Publications (10)36.78 Total impact
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Article: Early Gag immunodominance of the HIV-specific T-cell response during acute/early infection is associated with higher CD8+ T-cell antiviral activity, and correlates with the preservation of the CD4+ T-cell compartment.
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ABSTRACT: The important role of the CD8(+) T-cell response on HIV control is well established. Moreover, the acute phase of infection represents a proper scenario to delineate the antiviral cellular functions that best correlate with control. Here, multiple functional aspects (specificity, ex vivo viral inhibitory activity -VIA- and polyfunctionality) of the HIV-specific CD8(+) T-cell subset arising early after infection, and their association with disease progression markers, were examined. Blood samples from 44 subjects recruited within six months from infection (Primary HIV Infection -PHI- group), 16 chronically infected subjects, 11 Elite Controllers (EC) and ten healthy donors were obtained. Results indicated that, although Nef dominated the anti-HIV response during acute/early infection, a higher proportion of early anti-Gag T-cells correlated with delayed progression. Polyfunctional HIV-specific CD8(+) T-cells were detected at early time-points but did not associate with virus control. Conversely, higher CD4(+) T-cell set-points were observed in PHI subjects with higher HIV-specific CD8(+) T-cell VIA at baseline. Importantly, VIA levels correlated with the magnitude of the anti-Gag cellular response. The advantage of Gag-specific cells may result from their enhanced ability to mediate lysis of infected cells (evidenced by higher capacity to degranulate and to mediate VIA) and to simultaneously produce IFN-γ. Finally, Gag-immunodominance was associated with elevated plasma levels of IL-2 and MIP-1β. Altogether, this study underscores the importance of CD8(+) T-cell specificity in the improved control of disease progression, which was related to the capacity of Gag-specific cells to mediate both lytic and nonlytic antiviral mechanisms at early time-points post-infection.Journal of Virology 04/2013; · 5.40 Impact Factor -
Article: HIV-1 BF intersubtype recombinant Vpu second alpha helix plays an important role in the viral release and BST-2 degradation.
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ABSTRACT: We previously reported a naturally occurring BF intersubtype recombinant Vpu variant with augmented capacity to enhance viral replication. Structural analysis of this variant revealed that its transmembrane domain (TMD) and α-helix I in the cytoplasmic domain (CTD) corresponded to subtype B, whereas CTD α-helix II corresponded to subtype F1. This work was aimed at evaluating the role of Vpu CTD α-helix II domain on viral release enhancement and down-modulation of BST-2 and CD4 from cell surface. In addition, as serine residues in either Vpu amino acid positions 61 or 64 have been shown to regulate Vpu intracellular half-life, which in turn could influence the magnitude of viral release, we also studied the impact of these residues in the BF Vpu functions, since S61 and S64 are infrequently found among BF recombinant Vpu variants. Our results showed that interchange of Vpu α-helix II between subtypes (B→F) directly correlated with enhancement of viral release and, to a lesser extent, with changes in the capacity to down-modulate BST-2 and CD4 of the resulting chimera. No statistical differences on viral release and BST-2 down-modulation were observed between Vpu BF and VpuBF E61S. On the other hand, VpuBF A64S showed a slightly reduced capacity to enhance viral production but was modestly more efficient than VpuBF in down-modulating BST-2. In summary, our observations clearly evidence that α-helix II is actively involved in Vpu viral release-promoting activity, and that intersubtype recombination between subtypes B and F1 originated a protein variant with higher potential to boost the spread of the recombinant strain that harbors it.Journal of General Virology 12/2012; · 3.36 Impact Factor -
Article: Hepatitis B precore/core promoter mutations in isolates from HBV-monoinfected and HBV-HIV coinfected patients: a 3-yr prospective study.
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ABSTRACT: The course of chronic HBV infection is modified by HIV-coexistence. To analyze the role of HBV genomic heterogeneity in basal core promoter (BCP) and precore (Pc) genomic regions. In a 3-yr prospective study, 39 HBV infected patients (20 monoinfected and 19 HIV-coinfected) were included. Eighty-two HBV isolates were studied at quasispecies level in the BCP/Pc genomic region. Clinical records obtained include data on lamivudine therapy and resistance mutations, HBV and HIV-viral load. HBV isolates were predominantly ascribed to genotype (Gt) A2 among HBV-monoinfected and HIV-coinfected patients. BCP mutations in isolates from monoinfected patients were significantly more frequent than in those from coinfected ones, irrespective of the HBe expression pattern (p<0.0001). Regardless of the HIV-coexistence, the Pc mutation at G1896A only barely appeared among clone-derived sequences of GtF1 isolates, mainly from HBe(-) HBV-monoinfected patients. HBV isolates characterized from HIV-coinfected patients seem to be more prone to exhibit a wild type genomic pattern at BCP regulatory region with respect to those from HBV-monoinfected ones. Besides, mutations at Pc region might be genotype-dependent in their frequency but not on HIV co-presence related.Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 10/2009; 46(4):354-9. · 3.12 Impact Factor -
Article: Single Nef proteins from HIV type 1 subtypes C and F fail to upregulate invariant chain cell surface expression but are active for other functions.
