIENTS AND METHODS: This was a multicenter genetic association case-control study. Two single nucleotide polymorphisms (SNPs), V64I (G > A) of the CCR2 gene and -2518 (A > G) of the CCL2 gene, were assessed in 318 individuals: 73 HIV-1-infected long-term nonprogressors (LTNPs) of >16 years duration, 109 HIV-1-infected usual progressors (UPs), 36 heavily exposed to HIV-1 but uninfected individuals (EUs), and 100 control subjects. The distribution of the CCR5Delta32 allele was also assessed. Genotyping was performed using polymerase chain reaction (PCR) restriction fragment length polymorphisms (RFLPs) or PCR and automatic sequencing analysis methods on white blood cell DNA. Genotype and allele frequencies were compared by the chi2 test and the Fisher exact test. RESULTS: CCR2 genotype distribution and allele frequencies showed nonsignificant differences between groups. The distribution of CCL2 alleles showed no significant differences between groups. HIV-1-infected individuals had, however, a significantly higher prevalence of the variant homozygous CCL2 GG genotype compared with EUs (P = 0.02). This result persisted when we studied only individuals with wild-type CCR5. Genotype and allele distribution of CCL2 was similar in HIV-1-infected UPs and LTNPs. CONCLUSIONS: In our cohort of white Spaniards, homozygosity for the variant CCL2-2518GG genotype is overrepresented in HIV-1-infected subjects.

• An integral care telemedicine system for HIV/AIDS patients.

  Authors: Cesar Caceres, Enrique J Gomez, Felipe Garcia, Jose M Gatell, Francisco Del Pozo

  International journal of medical informatics. 10/2006; 75(9):638-42.

  OBJECTIVE: In this article we will describe a new approach to improve the quality of care of chronic HIV/AIDS patients, combining the integral care approach with a telemedicine system. METHODS:OBJECTIVE: In this article we will describe a new approach to improve the quality of care of chronic HIV/AIDS patients, combining the integral care approach with a telemedicine system. METHODS: Following the integral care approach, we included the patient in a multidisciplinary care team, covering the whole process of care with a telemedicine system that allows the patient to improve his/her self-care and to be remotely followed-up by the healthcare professionals. RESULTS: This challenge has been met by the creation of the "VIHrtual Hospital" project. Its main goal is the definition, development, clinical routine installation and evaluation of a telemedicine service that complements standard care with a telecare follow-up for treating stable HIV infected patients, in a chronic stage of their disease, and study if that improves the quality of assistance and the expense per patient compared to the conventional control (without telemedicine service) that patients usually have. Although the study is not yet finished, in the discussion the main benefits and drawbacks of this telemedicine system are described. CONCLUSIONS: The main conclusion of the article is that a new home telecare model for chronic HIV/AIDS patients has been created and has been implemented through the "VIHrtual Hospital" in the Clinic Hospital in Barcelona (Spain). The architecture of this web-based system fulfills the demanding security and integration requirements of the IT department of the hospital. An easy-to-use graphical interface for both patients and professionals has also been developed. The low costs of the system allow us to cover a wide range of patients and promising results are being obtained regarding the use of telemedicine systems for improving the follow-up care of chronic HIV/AIDS patients and for creating a new care model for this disease.

• Dynamics of T cells subsets and lymphoproliferative responses during structured treatment interruption cycles and after definitive interruption of HAART in early chronic HIV type-1-infected patients.

  Authors: Agnès Libois, Anna López, Felipe Garcia, Pedro Castro, María J Maleno, Ana García, Nuria Climent, Mireia Arnedo, Teresa Gallart, José M Gatell, Montserrat Plana

  AIDS research and human retroviruses. 07/2006; 22(7):657-66.

