María Eugenia Socías

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 Preservation of the CD4+ T-Cell Compartment

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 6 months from infection (primary HIV infection [PHI] group), 16 chronically infected subjects, 11 elite controllers (EC), and 10 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 a higher capacity to degranulate and to mediate VIA) and to simultaneously produce IFN-γ. Finally, Gag immunodominance was associated with elevated plasma levels of interleukin 2 (IL-2) and macrophage inflammatory protein 1β (MIP-1β). All together, 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 postinfection.

Factors associated with healthcare avoidance among transgender women in Argentina

IntroductionTransgender (TG) women in many settings continue to contend with barriers to healthcare, including experiences of stigma and discrimination. Argentina has a universal health care system and laws designed to promote healthcare access among TG women. However, little is known about barriers to healthcare access among TG women in this setting. The aim of this study was to explore individual, social-structural and environmental factors associated with healthcare avoidance among TG women in Argentina.MethodsData were derived from a 2013 nation-wide, cross-sectional study involving TG women in Argentina. We assessed the prevalence and factors associated with avoiding healthcare using multivariable logistic regression.ResultsAmong 452 TG women included in the study, 184 (40.7%) reported that they avoided seeking healthcare because of their transgender identity. In multivariable analysis, factors positively associated with avoiding seeking healthcare were: having been exposed to police violence (adjusted odd ratio [aOR] = 2.20; 95% CI: 1.26 - 3.83), internalized stigma (aOR = 1.60, 95% CI: 1.02-2.51), having experienced discrimination by healthcare workers (aOR = 3.36: 95% CI: 1.25 - 5.70) or patients (aOR = 2.57; 95% CI: 1.58 - 4.17), and currently living in the Buenos Aires metropolitan area (aOR = 2.32; 95% CI: 1.44 - 3.76). In contrast, TG women with extended health insurance were less likely to report avoiding healthcare (aOR = 0.49; 95% CI: 0.26 - 0.93).ConclusionsA high proportion of TG women in our sample reported avoiding healthcare. Avoiding healthcare was associated with stigma and discrimination in healthcare settings, as well as police violence experiences. Although further research is warranted, these finding suggests that socio-structural interventions tailored TG women needs are needed to improve access to healthcare among this population.

Th17 and Th17/Treg ratio at early HIV infection associate with protective HIV-specific CD8 + T-cell responses and disease progression

The aim of this study was to analyze Th17 and Treg subsets and their correlation with anti-HIV T-cell responses and clinical parameters during (acute/early) primary HIV infection (PHI) and up to one year post-infection (p.i). Samples from 14 healthy donors (HDs), 40 PHI patients, 17 Chronics, and 13 Elite controllers (ECs) were studied. The percentages of Th17 and Treg subsets were severely altered in Chronics, whereas all HIV-infected individuals (including ECs) showed Th17/Treg imbalance compared to HDs, in concordance with higher frequencies of activated CD8+ T-cells (HLA-DR+/CD38+). Better clinical status (higher CD4 counts, lower viral loads and activation) was associated with higher Th17 and lower Treg levels. We found positive correlations between Th17 at baseline and anti-HIV CD8+ T-cell functionality: viral inhibitory activity (VIA) and key polyfunctions (IFN-γ+/CD107A/B+) at both early and later times p.i, highlighting the prognostic value of Th17 cells to preserve an effective HIV T-cell immunity. Th17/Treg ratio and the IL-17 relative mean fluorescence intensity (rMFI of IL-17) were also positively correlated with VIA. Taken together, our results suggested a potential link between Th17 and Th17/Treg ratio with key HIV-specific CD8+ T-cell responses against the infection.

