The microbiome as a biomarker of anal precancerous lesions in people with HIV.

PURPOSE OF REVIEW: Early detection and treatment of human papillomavirus (HPV)-related anal dysplasia in some high-risk groups can help anal cancer prevention, but new tools to improve diagnostic and risk assessment are needed. Here, we aim to discuss the evidence on the role of the microbiome as a potential biomarker for anal high-grade squamous intraepithelial lesions (HSILs) in people with HIV (PWH). RECENT FINDINGS: This review covers relevant studies on the links between the microbiome and HPV infection, cervical dysplasia/cancer, and anal HPV disease. It focuses on anal samples and precancerous lesions. SUMMARY: The review highlights the promising potential of the anal microbiome as a novel biomarker for precancerous lesions in people with HIV, while also discussing limitations and future research needs.

Proteomic snapshot of saliva samples predicts new pathways implicated in SARS-CoV-2 pathogenesis.

BACKGROUND: Information on the microbiome's human pathways and active members that can affect SARS-CoV-2 susceptibility and pathogenesis in the salivary proteome is very scarce. Here, we studied a unique collection of samples harvested from April to June 2020 from unvaccinated patients. METHODS: We compared 10 infected and hospitalized patients with severe (n = 5) and moderate (n = 5) coronavirus disease (COVID-19) with 10 uninfected individuals, including non-COVID-19 but susceptible individuals (n = 5) and non-COVID-19 and nonsusceptible healthcare workers with repeated high-risk exposures (n = 5). RESULTS: By performing high-throughput proteomic profiling in saliva samples, we detected 226 unique differentially expressed (DE) human proteins between groups (q-value ≤ 0.05) out of 3376 unambiguously identified proteins (false discovery rate ≤ 1%). Major differences were observed between the non-COVID-19 and nonsusceptible groups. Bioinformatics analysis of DE proteins revealed human proteomic signatures related to inflammatory responses, central cellular processes, and antiviral activity associated with the saliva of SARS-CoV-2-infected patients (p-value ≤ 0.0004). Discriminatory biomarker signatures from human saliva include cystatins, protective molecules present in the oral cavity, calprotectins, involved in cell cycle progression, and histones, related to nucleosome functions. The expression levels of two human proteins related to protein transport in the cytoplasm, DYNC1 (p-value, 0.0021) and MAPRE1 (p-value, 0.047), correlated with angiotensin-converting enzyme 2 (ACE2) plasma activity. Finally, the proteomes of microorganisms present in the saliva samples showed 4 main microbial functional features related to ribosome functioning that were overrepresented in the infected group. CONCLUSION: Our study explores potential candidates involved in pathways implicated in SARS-CoV-2 susceptibility, although further studies in larger cohorts will be necessary.

CD4/CD8 Ratio During Human Immunodeficiency Virus Treatment: Time for Routine Monitoring?

In the last decade, studies in persons with HIV (PWH) on antiretroviral therapy (ART) have shed light on the significance of persistently high CD8 counts and low CD4/CD8 ratios. A low CD4/CD8 ratio reflects increased immune activation and is associated with an increased risk of severe non-AIDS events. As a result, many clinicians now believe that the CD4/CD8 ratio can help in HIV monitoring, and many researchers now report it as an efficacy marker in interventional studies. However, the topic is more complex. Recent studies have not yielded unanimous conclusions on the ability of the CD4/CD8 ratio to predict adverse outcomes, and only some clinical guidelines recommend monitoring it. Knowledge gaps remain on the best cutoff points, associated clinical events, effects of treatments, and how the CD4/CD8 ratio could improve decision making in the clinic. Here, we critically review the literature, identify knowledge gaps, and discuss the role of the CD4/CD8 ratio as a marker for HIV monitoring.

Metabolic-Related Outcomes After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in Adults With Human Immunodeficiency Virus (HIV): A Multicenter Prospective Cohort Study.