  Little is known about the consequences of short cycles of structured treatment interruption or definitive interruption of HAART for both T cell subset dynamics and T lymphoproliferative responsesLittle is known about the consequences of short cycles of structured treatment interruption or definitive interruption of HAART for both T cell subset dynamics and T lymphoproliferative responses (LPR). Immunological follow-up was performed in 45 early chronical HIV-1-infected patients during short STI cycles during the first 12 weeks after the definitive interruption of HAART (DTI) and, thereafter, until VL reached a plateau. During STI cycles, CD8(+), CD8(+), CD28(+), activation markers and naive CD4(+) T cells increased significantly (p < 0.0001), while both naive CD8(+) and memory CD4(+) T cells decreased. During DTI, CD8(+) CD28(+) T cells fell and CD4(+) naive T cells stabilized and the rest of the T cell subsets presented changes similar to those during STI cycles. Despite a transient increase in LPR to recall antigens and HIV proteins during STI cycles, LPR to polyclonal stimuli and pathogens decreased over the study. Differences in T cell subset dynamics and LPR observed throughout the study suggest that multiple exposures to low levels of antigen could improve the immune system, mainly by driving T cell maturation. Conversely, higher and longer viral replication after cessation of HAART overwhelms the immune system. These data may help to guide future immune-based therapies.

• Transmission of hepatitis C virus by discarded-needle injury.

  Authors: Agnès Libois, Emilio Fumero, Pedro Castro, Meritxell Nomdedeu, Anna Cruceta, José Maria Gatell, Felipe Garcia

  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 08/2005; 41(1):129-30.

• Immunoarchitecture of lymphoid tissue in HIV-infection during antiretroviral therapy correlates with viral persistence.

  Authors: Llúcia Alòs, Pilar Navarrete, Vanesa Morente, Felipe Garcia, Marta Garrido, Montse Plana, Anna Mozos, Anna López, Cristina Gil, Tomás Pumarola, Miguel Caballero, Jose L Blanch, Emilio Fumero, José M Miró, Teresa Gallart, José M Gatell, Elias Campo

  Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 02/2005; 18(1):127-36.

  Plasma viral load and T-cell subset determinations in blood are the markers used for monitoring HIV-1 infection. However, key pathogenesis events, viral replication and most immunologic changes occurPlasma viral load and T-cell subset determinations in blood are the markers used for monitoring HIV-1 infection. However, key pathogenesis events, viral replication and most immunologic changes occur in the lymphoid tissues. We have studied the tonsillar biopsies of 30 patients in the early stages of the disease, before initiating treatment and after 12 and 36 months of fully effective highly active antiretroviral therapy. We have investigated the HIV RNA by polymerase chain reaction (lymphoid tissue viral load), the immunohistochemical HIV-p24 antigen expression, as well as the lymphoid tissue architecture and lymphoid cell subsets using morphometry. The lymphoid tissue viral load and the immunoexpression of p24, which was found to be mainly associated with follicular dendritic cells, decreased significantly after treatment, but did not disappear in all cases, even after 36 months of treatment. A significant improvement of the lymphoid tissue architecture was also observed after treatment, with recovery of follicular structures. These histological changes correlated with the lymphoid tissue viral load. Moreover, the counts of CD4+ increased whereas CD8+ and cytotoxic lymphocytes (CD8+ granzyme B+) decreased significantly, the latter in both interfollicular and intrafollicular areas. However, these cellular counts after treatment did not reach those of lymphoid tissue of non-HIV-infected patients used as control cases. Naive (CD45RA+) and memory (CD45RO+) cells also improved significantly after treatment. In conclusion, in HIV-infection the impact of treatment can only be assessed completely in the lymphoid tissue reservoir, where most of the virus is stored and associated with follicular dendritic cells. Highly active antiretroviral therapy produces a significant recovery of lymphoid tissue architecture and lymphoid cell subsets, which are associated with the decrease of lymphoid tissue viral load. However, these parameters studied in lymphoid tissue are not re-established completely, even after 36 months of highly active antiretroviral therapy.

• A Home Integral Telecare System for HIV/AIDS Patients.

