Kawthar Machmach

Hospital Universitario Virgen del Rocío, Hispalis, Andalusia, Spain

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Publications (12)49.94 Total impact

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    ABSTRACT: The single nucleotide polymorphism (SNP) near the IL28B gene, rs12979860, has been associated with the spontaneous clearance of the Hepatitis C virus. We sought to determine whether this SNP could be associated with the spontaneous control of HIV infection. We studied the prevalence of the IL28B-CC genotype in 53 Caucasian HIV controllers compared to 389 HIV-infected non-controllers. We found that the IL28B-CC genotype was independently associated with spontaneous HIV control (p= 0.017; OR: 2.669), as were female gender (p= <0,001; OR: 7,077) and the presence of HLA-B57 and/or B27 (p= 0,017; OR: 3,080). This result supports the idea that common host mechanisms are involved in the spontaneous control of these two chronic infections.
    The Journal of Infectious Diseases 12/2012; · 5.85 Impact Factor
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    ABSTRACT: The potential effect of blocking the CCR5 receptor on HIV disease progression biomarkers is not well understood. We showed that an 8-day maraviroc (MVC) monotherapy clinical test (MCT) can be used in selecting patients to receive MVC-containing combined antiretroviral therapy (cART). Using this MCT model, we assessed the effect of MVC on several HIV disease progression biomarkers during the MCT (MVC-specific effect) and following short-term (12-week) cART. We compared 45 patients on MVC monotherapy with a control group of 25 patients on MVC-sparing cART. We found that MVC did not modify any biomarkers in patients that had no virological response after the MCT. MVC-specific effects in patients with virological responses included increased CD8(+) T-cell activation and senescence levels, preservation of an increase in soluble CD14 (sCD14), and a decrease in D dimer levels. After 12 weeks, MVC-containing cART increased CD8(+) T-cell counts and preserved CD4(+) T-cell senescence levels compared with MVC-sparing cART. Moreover, there was a decrease in sCD14 levels in patients that received MVC-containing cART. In conclusion, effects compatible with CD8(+) T-cell redistribution in peripheral blood were observed after MVC therapy. However, MVC was associated with a favorable profile in HIV disease progression biomarkers only in patients with a virological response. These results support a potential clinical benefit of a therapy which includes MVC in HIV-infected patients.
    Antimicrobial Agents and Chemotherapy 09/2012; 56(11):5858-64. · 4.57 Impact Factor
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    ABSTRACT: The maraviroc clinical test (MCT) is a clinical approach to establish the indication of maraviroc treatment. In this study, we analysed the long-term outcome of patients receiving a combined antiretroviral therapy (cART) selected according to MCT results. Ninety-two consecutive HIV-infected patients underwent MCT. A virological response (<40 HIV-RNA copies/ml after 24 weeks) was observed in 76/92 patients (82.6%). These patients (n=76) were included in a time to treatment failure analysis; after a mean follow-up period of 88 weeks, treatment failure was confirmed in 14 patients (18.4%). Tropism switch during MCT was observed in 3/35 patients (8.6%); these patients experienced excellent long-term outcome on cART. In conclusion, MCT should be considered as an additional method before CCR5-antagonists prescription.
    Antiviral research 06/2012; 95(3):207-11. · 3.61 Impact Factor
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    ABSTRACT: Bacterial lipopolysaccharide (LPS) and soluble CD14 (sCD14) levels have been indistinctly used to measure bacterial translocation independently of the immunovirological stage in HIV infection; however, when the association of both markers with different HIV-progression end-points has been studied, discrepant results have been reported. The aim of this study was to assess the relationship between LPS and sCD14 in different HIV-infection immune stages and to determine the relationship between these biomarkers with established HIV-disease-progression-related markers, as T-cell immune activation, high-sensitivity C-reactive protein and D-dimer. Seventy-three chronically HIV-1-infected patients with detectable HIV-1 RNA levels were analyzed. LPS levels by use of limulus lysate assay, sCD14, intestinal fatty acid binding protein and inflammation-coagulation-associated biomarkers were assessed. In this study, we found that LPS and sCD14 levels were only associated when low CD4+ T-cell levels and high HIV RNA levels were present. In addition, only sCD14 levels, but not LPS, were independently associated with HIV-disease progression-related markers, supporting the clinical importance of sCD14. These results indicate that LPS and sCD14 have a different biological significance and should not be indistinctly used without taking the HIV immunovirological stage into account.