BACKGROUND: Tenofovir alafenamide (TAF) has replaced tenofovir disoproxil fumarate (TDF) in many clinical settings. However, concerns remain about potential metabolic complications of TAF. We aimed to evaluate changes in weight, laboratory markers, and metabolic-related clinical events after replacing TDF with TAF. METHODS: Multicenter prospective cohort study in the Spanish CoRIS cohort. We included virologically suppressed adults with human immunodeficiency virus (HIV) receiving TDF for more than 12 months who either switched to TAF or maintained TDF, with no changes in the core agent. Participants were matched by propensity score. We fitted generalized equation models to assess changes in weight, blood lipids, and hepatic steatosis index, and to compare the incidence of diabetes, hypertension, and lipid-lowering drug use after 144 weeks. RESULTS: In total, 1446 participants were matched in each group. Median age was 38 years, 85% were male, mean weight at baseline was 73 kg. Participants who switched to TAF had a mean weight increase of +0.5 kg at 144 weeks over those who maintained TDF, with no difference in the occurrence of overweight or obesity. Individuals who switched to TAF had a significant increase in total cholesterol (+7.9 mg/dL) and triglycerides (+11.2 mg/dL), with no differences in the total cholesterol-high-density lipoprotein (HDL) ratio. However, no increased incidence of diabetes, hypertension, or lipid-lowering drug use was observed after the follow-up period. CONCLUSIONS: Switching from TDF to TAF is associated with modest weight gain and increases in total cholesterol and triglycerides, without an impact on the incidence of obesity or metabolic-related clinical events, in this Spanish cohort with a majority White male population.

Contribution of Low CD4 Cell Counts and High Human Immunodeficiency Virus (HIV) Viral Load to the Efficacy of Preferred First-Line Antiretroviral Regimens for Treating HIV Infection: A Systematic Review and Meta-Analysis.

We assessed whether low CD4 count and high viral load (VL) affect the response to currently preferred ART. We performed a systematic review of randomized, controlled clinical trials that analyzed preferred first-line ART and a subgroup analysis by CD4 count (≤ or >200 CD4/µL) or VL (≤ or >100 000 copies/mL). We computed the odds ratio (OR) of treatment failure (TF) for each subgroup and individual treatment arm. Patients with ≤200 CD4 cells or VL ≥100 000 copies/mL showed an increased likelihood of TF at 48 weeks: OR, 1.94; 95% confidence interval (CI): 1.45-2.61 and OR, 1.75; 95% CI: 1.30-2.35, respectively. A similar increase in the risk of TF was observed at 96 weeks. There was no significant heterogeneity regarding integrase strand transfer inhibitor or nucleoside reverse transcriptase inhibitor backbone. Our results show that CD4 <200 cells/µL and VL ≥100,000 copies/mL impair ART efficacy in all preferred regimens.

Global DNA methylation and telomere length as markers of accelerated aging in people living with HIV and non-alcoholic fatty liver disease.

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a comorbidity that generally increases in people living with HIV (PLWH). This condition is usually accompanied by persistent inflammation and premature immune system aging. In this prospective cohort study, we describe a straightforward methodology for quantifying biomarkers of aging, such as DNA methylation and telomere length, in PLWH and in the context of another relevant condition, such as MAFLD. Fifty-seven samples in total, thirty-eight from PLWH and nineteen from non-PLWH participants with or without MAFLD, were obtained and subjected to DNA extraction from peripheral blood mononuclear cells (PBMCs). Global DNA methylation and telomere length quantification were performed using an adapted enzyme-linked immunosorbent assay (ELISA) and qPCR, respectively. The quantification results were analysed and corrected by clinically relevant variables in this context, such as age, sex, and metabolic syndrome. Our results show an increased association of these biomarkers in PLWH regardless of their MAFLD status. Thus, we propose including the quantification of these age-related factors in studies of comorbidities. This will allow a better understanding of the effect of comorbidities of HIV infection and MAFLD and prevent their effects in these populations in the future.

Folliculitis Decalvans Has a Heterogeneous Microbiological Signature and Impaired Immunological Response.