  Authors: Cesar Caceres, Enrique J Gomez, Felipe Garcia, Paloma Chausa, Jorge Guzman, Francisco Del Pozo, Jose Maria Gatell

  Studies in health technology and informatics. 02/2005; 114:23-9.

  VIHrtual Hospital is a telemedicine web system for improving home integral care of chronic HIV patients through the Internet. Using the videoconference, chat or messaging tools included in theVIHrtual Hospital is a telemedicine web system for improving home integral care of chronic HIV patients through the Internet. Using the videoconference, chat or messaging tools included in the system, patients can visit their healthcare providers (physician, psychologist, nurse, psychiatrist, pharmacist, and social worker), having these access to the Electronic Patient Record. The system also provides a telepharmacy service that controls treatment adherence and side effects, sending the medication to the patient's home by courier. A virtual community has been created, facilitating communication between patients and improving the collaboration between professionals, creating a care plan for each patient. As a complement, there is a virtual library where users can find validated HIV/AIDS information helping to enhance prevention. This system has been developed using low cost technologies in order to extend the number of patients involved in its trial. Thus, VIHrtual Hospital is now on trial in the Hospital Clinic (Barcelona, Spain) involving a hundred patients and twenty healthcare professionals during two years.Although we are still waiting for the final results of the trial, we can already say that the use of telemedicine systems developed ad hoc for a chronic disease, like HIV/AIDS, improve the quality of care of the patients and their care team. The system described is a good example of the possibilities that technologies are offering to create new chronic patient care models based on telemedicine.

• Similar HIV-1 evolution and immunological responses at 10 years despite several therapeutic strategies and host HLA Types.

  Authors: Mireia Arnedo-Valero, Montserrat Plana, Antonio Mas, Meritxell Guilà, Cristina Gil, Pedro Castro, Felipe Garcia, Esteban Domingo, Josep Ma Gatell, Tomàs Pumarola

  Journal of medical virology. 09/2004; 73(4):495-501.

  Two sexual partners infected with related HIV-1 viruses and enrolled in different therapeutic strategies including structured treatment interruptions (STI) provided us an opportunity to compare longTwo sexual partners infected with related HIV-1 viruses and enrolled in different therapeutic strategies including structured treatment interruptions (STI) provided us an opportunity to compare long term (10 years) viral genetic evolution for closely related isolates in different hosts. HLA loci were molecularly typed and different genetic markers were studied. The viral genetic evolution was studied by sequencing pol and env genes. The HIV-specific CD4+ and CD8+ T cell responses were assessed by the lymphoproliferative response (LPR) and an ELISPOT assay, respectively. HLA class I loci of patients A and B were different and both of them were heterozygous for CCR5delta32 gene. During the two STI studies, viral load of both patients rebounded after treatment interruption and both developed a transitory strong helper and CTL responses. After definitive interruption of therapy, viral load remained below 5,000 copies/ml without therapy during the two years of follow-up. Two patients infected with related viruses showed a similar dynamics of viral evolution and CD4 T cells, despite hosts having a different HLA type and being treated with several therapeutic protocols, after 10 years of infection. These results suggest that, in this case, an effective immunological response to STI depended more on the virus than on the characteristics of the host.

• Relevance of HIV-1-specific CD4+ helper T-cell responses during structured treatment interruptions in patients with CD4+ T-cell nadir above 400/mm3.

  Authors: Montserrat Plana, Felipe Garcia, Annette Oxenius, Gabriel M Ortiz, Anna Lopez, Anna Cruceta, Gabriel Mestre, Emilio Fumero, Catherine Fagard, Maria Antonia Sambeat, Ferran Segura, José M Miró, Mireia Arnedo, Lucia Lopalcos, Tomas Pumarola, Bernard Hirschel, Rodney E Phillips, Douglas F Nixon, Teresa Gallart, Jose M Gatell

  Journal of acquired immune deficiency syndromes (1999). 07/2004; 36(3):791-9.