    The Journal of infection 06/2012; 65(5):431-8. · 4.13 Impact Factor
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    ABSTRACT: Human immunodeficiency virus (HIV) controllers spontaneously control viremia and CD4 T-cell depletion in contrast to viremic patients. After HIV exposure, plasmacytoid dendritic cells (pDCs) produce high levels of interferon alpha (IFN-α) and express the apoptotic ligand TRAIL (tumor necrosis factor-related apoptosis inducing ligand). Simian models have shown that prolonged high levels of IFN-α production could be responsible for AIDS progression. We studied pDC activation in response to human immunodeficiency virus (HIV) using flow cytometry and 3D microscopy. We show here that pDCs from controller patients produced higher levels of IFN-α in response to HIV than pDCs from viremic patients but similar levels to pDCs from healthy donors. Because binding of HIV to CD4 is essential for pDC activation, the low CD4 expression by pDCs from viremic patients may explain the weak IFN-α response to HIV. Three-dimensional microscopy revealed that pDCs from controllers and healthy donors expressed intracellular TRAIL that is relocalized to the membrane after HIV exposure. In contrast, pDCs from viremic patients expressed membrane TRAIL without any stimulation. We demonstrate that, in response to HIV, pDCs from controller patients produce IFN-α, express membrane TRAIL, and induce apoptosis of T-cell lines.
    The Journal of Infectious Diseases 06/2012; 206(5):790-801. · 5.85 Impact Factor
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    ABSTRACT: HIV elite controllers (EC) are a rare group of HIV-infected patients who are able to maintain undetectable viral loads during a long period of time in the absence of antiretroviral treatment. Adaptive immunity and host genetic factors, although implicated, do not entirely explain this phenomenon. On the other hand, plasmacytoid dendritic cells (pDCs) are the principal type I interferon (IFN) producers in response to viral infection, and it is unknown whether pDCs are involved in the control of HIV infection in EC. In our study, we analyzed peripheral pDC levels and IFN-α production by peripheral blood mononuclear cells (PBMCs) in EC compared to other groups of HIV-infected patients, the ability of pDCs to reduce HIV production in vitro, and the mechanisms potentially involved. We showed preserved pDC counts and IFN-α production in EC. We also observed a higher capacity of pDCs from EC to reduce HIV production and to induce T cell apoptosis, whereas pDCs from viremic patients barely responded without previous Toll-like receptor 9 (TLR-9) stimulus. The preserved functionality of pDCs from EC to reduce viral production may be one of the mechanisms involved in the control of HIV viremia in these subjects. These results demonstrate the importance of innate immunity in HIV pathogenesis, and an understanding of pDC mechanisms would be helpful for the design of new therapies.
    Journal of Virology 02/2012; 86(8):4245-52. · 5.08 Impact Factor
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    ABSTRACT: A small fraction of HIV-infected individuals (<1%), referred to as elite controllers (EC), are able to maintain undetectable viral loads indefinitely without treatment. The role of the maturational phenotype of T cells in the control of HIV infection in these individuals is not well described. We compared the maturational and functional phenotypes of Gag-specific CD4 and CD8 T cells from EC, who maintain undetectable viral loads without treatment; relative controllers (RC), who maintain viral loads of <1,000 copies/ml without treatment; and noncontrollers (NC), who fail to control viral replication. EC maintained higher frequencies of HIV-specific CD4 T cells, less mature polyfunctional Gag-specific CD4 T cells (CD27(+) CD57(-) CD45RO(+)), and Gag-specific polyfunctional CD4 T cells than those observed in NC. In EC, the frequency of polyfunctional Gag-specific CD8 T cells was higher than that observed in RC and NC. RC had a similar functional phenotype to that observed in NC, despite consistently lower viral loads. Finally, we found a direct correlation between the frequency of Gag-specific CD27(+) CD57(-) CD45RO(+) CD4(+) T cells and the frequency of mature HIV-specific CD8 T cells. Altogether, our data suggest that immature Gag-specific interleukin-2 (IL-2)-producing CD4(+) T cells may play an important role in spontaneous control of HIV viremia by effectively supporting HIV-specific CD8 T lymphocytes. This difference appears to differentiate EC from RC.
    Journal of Virology 01/2012; 86(7):3667-74. · 5.08 Impact Factor
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    ABSTRACT: Analyze the short-term immunological effect directly attributable to MRV without interference of other drugs. MRV group included experienced HIV-infected patients undergoing an 8-day MRV monotherapy. A comparison population included naïve HIV-infected patients starting combined antiretroviral therapy (cART group). Absolute CD4(+) and CD8(+) T-cells and T-lymphocyte subsets were determined at day 0 and 8. Fifty-nine patients who underwent MRV monotherapy and 28 naïve patients were analyzed. Forty-one patients in the MRV group experienced a significant viral load decrease (MRV positive subgroup). Virological response and CD4(+) T-cell change were comparable in the MRV positive and cART groups. CD8(+) T-cell increase in the MRV positive subgroup showed a trend toward superiority when compared with the cART group. T-lymphocyte subset changes showed a similar profile in the MRV positive and cART groups with a differential effect in the TemRA cells related to MRV. No immunological effect (absolute lymphocyte counts or subsets) was observed in patients without virological response to MRV. MRV produced CD4(+) and CD8(+) T-cell gains related to antiviral activity and comparable or even superior in terms of CD8(+) T-cells to naïve patients starting cART. No immunological effect occurred in subjects without virological response to MRV.