BACKGROUND: Folliculitis decalvans (FD) is a rare primary neutrophilic scarring alopecia whose etiology has not been completely elucidated yet. OBJECTIVE: The aim of the study was to determine if the follicular microbiota residing in FD-affected hair follicles had a distinct microbiological signature and if an aberrant immune response was present in the pathogenesis of FD. METHODS: We conducted a cross-sectional study of 10 patients affected by FD. Trichoscopy-guided follicular biopsies were taken from affected and healthy scalp to identify the follicular microbiome using next-generation sequencing. We searched for microbiological biomarkers of FD-affected follicles using the linear discriminant analysis (LDA) effect size (LEfSe) tool. Additionally, peripheral blood mononuclear cells were obtained, and their cytokine production was quantified after incubation with pathogen-associated molecular patterns isolated from patients' biopsies and compared with healthy controls. RESULTS: ß-diversity analysis showed statistically significant differences regarding bacteria comparing follicular microbiota of healthy and FD-affected hairs. Ruminococcaceae, Agathobacter sp., Tyzzerella sp., and Bacteriodales vadin HA21 family were good predictors of disease status. IL-10, TNF-α, and IL-6 levels were significantly decreased in patients after incubation with various strains of bacteria compared with controls. CONCLUSION: FD hair follicles have a specific heterogenous follicular bacterial microbiota signature. Additionally, these patients seem to have an impaired immunological response.

Metabolic Snapshot of Plasma Samples Reveals New Pathways Implicated in SARS-CoV-2 Pathogenesis.

Despite the scientific and human efforts to understand COVID-19, there are questions still unanswered. Variations in the metabolic reaction to SARS-CoV-2 infection could explain the striking differences in the susceptibility to infection and the risk of severe disease. Here, we used untargeted metabolomics to examine novel metabolic pathways related to SARS-CoV-2 susceptibility and COVID-19 clinical severity using capillary electrophoresis coupled to a time-of-flight mass spectrometer (CE-TOF-MS) in plasma samples. We included 27 patients with confirmed COVID-19 and 29 healthcare workers heavily exposed to SARS-CoV-2 but with low susceptibility to infection ("nonsusceptible"). We found a total of 42 metabolites of SARS-CoV-2 susceptibility or COVID-19 clinical severity. We report the discovery of new plasma biomarkers for COVID-19 that provide mechanistic explanations for the clinical consequences of SARS-CoV-2, including mitochondrial and liver dysfunction as a consequence of hypoxemia (citrulline, citric acid, and 3-aminoisobutyric acid (BAIBA)), energy production and amino acid catabolism (phenylalanine and histidine), and endothelial dysfunction and thrombosis (citrulline, asymmetric dimethylarginine (ADMA), and 2-aminobutyric acid (2-AB)), and we found interconnections between these pathways. In summary, in this first report several metabolic pathways implicated in SARS-CoV-2 susceptibility and COVID-19 clinical progression were found by CE-MS based metabolomics that could be developed as biomarkers of COVID-19.

Effect of the use of Galectin-9 and blockade of TIM-3 receptor in the latent cellular reservoir of HIV-1.

Reactivation of latent HIV-1 is a necessary step for the purging of the viral reservoir, although it does not seem to be enough. The stimulation of HIV-1 specific cytotoxic T lymphocytes (CTL) may be just as essential for this purpose. In this study, we aimed to show the effect of galectin-9 (Gal-9), known to revert HIV-1 latency, in combination with the blockade of TIM-3, a natural receptor for Gal-9 and an exhaustion marker. We confirmed the ability of Gal-9 to reactivate latent HIV-1 in Jurkat-LAT-GFP cells, as well as in an IL-7-based cellular model. This reactivation was not mediated via the TIM-3 receptor, but rather by the recognition of the Gal-9 of a specific oligosaccharide pattern of resting memory CD4+ T cells' surfaces. The potency of Gal-9 in inducing transcription of latent HIV-1 was equal to or greater than that of other latency-reversing agents (LRA). Furthermore, the combination of Gal-9 with other LRA did not show synergistic effects in the reactivation of the latent virus. To evaluate the impact of TIM-3 inhibition on the CTL-response, different co-culture experiments with CD4+T, CD8+ T, and NK cells were performed. Our data showed that blocking TIM-3 was associated with control of viral replication in both in vitro and ex vivo models in cells from PLWH on antiretroviral therapy. A joint strategy of the use of Gal-9 to reactivate latent HIV-1 and the inhibition of TIM-3 to enhance the HIV-1 CTL specific-response was associated with control of the replication of the virus that was being reactivated, thus potentially contributing to the elimination of the viral reservoir. Our results place this strategy as a promising approach to be tested in future studies. Reactivation of latent-HIV-1 by Gal-9 and reinvigoration of CD8+ T cells by TIM-3 blockade could be used separately or in combination.ImportanceHIV-1 infection is a health problem of enormous importance that still causes significant mortality. Antiretroviral treatment (ART) has demonstrated efficacy in the control of HIV-1 replication, decreasing the morbidity and mortality of the infection, but it cannot eradicate the virus. In our work, we tested a protein, galectin-9 (Gal-9), an HIV-1 latency-reversing agent, using an in vitro cellular model of latency and in cells from people living with HIV-1 (PLWH) on antiretroviral therapy. Our results confirmed the potential role of Gal-9 as a molecule with a potent HIV-1 reactivation capacity. More importantly, using a monoclonal antibody against T cell immunoglobulin and the mucin domain-containing molecule 3 (TIM-3) receptor we were able to enhance the HIV-1 cytotoxic T lymphocytes (CTL) specific response to eliminate the CD4+ T cells in which the virus had been reactivated. When used together, i.e., Gal-9 and TIM-3 blockade, control of the replication of HIV-1 was observed, suggesting a decrease in the cellular reservoir.