Comparative efficacy and safety of first-line antiretroviral therapy for the treatment of HIV infection: a systematic review and network meta-analysis

BACKGROUND New antiretroviral therapy (ART) regimens for HIV could improve clinical outcomes for patients. To inform global guidelines, we aimed to assess the comparative effectiveness of recommended ART regimens for HIV in ART-naive patients. METHODS For this systematic review and network meta-analysis, we searched for randomised clinical trials published up to July 5, 2015, comparing recommended antiretroviral regimens in treatment-naive adults and adolescents (aged 12 years or older) with HIV. We extracted data on trial and patient characteristics, and the following primary outcomes: viral suppression, mortality, AIDS defining illnesses, discontinuations, discontinuations due to adverse events, and serious adverse events. We synthesised data using network meta-analyses in a Bayesian framework and included older treatments, such as indinavir, to serve as connecting nodes. We defined network nodes in terms of specific antivirals rather than specific ART regimens. We categorised backbone regimens and adjusted for them through group-specific meta-regression. We used the GRADE framework to interpret the strength of inference. FINDINGS We identified 5865 citations through database searches and other sources, of which, 126 articles related to 71 unique trials were included in the network analysis, including 34 032 patients randomly assigned to 161 treatment groups. For viral suppression at 48 weeks, compared with efavirenz, the odds ratio (OR) for viral suppression was 1·87 (95% credible interval [CrI] 1·34-2·64) with dolutegravir and 1·40 (1·02-1·96) with raltegravir; with respect to viral suppression, low-dose efavirenz was similar to all other treatments. Both low-dose efavirenz and integrase strand transfer inhibitors tended to be protective of discontinuations due to adverse events relative to normal-dose efavirenz. The most protective effect relative to efavirenz in network meta-analyses was that of dolutegravir (OR 0·26, 95% CrI 0·14-0·47), followed by low-dose efavirenz (0·39, 0·16-0·92). Owing to insufficient data, we could make no conclusions about serious adverse events. Low event rates also limited the quality of evidence with regard to mortality and AIDS defining illnesses. INTERPRETATION The efficacy and safety of ART has substantially improved with the introduction of newer drug classes of antiretrovirals that are now available to patients and HIV care providers. Their improved tolerance could be part of a larger solution to improve retention, which is a challenge, particularly in low-income and middle-income country settings. FUNDING The World Health Organization.

Early Skewed Distribution of Total and HIV-Specific CD8+ T-Cell Memory Phenotypes during Primary HIV Infection Is Related to Reduced Antiviral Activity and Faster Disease Progression

The important role of the CD8+ T-cells on HIV control is well established. However, correlates of immune protection remain elusive. Although the importance of CD8+ T-cell specificity and functionality in virus control has been underscored, further unraveling the link between CD8+ T-cell differentiation and viral control is needed. Here, an immunophenotypic analysis (in terms of memory markers and Programmed cell death 1 (PD-1) expression) of the CD8+ T-cell subset found in primary HIV infection (PHI) was performed. The aim was to seek for associations with functional properties of the CD8+ T-cell subsets, viral control and subsequent disease progression. Also, results were compared with samples from Chronics and Elite Controllers. It was found that normal maturation of total and HIV-specific CD8+ T-cells into memory subsets is skewed in PHI, but not at the dramatic level observed in Chronics. Within the HIV-specific compartment, this alteration was evidenced by an accumulation of effector memory CD8+ T (TEM) cells over fully differentiated terminal effector CD8+ T (TTE) cells. Furthermore, higher proportions of total and HIV-specific CD8+ TEM cells and higher HIV-specific TEM/(TEM+TTE) ratio correlated with markers of faster progression. Analysis of PD-1 expression on total and HIV-specific CD8+ T-cells from PHI subjects revealed not only an association with disease progression but also with skewed memory CD8+ T-cell differentiation. Most notably, significant direct correlations were obtained between the functional capacity of CD8+ T-cells to inhibit viral replication in vitro with higher proportions of fully-differentiated HIV-specific CD8+ TTE cells, both at baseline and at 12 months post-infection. Thus, a relationship between preservation of CD8+ T-cell differentiation pathway and cell functionality was established. This report presents evidence concerning the link among CD8+ T-cell function, phenotype and virus control, hence supporting the instauration of early interventions to prevent irreversible immune damage.