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ABSTRACT: HIV-1 Nef protein plays a major role in viral immunopathogenesis, modulating surface expression of several immune receptors, altering signal transduction pathways, and enhancing viral infectivity, among other activities. Nef also exhibits great intersubtype diversity, but most studies have been focused only on Nef proteins from subtype B. Thus, little is known about the functional capacities of nonsubtype B Nef proteins in host cells. Here, we investigated cell surface regulation of MHC-I, MHC-II, the MHC-II-associated chaperone invariant chain (Ii), CD4, CD3, and CD28 in cells transfected or infected with five different Nef alleles including one HIV-1 subtype C and F allele. No significant difference among the Nef proteins regarding CD3, CD28, and MHC-II downregulation was observed. The NefC showed a slightly, yet significant, diminished capacity to downregulate MHC-I in all cells, as well as to downregulate CD4 in Jurkat cells and PBMCs. Strikingly, the two alleles from NefC and NefF were unable to upregulate the Ii chain both in transfected and infected cells. Moreover, the internalization rate of the surface Ii chain was only slightly affected by NefC and NefF, whereas it was drastically reduced by NefB. Nef domains known to be involved in Ii chain upregulation were conserved among the five alleles analyzed here. In summary, we identified two primary HIV-1 NefC and NefF alleles that are selectively impaired for Ii upregulation and that may help to elucidate the mechanism of this Nef function in the future. It will be important to determine whether the observed differences are HIV-1 subtype dependent and influence viral immunopathogenesis.AIDS research and human retroviruses 04/2009; 25(3):285-96. · 2.18 Impact Factor -
Article: Magnitude, breadth, and functional profile of T-cell responses during human immunodeficiency virus primary infection with B and BF viral variants.
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ABSTRACT: The molecular pattern of the human immunodeficiency virus (HIV) epidemic in Argentina provides an appropriate scenario to study cellular immune responses in patients with non-clade B infection. We aimed to map T-cell responses in patients infected with BF recombinant variants and compare them with those of clade B patients. Sixteen recently infected patients were enrolled and grouped by viral subtype. Nef-specific responses were evaluated with a peptide matrix-based gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay using B and BF overlapping peptides. Cross-clade and clade-specific responses were found. A correlation between B versus BF Nef-specific responses was identified. Detailed analysis at the single-peptide level revealed that BF patients show a narrower response but greater magnitude. Nef immunodominant responses agreed with previous publications, although the B loop was targeted at an unexpectedly high frequency. The putative HLA allele(s) restricting each positive response was determined. Single-peptide level screening with two different peptide sets uncovered discordant responses (mostly caused by peptide offsetting) and allowed detection of increased breadth. Positive responses identified by ELISPOT assay were further studied by intracellular cytokine staining. These were almost exclusively mediated by CD8 T cells. Characterization of concordant responses revealed that cells show distinct functional profiles, depending on the peptide presented. Last, quality (in terms of polyfunctionality) of T cells was associated with better viral replication containment. Overall, interclade differences in the frequency of epitopes recognized, structural domains targeted, and magnitude of responses were identified. Screening T-cell responses with multiple sets increased sensitivity. Further support for the notion of polyfunctional CD8(+) T-cell requirement to better control viral replication is also provided.Journal of Virology 04/2008; 82(6):2853-66. · 5.40 Impact Factor -
Article: [HBV and HCV co-infections in HIV positive patients in the "HAART era": new challenges].
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ABSTRACT: Co-infections with HIV and HCV/HBV are frequently found due to the similar routes of transmission (sexual, parenteral and vertical). Since the introduction of highly active antiretroviral therapy (HAART) there has been a notably decrease in patients morbidity and mortality, nevertheless with the prolonged survival, many of these patients are at risk of developing chronic complication, secondary to the infection of hepatotropic viruses. End stage liver disease is one of the main causes of morbid-mortality among HIV patients in developed countries. Nowadays there are new available therapies, diagnostic and follow up techniques for HBV and HCV, what provides a better control of both co-infections.Medicina 02/2007; 67(1):82-91. · 0.47 Impact Factor -
Article: Human immunodeficiency virus type 1 and other viral co-infections among young heterosexual men and women in Argentina.