Exploiting the Microbiota for the Diagnosis of Anal Precancerous Lesions in Men Who Have Sex With Men.

BACKGROUND: While the microbiota has been associated with human papillomavirus malignant transformation, it is unclear whether anal bacteria could improve the low specificity of anal cytology for the screening of high-grade intraepithelial squamous neoplasia (HSIL). METHODS: We recruited men who have sex with men undergoing anal cytology and high-resolution anoscopy. We assessed the microbiota composition from fecal samples and cytobrush anal samples using 16S ribosomal DNA sequencing in participants with or without biopsy-proven HSIL (bHSIL). We selected bacterial biomarkers based on their linear discriminant analysis. We assessed their predictive performance using logistic regression and bootstrap resampling. RESULTS: We included 128 individuals, 47 (36.7%) with bHSIL and 99 (77.3%) with human immunodeficiency virus. We detected 40 potential predictors of bHSIL. Ruminococcaceae NK4A214 group, Alloprevotella genus, Prevotella melanonigenica, and Ruminococcaceae UCG-014 were the most predictive of bHSIL. From 35 false-positive cytologic results, the combination of these 4 biomarkers with the anal cytology reclassified to true-negative 33 individuals (94%) and showed good diagnostic performance (area under the receiver operating characteristic curve, 0.805; 95% confidence interval, .728-.882). CONCLUSIONS: We found anal-associated bacteria indicative of a higher risk of precancerous anal lesions, which combination was highly specific. The microbiota could be developed as a complementary diagnostic tool to overcome the limitations of the current screening strategy for anal cancer.

Blood Bacterial Profiles Associated With Human Immunodeficiency Virus Infection and Immune Recovery.

Human immunodeficiency virus (HIV) infection impairs mucosal immunity and leads to bacterial translocation, fueling chronic inflammation and disease progression. While this is well established, questions remain about the compositional profile of the translocated bacteria, and to what extent it is influenced by antiretroviral therapy (ART). Using 16S ribosomal DNA targeted sequencing and shotgun proteomics, we showed that HIV increases bacterial translocation from the gut to the blood. HIV increased alpha diversity in the blood, which was dominated by aerobic bacteria belonging to Micrococcaceae (Actinobacteria) and Pseudomonadaceae (Proteobacteria) families, and the number of circulating bacterial proteins was also increased. Forty-eight weeks of ART attenuated this phenomenon. We found that enrichment with Lactobacillales order, and depletion of Actinobacteria class and Moraxellaceae and Corynebacteriacae families, were significantly associated with greater immune recovery and correlated with several inflammatory markers. Our findings suggest that the molecular cross talk between the host and the translocated bacterial products could influence ART-mediated immune recovery.

Possible role of HLA class-I genotype in SARS-CoV-2 infection and progression: A pilot study in a cohort of Covid-19 Spanish patients.

