Early and Prolonged Antiretroviral Therapy Is Associated with an HIV-1-Specific T-Cell Profile Comparable to That of Long-Term Non-Progressors

Background: Intervention with antiretroviral treatment (ART) and control of viral replication at the time of HIV-1 seroconversion may curtail cumulative immunological damage. We have therefore hypothesized that ART maintenance over a very prolonged period in HIV-1 seroconverters could induce an immuno-virological status similar to that of HIV-1 long-term non-progressors (LTNPs).Methodology/Principal Findings: We have investigated a cohort of 20 HIV-1 seroconverters on long-term ART (LTTS) and compared it to one of 15 LTNPs. Residual viral replication and reservoirs in peripheral blood, as measured by cell-associated HIV-1 RNA and DNA, respectively, were demonstrated to be similarly low in both cohorts. These two virologically matched cohorts were then comprehensively analysed by polychromatic flow cytometry for HIV-1-specific CD4(+) and CD8(+) T-cell functional profile in terms of cytokine production and cytotoxic capacity using IFN-gamma, IL-2, TNF-alpha production and perforin expression, respectively. Comparable levels of highly polyfunctional HIV-1-specific CD4(+) and CD8(+) T-cells were found in LTTS and LTNPs, with low perforin expression on HIV-1-specific CD8+ T-cells, consistent with a polyfunctional/non-cytotoxic profile in a context of low viral burden.Conclusions: Our results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs, strengthening the recent emphasis on the positive impact of early treatment initiation and paving the way for further interventions to promote virological control after treatment interruption

T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy

HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy

Species-Specific Traits Rather Than Resource Partitioning Mediate Diversity Effects on Resource Use

Background: The link between biodiversity and ecosystem processes has firmly been established, but the mechanisms underpinning this relationship are poorly documented. Most studies have focused on terrestrial plant systems where resource use can be difficult to quantify as species rely on a limited number of common resources. Investigating resource use at the bulk level may not always be of sufficient resolution to detect subtle differences in resource use, as species-specific nutritional niches at the biochemical level may also moderate diversity effects on resource use. Methodology/Principal Findings: Here we use three co-occurring marine benthic echinoderms (Brissopsis lyrifera, Mesothuria intestinalis, Parastichopus tremulus) that feed on the same phytodetrital food source, to determine whether resource partitioning is the principal mechanism underpinning diversity effects on resource use. Specifically we investigate the use of phytodetrital pigments ( chlorophylls and carotenoids) because many of these are essential for biological functions, including reproduction. Pigments were identified and quantified using reverse-phase high performance liquid Chromatography ( HPLC) and data were analysed using a combination of extended linear regression with generalised least squares (GLS) estimation and standard multivariate techniques. Our analyses reveal no species-specific selectivity for particular algal pigments, confirming that these three species do not partition food resources at the biochemical level. Nevertheless, we demonstrate increased total resource use in diverse treatments as a result of selection effects and the dominance of one species (B. lyrifera). Conclusion: Overall, we found no evidence for resource partitioning at the biochemical level, as pigment composition was similar between individuals, which is likely due to plentiful food availability. Reduced intra-specific competition in the species mixture combined with greater adsorption efficiency and differences in feeding behaviour likely explain the dominant use of resources by B. lyrifera

Spleen stiffness measurement can predict clinical complications in compensated HCV-related cirrhosis: a prospective study

Hepatic venous pressure gradient (HVPG) measurement represents the best predictor of clinical decompensation (CD) in cirrhotic patients. Recently data show that measurement of spleen stiffness (SS) has an excellent correlation with HVPG levels. Aim of the present prospective study was to assess SS predictive value for CD compared to HVPG, liver stiffness (LS), and other non-invasive tests for portal hypertension in a cohort of patients with HCV-related compensated cirrhosis

Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis

BACKGROUND & AIMS: The hepatic vein pressure gradient (HVPG) is the standard used to determine the degree of portal hypertension (PH) and an important prognostic factor for patients with cirrhosis; HVPG values correlate with the presence of esophageal varices (EV). However, HVPG can only be accurately determined at specialized centers; noninvasive methods are needed to predict HVPG values and the presence of EV. We compared the diagnostic performance of spleen stiffness (SS) measurement by transient elastography with that of liver stiffness (LS) and of other recently proposed noninvasive tests. METHODS: We measured SS and LS in 100 consecutive patients with hepatitis C virusinduced cirrhosis. Patients were also assessed by FibroScan, HVPG, esophagogastroduodenoscopy, and liver biopsy. We also analyzed LSspleen diameter to platelet ratio score and platelet count to spleen diameter. RESULTS: SS and LS were more accurate than other noninvasive parameters in identifying patients with EV and different degrees of PH. A linear model that included SS and LS accurately predicted HVPG values (R 2 = 0.85). The results were internally validated using bootstrap analysis. CONCLUSIONS: Measurement of SS can be used for noninvasive assessment and monitoring of PH and to detect EV in patients with hepatitis C virusinduced cirrhosi

Human immunodeficiency virus-1 B and non-B subtypes with the same drug resistance pattern respond similarly to antiretroviral therapy.

We analysed the 12-week virological response to protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) therapy in 1108 patients carrying B or non-B human immunodeficiency virus (HIV)-1 subtypes with matched resistance mutation patterns. Response rates were not significantly different for non-B and B subtypes stratified for treatment status (51.5% vs. 41.5% in naïve patients; 46.7% vs. 38.7% in experienced patients) or regimens (46.9% vs. 39.7% with PI; 56.7% vs. 40% with NNRTI). No difference in response was detected in patients harbouring B and non-B subtypes with any resistance profile. Further studies are advisable to fully test this approach on larger datasets