    The Journal of infection 12/2011; 64(4):417-23. · 4.13 Impact Factor
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    ABSTRACT: The virological response after an 8-day maraviroc monotherapy has been proposed to be an alternative method to determine whether an CCR5 antagonist should be prescribed to HIV-infected patients. The frequency of patients eligible for a combined antiretroviral therapy which includes maraviroc on the basis of the result of this clinical test is not well-known at the moment. In the same way, clinical and immunovirological factors associated with the virological response after antagonist exposure need to be determined. Ninety consecutive HIV-infected patients were exposed to an 8-day maraviroc monotherapy. The virological response was considered positive if either a reduction of ≥1-log(10) HIV RNA copies/ml or an undetectable viral load (<40 HIV RNA copies/ml) was achieved. CXCR4- and CCR5-tropic virus levels were determined by using patients' viral isolates and multiple rounds of infection of indicator cell lines (U87-CXCR4 and U87-CCR5). The frequency of patients with a positive virological response was 72.2% (94.7% and 66.2% for treatment-naïve and pretreated patients, respectively). The positive response rates dramatically decreased in patients with lower CD4(+) T-cell counts. The CXCR4-tropic virus level was the only variable independently associated with the virological response after short-term maraviroc exposure. Lower CD4(+) T-cell strata were associated with higher CXCR4-tropic virus levels. These results support the suggestion that CCR5 antagonists should be an early treatment option before the expansion of CXCR4-tropic strains.
    Antimicrobial Agents and Chemotherapy 08/2011; 55(10):4664-9. · 4.57 Impact Factor
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    ABSTRACT: Whether HIV controllers, patients who spontaneously control HIV viraemia, are able to control hepatitis C virus (HCV) infection, in terms of spontaneous clearance or lower HCV replication, is not well understood. To assess to what extent Caucasian HIV controllers are able to control HCV replication and potential associated factors, plasma HIV-1 and HCV RNA levels, anti-HCV antibodies, HCV genotype and human leucocyte antigens (HLA) typing were determined in samples from 75 HIV controllers (33 viraemic controllers, <1000 HIV-1 RNA copies/mL, and 42 elite controllers, <40 HIV-1 RNA copies/mL) and compared with 261 HIV-infected noncontrollers. We did not find differences in the HCV spontaneous clearance rates between groups. However, we interestingly found a lower HCV viral load in HIV controllers, alongside a different distribution of HCV genotypes in relation to the comparison group. In addition, HLA-B57 was associated with a lower HCV viral load in the control group and HIV controllers, and conversely, HLA-B35 with higher HCV viral load in HIV controllers. The subrepresentation of HCV genotype 1 and the overrepresentation of HLA-B57 only partly explained the lower HCV viral load found in HIV controllers. In fact, HIV controller status was independently associated with lower HCV viral load, together with HCV genotype non-1, the presence of HLA-B57 and absence of HLA-B35. Caucasian HIV controllers are able to better control HCV replication, in terms of lower HCV viral load levels. These findings support the idea that some common host mechanisms are involved in the defence against these two persistent infections.
    Journal of Viral Hepatitis 07/2011; 18(7):e350-7. · 3.08 Impact Factor
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    ABSTRACT: The study of clinical and demographic characteristics related to virus control and disease progression in patients who spontaneously control HIV vireamia (HIV-controllers) is of major interest. A particular cause of HIV control has not been found and the scenario could be partially explained by special homeostatic and immunological features. In this study, CD57+CD28- phenotype, T-cell activation and levels of proliferating T-cells in elite-controllers were studied in relation to spontaneous virus control. In HIV-controllers, 9% were AIDS-diagnosed and there was a high proportion of women. In elite-controllers, high T-cell CD57+CD28- phenotype and activation levels were found and, interestingly, there was a low proliferation of total and naive T-cells and a high proliferation of the CD4+ TEMRA subset. Low T-cell proliferation and preferential expansion of terminally differentiated effector T-cell subsets could be an important factor for virus control in elite-controllers.
    Current HIV Research 08/2010; 8(6):471-481. · 2.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The study of clinical and demographic characteristics related to virus control and disease progression in patients who spontaneously control HIV vireamia (HIV-controllers) is of major interest. A particular cause of HIV control has not been found and the scenario could be partially explained by special homeostatic and immunological features. In this study, CD57+CD28- phenotype, T-cell activation and levels of proliferating T-cells in elite-controllers were studied in relation to spontaneous virus control. In HIV-controllers, 9% were AIDS-diagnosed and there was a high proportion of women. In elite-controllers, high T-cell CD57+CD28- phenotype and activation levels were found and, interestingly, there was a low proliferation of total and naïve T-cells and a high proliferation of the CD4+ T(EM)RA subset. Low T-cell proliferation and preferential expansion of terminally differentiated effector T-cell subsets could be an important factor for virus control in elite-controllers.
    Current HIV research 07/2010; 8(6):471-81. · 1.98 Impact Factor