Inclusion of trans women in pre-exposure prophylaxis trials: a review

Trans women are at high risk of HIV infection. We conducted a review to determine the extent to which trans women were eligible for inclusion in and enrolled into pre-exposure prophylaxis (PrEP) efficacy trials. Out of seven trials analyzing PrEP efficacy, we found that trans women comprised only 1.2% of one trial and 0.2% of total trial enrollments. Although an additional PrEP trial to determine efficacy among trans women may not be warranted, further research is needed to determine the effectiveness of PrEP in this marginalized population, through observational and feasibility studies. These studies should focus on unique barriers that trans women may experience while obtaining access to PrEP, such as gender discrimination, transphobia, and violence.

Env-Specific IgA from Viremic HIV-Infected Subjects Compromises Antibody-Dependent Cellular Cytotoxicity

ABSTRACT Elucidating the factors that modulate HIV-specific antibody-dependent cellular cytotoxicity (ADCC) will help in understanding its role in HIV immunity. The aim of this study was to determine whether IgA could modify the magnitude of ADCC in HIV infection, abrogating its protective role. Plasma samples from 20 HIV-positive (HIV+) subjects enrolled during primary HIV infection (PHI), 10 chronically infected subjects (chronic), and 7 elite controllers (EC) were used. ADCC was determined by using a fluorometric ADCC assay, before and after removal of plasma IgA. Data were analyzed by using nonparametric statistics. ADCC was documented in 80% of PHI enrollment samples and in 100% of PHI 12-month, chronic, and EC samples; it peaked after acute infection, reached a plateau in chronic infection, and decreased after initiation of antiretroviral treatment (ART). Significant associations between ADCC and disease progression were found only after removal of plasma IgA from 12-month PHI samples: the magnitude of ADCC not only increased after IgA removal but also correlated with CD4+ T-cell preservation. This work provides evidence that gp120-specific IgA was capable of modifying ADCC responses during natural HIV infection for the first time and adds to similar evidence provided in other settings. Furthermore, it underscores the complexity of the ADCC phenomenon and will help in an understanding of its underlying mechanisms. IMPORTANCE Although the induction of ADCC-mediating antibodies in HIV-infected subjects has been extensively documented, the association of these antibodies with protection from disease progression is poorly understood. Here, we demonstrate that plasma IgA is a factor capable of modifying the magnitude of IgG-mediated ADCC in HIV infection, mitigating its beneficial effect. These results help in understanding why previous studies failed to demonstrate correlations between ADCC and disease progression, and they also contribute to the notion that an HIV vaccine should stimulate the production of ADCC-mediating IgG antibodies but not IgA.

Prevalence and Correlates of Lifetime Suicide Attempts Among Transgender Persons in Argentina

ABSTRACT This study examined the lifetime prevalence and correlates of attempted suicide among transgender persons in Argentina. Data were derived from a nation-wide, cross-sectional survey conducted in 2013. We assessed individual, social, and structural correlates of reporting a history of attempting suicide using logistic regression. Among 482 participants, the median age was 30, 91% identified as transwomen, and 32% resided in the Buenos Aires metropolitan area. A lifetime suicide attempt was reported by 159 (33%), among whom the median age at first attempt was 17. In a multivariate model, internalized stigma was positively associated with a history of suicidal behavior, while participants with stable housing had reduced odds of prior suicide attempt(s). These findings suggest that reducing stigma and mitigating structural vulnerabilities (through, for example, the enactment and enforcement of laws that prohibit discrimination based on gender identity to ensure equitable access to housing) could be effective targets for intervention to reduce suicide attempts among transgender individuals in Argentina.

Towards full citizenship: correlates of engagement with the gender identity law among transwomen in Argentina.