  OBJECTIVES: To analyze the dynamics of both HIV-1-specific CD4 and CD8 T-cell responses during structured treatment interruptions (STIs) in chronically HIV-1-infected (CHI) patients and to correlateOBJECTIVES: To analyze the dynamics of both HIV-1-specific CD4 and CD8 T-cell responses during structured treatment interruptions (STIs) in chronically HIV-1-infected (CHI) patients and to correlate them with the viral set point achieved. METHODS: Forty-five early-stage CHI patients who were on highly active antiretroviral therapy (HAART) for at least 1 year and underwent STI were included. Plasma viral load (VL), peripheral blood mononuclear cell (PBMC) lymphoproliferative (LPR) response to HIV p24 protein, and HIV-1 epitope-specific interferon-gammarelease from CD8 T cells were measured over a minimum study period of 2 years. RESULTS: VL set point during final STI was both significantly lower than, and positively correlated to, baseline VL (P < 0.0001: mean VL reduction 0.77 log10, and r = 0.42, P = 0.004, respectively). CD4 LPRs to p24 increased significantly (P = 0.001) between day 0 of the first STI cycle and 4th STI but decreased thereafter. VL set point during final STI was significantly and negatively correlated with LPRs to p24 at both 2nd STI and 4th STI. Nevertheless, at week 52, 12 weeks after the end of the last STI, LPRs were weak and transient in all patients and were not correlated with VL set point. Moreover, the magnitude and breadth of HIV-1-specific CD8 T-cell responses increased significantly (P < 0.0001) between day 0 and week 52. The largest increases occurred during the final STI. Even though VL reached set point by week 12 of the final STI, HIV-1-specific CD8 T-cell responses did not stabilize but rather increased until the end of the follow-up and did not correlate with plasma VL (r = 0.01, P = 0.88). CONCLUSIONS: STIs do not lead to control of viral replication in CHI patients, probably due to the fact that boosted CTL responses lack strong and durable helper T-cell responses. To reset the VL set point, new approaches that effectively augment and preserve helper T-cell responses should be investigated.

• A prospective trial of structured treatment interruptions in human immunodeficiency virus infection.

  Authors: Catherine Fagard, Annette Oxenius, Huldrych Günthard, Felipe Garcia, Michelle Le Braz, Gabriel Mestre, Manuel Battegay, Hansjakob Furrer, Pietro Vernazza, Enos Bernasconi [......] Sara J Dawson, Thomas Klimkait, Thomas V Perneger, Angela McLean, Bonaventura Clotet, Jose M Gatell, Luc Perrin, Montserrat Plana, Rodney Phillips, Bernard Hirschel

  Archives of internal medicine. 05/2003; 163(10):1220-6.