Human Leukocyte Antigen (HLA) includes a large set of genes with important actions in immune response against viral infection. Numerous studies have revealed the existence of significant associations between certain HLA alleles and the susceptibility and prognosis of different infectious diseases. In this pilot study we analyse the binding affinity between 66 class I HLA alleles and SARS-CoV-2 viral peptides, and its association with the severity of the disease. A total of 45 Spanish patients with mild, moderate and severe SARS-CoV-2 infection were typed for HLA class I; after that, we analysed if an in silico model of HLA I-viral peptide binding affinity and classical HLA supertypes could be correlated to the severity of the disease. Our results suggest that patients with mild disease present Class I HLA molecules with a higher theoretical capacity for binding SARS-Cov-2 peptides and showed greater heterozygosity when comparing them with moderate and severe groups. In this regard, identifying HLA-SARS-CoV-2 peptides binding differences between individuals would help to clarify the heterogeneity of clinical responses to the disease and will also be useful to guide a personalized treatment according to its particular risk.

Impact of first-line antiretroviral therapy regimens on the restoration of the CD4/CD8 ratio in the CNICS cohort.

BACKGROUND: The CD4/CD8 ratio is an indicator of immunosenescence and a predictor of all-cause mortality in HIV-infected patients. The effects of different ART regimens on CD4/CD8 ratio recovery remain unclear. METHODS: Clinical cohort study of ART-treated patients from the CFAR Network of Integrated Clinical Systems (CNICS). We included ART-naive adults with HIV infection who achieved undetectable HIV RNA during the first 48 weeks of treatment and had additional follow-up 48 weeks after virological suppression (VS). Primary endpoints included increase in CD4/CD8 ratio at both timepoints and secondary endpoints were CD4/CD8 ratio recovery at cut-offs of ≥0.5 or ≥1.0. RESULTS: Of 3971 subjects who met the study criteria, 1876 started ART with an NNRTI, 1804 with a PI and 291 with an integrase strand transfer inhibitor (INSTI). After adjusting for age, sex, race, year of entry, risk group, HCV serostatus, baseline viral load and baseline CD4/CD8 ratio, subjects on an NNRTI showed a significantly greater CD4/CD8 ratio gain compared with those on a PI, either 48 weeks after ART initiation or after 48 weeks of HIV RNA VS. The greater CD4/CD8 ratio improvement in the NNRTI arm was driven by a higher decline in CD8 counts. The INSTI group showed increased rates of CD4/CD8 ratio normalization at the ≥1.0 cut-off compared with the PI group. CONCLUSIONS: NNRTI therapy was associated with a greater increase in the CD4/CD8 ratio compared with PIs. NNRTI- and INSTI-based first-line ART were associated with higher rates of CD4/CD8 ratio normalization at a cut-off of 1.0 than a PI-based regimen, which might have clinical implications.

Effects of Immunonutrition in Advanced Human Immunodeficiency Virus Disease: A Randomized Placebo-controlled Clinical Trial (Promaltia Study).

Background: While nutritional interventions with prebiotics and probiotics seem to exert immunological effects, their clinical implications in human immunodeficiency virus (HIV)-infected subjects initiating antiretroviral therapy (ART) at advanced HIV disease remain unclear. Methods: This was a pilot multicenter randomized, placebo-controlled, double-blind study in which 78 HIV-infected, ART-naive subjects with <350 CD4 T cells/µL or AIDS were randomized to either daily PMT25341 (a mixture of synbiotics, omega-3/6 fatty acids and amino acids) or placebo for 48 weeks, each in combination with first-line ART. Primary endpoints were changes in CD4 T-cell counts and CD4/CD8 ratio from baseline to week 48 and safety. Secondary endpoints were changes in markers of T-cell activation, bacterial translocation, inflammation, and α and ß microbiota diversity. Results: Fifty-nine participants completed the follow-up with a mean CD4+ T-cell count of 221 ± 108 cells/µL and mean CD4/CD8 ratio of 0.26 ± 0.19. PMT25341 was well tolerated, without grade 3-4 adverse effects attributable to the intervention. While most of the assessed biomarkers improved during the follow-up in both arms, PMT25341-treated subjects did not experience any significant change, compared to placebo-treated subjects, in mean CD4+ T-cell count change (278 vs 250 cells/µL, P = .474) or CD4/CD8 ratio change (0.30 vs 0.32, P = .854). Similarly, we did not detect differences between treatment arms in secondary endpoints. Conclusions: In HIV-infected patients initiating ART at advanced disease, the clear immunological benefits of ART were not enhanced by this nutritional intervention targeting the gut-associated lymphoid tissue and microbiota. Clinical Trials Registration: NCT00870363.