Introduction In May 2012, Argentina passed its “Gender Identity” Law, which aimed to address the legal invisibility, discrimination and marginalization that transgender individuals have historically faced. The aim of this study was to explore factors associated with engagement with the Gender Identity Law among transwomen living in Argentina. Methods Data were derived from a 2013 nationwide, cross-sectional study involving transwomen in Argentina. Using multivariate logistic regression, we assessed the prevalence and factors associated with acquiring a gender-congruent identity card within the first 18 months of enactment of the Gender Identity Law. Results Among 452 transwomen, 260 (57.5%) reported that they had obtained a new gender-congruent identity card. In multivariate analysis, factors positively associated with acquiring a new ID were: previously experiencing discrimination by healthcare workers (adjusted odd ratio [aOR] = 2.01, 95% CI: 1.27–3.20); having engaged in transition procedures (aOR = 3.06, 95% CI: 1.58–5.93); and having a job other than sex work (aOR = 1.81, 95% CI: 1.06–3.10). Foreign born transwomen were less likely to have obtained a new ID (aOR = 0.14, 95% CI: 0.06–0.33). Conclusions More than half of transwomen in our sample acquired a new gender-congruent ID within the first 18 months of enactment of the Gender Identity Law. However, access to and uptake of this right has been heterogeneous. In particular, our findings suggest that the most empowered transwomen may have been among the first to take advantage of this right. Although educational level, housing conditions, HIV status and sex work were not associated with the outcome, foreign-born status was a strong negative correlate of new ID acquisition. Therefore, additional efforts should be made in order to ensure that benefits of this founding policy reach all transwomen in Argentina.

Host genetic factors associated with symptomatic primary HIV infection and disease progression among Argentinean seroconverters.

Background Variants in HIV-coreceptor C-C chemokine receptor type 5 (CCR5) and Human leukocyte antigen (HLA) genes are the most important host genetic factors associated with HIV infection and disease progression. Our aim was to analyze the association of these genetic factors in the presence of clinical symptoms during Primary HIV Infection (PHI) and disease progression within the first year. Methods Seventy subjects diagnosed during PHI were studied (55 symptomatic and 15 asymptomatic). Viral load (VL) and CD4 T-cell count were evaluated. HIV progression was defined by presence of B or C events and/or CD4 T-cell counts <350 cell/mm3. CCR5 haplotypes were characterized by polymerase chain reaction and SDM-PCR-RFLP. HLA-I characterization was performed by Sequencing. Results Symptoms during PHI were significantly associated with lower frequency of CCR5-CF1 (1.8% vs. 26.7%, p = 0.006). Rapid progression was significantly associated with higher frequency of CCR5-CF2 (16.7% vs. 0%, p = 0.024) and HLA-A*11 (16.7% vs. 1.2%, p = 0.003) and lower frequency of HLA-C*3 (2.8% vs. 17.5%, p = 0.035). Higher baseline VL was significantly associated with presence of HLA-A*11, HLA-A*24, and absence of HLA-A*31 and HLA-B*57. Higher 6-month VL was significantly associated with presence of CCR5-HHE, HLA-A*24, HLA-B*53, and absence of HLA-A*31 and CCR5-CF1. Lower baseline CD4 T-cell count was significantly associated with presence of HLA-A*24/*33, HLA-B*53, CCR5-CF2 and absence of HLA-A*01/*23 and CCR5-HHA. Lower 6-month CD4 T-cell count was associated with presence of HLA-A*24 and HLA-B*53, and absence of HLA-A*01 and HLA-B*07/*39. Moreover, lower 12-month CD4 T-cell count was significantly associated with presence of HLA-A*33, HLA-B*14, HLA-C*08, CCR5-CF2, and absence of HLA-B*07 and HLA-C*07. Conclusion Several host factors were significantly associated with disease progression in PHI subjects. Most results agree with previous studies performed in other groups. However, some genetic factor associations are being described for the first time, highlighting the importance of genetic studies at a local level.