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ABSTRACT: Infections with hepatitis C virus, (HCV), hepatitis B virus (HBV), and human T lymphotropic type I/II (HTLV-I/II) virus are commonly found in patients infected with human immunodeficiency virus type 1 (HIV-1). We conducted a seroepidemiologic study among 174 HIV-positive heterosexuals in Buenos Aires, Argentina in 1999. Evidence of exposure to HCV, HBV, and HTLV-I/II was found in 32%, 17%, and 5%, respectively. A higher prevalence of HBV infection was observed among males (33%) compared with females (12%; P < 0.05). Among women, a prior history of a sexually transmitted infection, injecting drug use (IDU), having had more than five lifetime sex partners, and having exchanged sex-for-goods were significantly associated with HCV infection, whereas an IDU history, syringe sharing, and having exchanged sex-for-goods were found to be associated with HBV infection. Among men, an IDU history and syringe/needle sharing were significantly associated with HCV infection. The IDU-related and sexual transmission of hepatitis viruses constitute a significant problem among young, HIV-infected, heterosexuals in Argentina.The American journal of tropical medicine and hygiene 09/2004; 71(2):153-9. · 2.59 Impact Factor -
Article: Origin of human immunodeficiency virus type 1 quasispecies emerging after antiretroviral treatment interruption in patients with therapeutic failure.
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ABSTRACT: The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure.Journal of Virology 08/2002; 76(14):7000-9. · 5.40 Impact Factor -
Article: Two HIV-1 epidemics in Argentina: different genetic subtypes associated with different risk groups.
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ABSTRACT: This study determined the risk behaviors and viral subtypes of HIV-1 found in 134 heterosexual HIV-seroprevalent maternity patients, 41 of their sexual partners (men who have sex with women [MSW]), and 95 homosexual men (men who have sex with men [MSM]) from Buenos Aires, Argentina. Peripheral blood mononuclear cells (PBMCs) were purified from blood and used for DNA extraction, amplification, and genotyping by the envelope heteroduplex mobility assay (env HMA). Most of the women had been infected by having sex with an already infected partner (84%), whereas most of the male partners had been infected via drug use (76%). Both the patients and their sexual partners were poorly educated, only 30% having completed secondary school. The MSM study subjects, however, were significantly better educated and had a lower prevalence of injecting drug use.Env HMA subtype F was found in 77% (103 of 134) of the maternity patients, with similar rates in their partners (73%). Most of the remaining samples were env subtype B. All but one of the couples was concordant in subtype. In the MSM risk group, however, only 10% were env HMA subtype F. Ninety percent of the MSM samples were subtype B. There are at least two independent epidemics of HIV-1 infection in Buenos Aires, Argentina. One, in heterosexual men and women, is dominated by env subtype F whereas the other, in homosexual men, is dominated by env subtype B, as determined by env HMA.JAIDS Journal of Acquired Immune Deficiency Syndromes 05/2002; 29(4):422-6. · 4.43 Impact Factor -
Article: Higher rate of toxicity with no increased efficacy when hydroxyurea is added to a regimen of stavudine plus didanosine and nevirapine in primary HIV infection.
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ABSTRACT: Twenty-four subjects presenting at a single treatment center with primary HIV infection were enrolled in a pilot study aimed to establish the possible role of hydroxyurea in this setting. Study participants were randomly assigned to receive or not to receive hydroxyurea in addition to stavudine (d4T) plus didanosine (ddI) and nevirapine (NVP). Seventy-five percent of patients without hydroxyurea had plasma HIV RNA below 50 copies/mL at 48 weeks by both intention-to-treat (ITT) and on-treatment (OT) analysis in comparison with 50% (ITT) and 67% (OT) of patients with hydroxyurea (p >.1). A median increase of >200 cells/mm3 was observed from baseline to week 48 whether or not hydroxyurea was included in the regimen. Overall, in 12 patients treated with hydroxyurea, 33 adverse events were reported versus 19 reported for 12 patients who did not receive hydroxyurea (p <.05). Our results suggest that that adding hydroxyurea to a regimen of d4T plus ddI and NVP increases toxicity without improving the antiviral effect.JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2002; 29(4):368-73. · 4.43 Impact Factor
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Institutions
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2007–2008
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University of Buenos Aires
- • Facultad de Medicina
- • Departamento de Microbiología
Buenos Aires, Buenos Aires F.D., Argentina
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