Maraviroc Is Associated with Latent HIV-1 Reactivation through NF-κB Activation in Resting CD4+ T Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy.

Maraviroc is a CCR5 antagonist used in the treatment of HIV-1 infection. We and others have suggested that maraviroc could reactivate latent HIV-1. To test the latency-reversing potential of maraviroc and the mechanisms involved, we performed a phase II, single-center, open-label study in which maraviroc was administered for 10 days to 20 HIV-1-infected individuals on suppressive antiretroviral therapy (EudraCT registration no. 2012-003215-66). All patients completed full maraviroc dosing and follow-up. The primary endpoint was to study whether maraviroc may reactivate HIV-1 latency, eliciting signaling pathways involved in the viral reactivation. An increase in HIV-1 transcription in resting CD4+ T cells, estimated by levels of HIV-1 unspliced RNA, was observed. Moreover, activation of the NF-κB transcription factor was observed in these cells. To elucidate the mechanism of NF-κB activation by maraviroc, we have evaluated in HeLa P4 C5 cells, which stably express CCR5, whether maraviroc could be acting as a partial CCR5 agonist, with no other mechanisms or pathways involved. Our results show that maraviroc can induce NF-κB activity and that NF-κB targets gene expression by CCR5 binding, since the use of TAK779, a CCR5 inhibitor, blocked NF-κB activation and functionality. Taking the results together, we show that maraviroc may have a role in the activation of latent virus transcription through the activation of NF-κB as a result of binding CCR5. Our results strongly support a novel use of maraviroc as a potential latency reversal agent in HIV-1-infected patients.IMPORTANCE HIV-1 persistence in a small pool of long-lived latently infected resting CD4+ T cells is a major barrier to viral eradication in HIV-1-infected patients on antiretroviral therapy. A potential strategy to cure HIV-1-infection is the use of latency-reversing agents to eliminate the reservoirs established in resting CD4+ T cells. As no drug has been shown to be completely effective so far, the search for new drugs and combinations remains a priority for HIV cure. We examined the ability of maraviroc, a CCR5 antagonist used as an antiretroviral drug, to activate latent HIV-1 in infected individuals on antiretroviral therapy. The study showed that maraviroc can activate NF-κB and, subsequently, induce latent HIV-1-transcription in resting CD4+ T cells from HIV-1-infected individuals on suppressive antiretroviral therapy. Additional interventions will be needed to eliminate latent HIV-1 infection. Our results suggest that maraviroc may be a new latency-reversing agent to interfere with HIV-1 persistence during antiretroviral therapy.

Correction: Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial.

[This corrects the article DOI: 10.1371/journal.ppat.1005381.].

Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial.

Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects.

Tissue Pharmacologic and Virologic Determinants of Duodenal and Rectal Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution in HIV-Infected Patients Initiating Antiretroviral Therapy.

Plasma, duodenal, and rectal tissue antiretroviral therapy (ART) drug concentrations, human immunodeficiency virus (HIV) RNA and HIV DNA copy numbers, and recovery of mucosal immunity were measured before and 9 months after initiation of 3 different ART regimens in 26 subjects. Plasma and tissue HIV RNA correlated at baseline and when 9-month declines were compared, suggesting that these compartments are tightly associated. Antiretroviral tissue:blood penetration ratios were above the 50% inhibitory concentration values in almost 100% of cases. There were no correlations between drug concentrations and HIV DNA/RNA. Importantly, no evidence was found for residual viral replication or deficient tissue drug penetration to account for delayed gastrointestinal-associated lymphoid tissue immune recovery.

Effects of Maraviroc versus Efavirenz in Combination with Zidovudine-Lamivudine on the CD4/CD8 Ratio in Treatment-Naive HIV-Infected Individuals.

A low CD4/CD8 ratio during treated HIV infection reflects heightened immune activation and predicts death. The effects of different antiretroviral therapy regimens on CD4/CD8 ratio recovery remains unclear. We performed a post hoc analysis of the MERIT study, a randomized, double-blind trial of maraviroc versus efavirenz in combination with zidovudine-lamivudine in treatment-naive HIV-infected individuals. We found higher rates of CD4/CD8 ratio normalization with efavirenz, which was driven by a greater CD8+ T-cell decline.