  BACKGROUND: According to the "autovaccination hypothesis," reexposure to human immunodeficiency virus (HIV) during treatment interruptions may stimulate the HIV-specific immune response and lead toBACKGROUND: According to the "autovaccination hypothesis," reexposure to human immunodeficiency virus (HIV) during treatment interruptions may stimulate the HIV-specific immune response and lead to low viremia after withdrawal of highly active antiretroviral treatment (HAART). Many patients who started HAART earlier in their disease course than is currently recommended would like to discontinue, but it is unknown whether it is safe to do so. OBJECTIVES: To determine whether repeated treatment interruptions of HAART (1) stimulated the cytotoxic HIV-specific immune response and whether such stimulation correlated with low viremia off treatment, and (2) were safe with respect to clinical complications, development of viral resistance, and decline in CD4 cell counts. DESIGN: Interventional study with before-after comparison. SETTING: Outpatient clinics of university hospitals in Switzerland and Spain. PATIENTS: A total of 133 patients receiving HAART, with a median CD4 cell count of 740/ microL, and whose viral load had been undetectable for a median of 21 months. INTERVENTIONS: HAART was interrupted for 2 weeks, restarted, and continued for 8 weeks. After 4 such cycles, treatment was indefinitely suspended 40 weeks after study entry. MAIN OUTCOME MEASURES: HIV-specific cytotoxic T-cell responses were evaluated by interferon gamma enzyme-linked immunospot analysis. The proportion of "responders" (viral load <5000 copies/mL) was measured at weeks 52 and 96. HIV-related diseases and CD4 cell counts were recorded. RESULTS: Seventeen percent of patients (95% confidence interval, 11%-25%) were responders at week 52, and 8% at week 96. Low pre-HAART viral load and lack of rebound during weeks 0 to 40 predicted response. HIV-specific CD8+ T cells increased between week 0 (median, 343 spot-forming cells per million peripheral blood lymphocytes [SFC/106 PBL]) and week 52 (median, 1930 SFC/106 PBL), but there was an inverse correlation between response and the number of spot-forming cells. Eighty-five (64%) of 133 patients stopped therapy for at least 12 weeks, and 55 (41%) for at least 56 weeks. The median CD4 cell count decreased from 792/ microL to 615/ microL during the first 12 weeks without treatment, but stabilized thereafter. One patient (0.75%) developed drug resistance necessitating salvage treatment. There were no AIDS-related clinical complications. CONCLUSIONS: Results of this study do not favor the autovaccination hypothesis. Treatment interruptions did not provoke clinical complications, and there was little drug resistance. Comparative trials will have to show what benefit, if any, is associated with intermittent, as opposed to continuous treatment.

• Genotypic and phenotypic resistance patterns in early-stage HIV-1-infected patients failing initial therapy with stavudine, didanosine and nevirapine.

  Authors: Carme Vidal, Mireia Arnedo, Felipe Garcia, Gabriel Mestre, Montserrat Plana, Anna Cruceta, Alicia Capon, Teresa Gallart, José M Miro, Tomas Pumarola, José M Gatell

  Antiviral therapy. 12/2002; 7(4):283-7.

  The objectives of this study were to determine the genotypic and phenotypic patterns of resistance in a group of early-stage antiretroviral-naive patients failing initial therapy with didanosine,The objectives of this study were to determine the genotypic and phenotypic patterns of resistance in a group of early-stage antiretroviral-naive patients failing initial therapy with didanosine, stavudine and nevirapine. These patterns of resistance were determined at baseline and at time of virological failure in 89 antiretroviral-naive patients with CD4 cells >500 cells/ml and viral load >5000 copies/ml who received initial antiretroviral therapy with didanosine plus stavudine and nevirapine as part of the SCAN study, and who failed after having reached undetectable plasma levels (<200 copies/ml). Of the 89 patients recruited in the SCAN study, 14 (16%) developed a virological failure after reaching a viral load below 200 copies/ml after a median of 20 months of follow-up. At baseline, none of these 14 patients had genotypic resistance. At time of failure, six out of 14 (43%) failing patients had wild-type genotype and no phenotypic resistance. Suboptimal compliance could be documented in four of these six patients. Seven patients (50%) had nevirapine resistance mutations (mainly K103N [4/7], Y181C/I [2/7], G190A/S [2/7] and V108I [1/7]) associated with phenotypic high-level resistance to nevirapine, delavirdine and efavirenz (nevirapine >47.4- to 58.1-fold, delavirdine >74.4- to 168.9-fold and efavirenz >56.0- to 347.2-fold). Four of these seven patients also had thymidine analogue-associated mutations (TAM) (T215Y/F [2/4], M41L [1/4], D67N [2/4] and K70R [1/4]). Finally, one patient (7%) had exclusively TAM mutations (M41L). None of the patients developed mutations associated with didanosine resistance or phenotypic resistance to didanosine or stavudine. Suboptimal compliance or selection of nevirapine resistance often with TAM mutations was frequently associated with virological failure in a cohort of early-stage chronic HIV-1-infected patients treated with a protease inhibitor-sparing regimen.