Publications

Background

We examine changes in soluble inflammatory cytokines and T-cell activation after antiretroviral therapy (ART) initiation in an ACTG nested case-control study.

Methods

Cases were 143 HIV-infected adults who developed a non-AIDS event; 315 controls remained event-free. Specimens were tested pre-ART, year 1 post-ART and at the visit preceding the event. Conditional logistic regression evaluated the associations of biomarker changes with non-AIDS events.

Results

Inflammatory and most activation biomarkers declined from pre-ART to year 1 for cases and controls. Subsequently, inflammatory biomarkers remained mostly stable in controls but not cases. Cellular activation markers generally declined for both cases and controls between year 1 and the pre-event sampling. Controls with greater pre-ART RNA levels or lower CD4+ levels had higher biomarker levels while also experiencing greater biomarker declines in the first year of ART. Changes in biomarkers to year 1 showed no significant associations with non-AIDS events. Cases, however, had significantly greater increases in all plasma biomarkers (but not cellular activation) from year 1 to the visit preceding the event.

Conclusions

Inflammation increases prior to non-AIDS events in treated HIV-infected adults. These biomarker changes may reflect subclinical disease processes or other alterations in the inflammatory environment that causally contribute to disease.

Clinical Trials registration

NCT00001137 https://clinicaltrials.gov/ct2/show/NCT00001137.

The contribution of the host immune system to the efficacy of new anti-hepatitis C virus (HCV) drugs is unclear. We undertook a longitudinal prospective study of 33 individuals with chronic HCV treated with combination pegylated IFN-α, ribavirin, and telaprevir/boceprevir. We characterized innate and adaptive immune cells to determine whether kinetics of the host response could predict sustained virologic response (SVR). We show that characteristics of the host immune system present before treatment were correlated with successful therapy. Augmentation of adaptive immune responses during therapy was more impressive among those achieving SVR. Most importantly, active memory T cell proliferation before therapy predicted SVR and was associated with the magnitude of the HCV-specific responses at week 12 after treatment start. After therapy initiation, the most important correlate of success was minimal monocyte activation, as predicted by previous in vitro work. In addition, subjects achieving SVR had increasing expression of the transcription factor T-bet, a driver of Th1 differentiation and cytotoxic effector cell maturation. These results show that host immune features present before treatment initiation predict SVR and eventual development of a higher frequency of functional virus-specific cells in blood. Such host characteristics may also be required for successful vaccine-mediated protection.

BACKGROUND

Inflammation is associated with the downregulation of drug metabolizing enzymes and transporters. Thus, we investigated the chronic inflammatory state associated with HIV-infection as a source of pharmacokinetic variability of atazanavir. We also explored the association of total bilirubin concentrations with markers of inflammation and endothelial activation.

METHODS

Apparent oral clearance (CL/F) of atazanavir was estimated from plasma samples collected from participants in AIDS Clinical Trials Group Study A5202. Several inflammatory and endothelial activation biomarkers were measured at baseline and weeks 24 and 96 as part of metabolic sub-study A5224s: high-sensitivity C-reactive protein (hsCRP), interleukin-6, tumor necrosis factor alpha and its soluble receptors, soluble vascular cellular and intracellular adhesion molecules, and total bilirubin. Statistical analysis was performed by a matrix of correlation coefficients between atazanavir CL/F and biomarker concentrations measured at week 24. The correlation between atazanavir clearance and percentage change in bilirubin from baseline to weeks 24 and 96, and between biomarkers and bilirubin concentrations at each week were also evaluated.

RESULTS

Among 107 participants, there were no significant correlations observed between atazanavir CL/F and inflammatory and endothelial activation biomarkers measured at week 24 (P ≥ 0.24). As expected, bilirubin increased with increasing exposure to atazanavir (rho = - 0.25, P = 0.01). Bilirubin concentrations were inversely correlated (P < 0.01) with each of the biomarkers except hsCRP.

CONCLUSIONS

Atazanavir CL/F did not correlate with the inflammatory biomarkers changes. Inflammatory-mediated inhibition of cytochrome P450 3A may have been attenuated due to atazanavir-associated increases of bilirubin, which has known anti-inflammatory properties.

Tissue-resident memory (T) CD8 T-cells are non-recirculating, long-lived cells housed in tissues that can confer protection against mucosal pathogens. Human immunodeficiency virus-1 (HIV-1) is a mucosal pathogen and the gastrointestinal tract is an important site of viral pathogenesis and transmission. Thus, CD8 T cells may be an important effector subset for controlling HIV-1 in mucosal tissues. This study sought to determine the abundance, phenotype, and functionality of CD8 T cells in the context of chronic HIV-1 infection. We found that the majority of rectosigmoid CD8 T-cells were CD69CD103S1PR1 and T-betEomesodermin, indicative of a tissue-residency phenotype similar to that described in murine models. HIV-1-specific CD8 T responses appeared strongest in individuals naturally controlling HIV-1 infection. Two CD8 T subsets, distinguished by CD103 expression intensity, were identified. CD103 CD8 T primarily displayed a transitional memory phenotype and contained HIV-1-specific cells and cells expressing high levels of Eomesodermin, whereas CD103 CD8 T primarily displayed an effector memory phenotype and were Eomesodermin. These findings suggest a large fraction of CD8 T-cells housed in the human rectosigmoid mucosa are tissue-resident and that T contribute to the anti-HIV-1 immune response. Further exploration of CD8 T will inform development of anti-HIV-1 immune-based therapies and vaccines targeted to the mucosa.

OBJECTIVES

HIV-1 subtypes A1 and D cocirculate in a rural community in Mbarara, Uganda. This study examines HIV-1 intersubtype recombination in this community under a full-genome sequencing context. We aim to estimate prevalence, examine time trends, and test for clinical correlates and outcomes associated with intersubtype recombinants.

METHODS

Near-full-genome HIV-1 Sanger sequence data were collected from plasma samples of 504 treatment-naïve individuals, who then received protease inhibitor or nonnucleoside reverse transcriptase inhibitor-containing regimens and were monitored for up to 7.5 years. Subtypes were inferred by Los Alamos Recombinant Identification Program (RIP) 3.0 and compared with Sanger/REGA and MiSeq/RIP. 'Nonrecombinants' and 'recombinants' infections were compared in terms of pretherapy viral load, CD4 cell count, posttherapy time to virologic suppression, virologic rebound, first CD4 rise above baseline and sustained CD4 recovery.

RESULTS

Prevalence of intersubtype recombinants varied depending on the genomic region examined: gag (15%), prrt (11%), int (8%), vif (10%), vpr (2%), vpu (9%), GP120 (8%), GP41 (18%), and nef (4%). Of the 200 patients with near-full-genome data, prevalence of intersubtype recombination was 46%; the most frequently observed recombinant was A1-D (25%). Sanger/REGA and MiSeq/RIP yielded generally consistent results. Phylogenetic tree revealed most recombinants did not share common ancestors. No temporal trend was observed (all P > 0.1). Subsequent subtype switches were detected in 27 of 143 (19%) study participants with follow-up sequences. Nonrecombinant versus recombinants infections were not significantly different in any pre nor posttherapy clinical correlates examined (all P > 0.2).

CONCLUSION

Intersubtype recombination was highly prevalent (46%) in Uganda if the entire HIV genome was considered, but was neither associated with clinical correlates nor therapy outcomes.