T-Cell Immune Dysregulation and Mortality in Women With Human Immunodeficiency Virus.

SUMMARY: In women with HIV, higher activation and exhaustion of CD4+ T cells were associated with risk of non-HIV-related mortality during a median of 13.3 years of follow-up, independent of baseline demographic, behavioral, HIV-related, and cardiometabolic factors and longitudinal HIV disease progression. BACKGROUND: Dysregulation of adaptive immunity is a hallmark of human immunodeficiency virus (HIV) infection that persists on antiretroviral therapy (ART). Few long-term prospective studies have related adaptive immunity impairments to mortality in HIV, particularly in women. METHODS: Among 606 women with HIV in the Women's Interagency HIV Study, peripheral blood mononuclear cells collected from 2002 to 2005 underwent multiparameter flow cytometry. Underlying cause of death was ascertained from the National Death Index up to 2018. We examined associations of CD4+ and CD8+ T-cell activation (%CD38+HLA-DR+), senescence (%CD57+CD28-), exhaustion (%PD-1+), and nonactivation/normal function (%CD57-CD28+) with natural-cause, HIV-related, and non-HIV-related mortality. RESULTS: At baseline, median participant age was 41, and 67% were on ART. Among 100 deaths during a median of 13.3 years follow-up, 90 were natural-cause (53 non-HIV-related, 37 HIV-related). Higher activation and exhaustion of CD4+ T cells were associated with risk of natural-cause and non-HIV-related mortality, adjusting for age, demographic, behavioral, HIV-related, and cardiometabolic factors at baseline. Additional adjustment for time-varying viral load and CD4+ T-cell count did not attenuate these associations. CD8+ T-cell markers were not associated with any outcomes adjusting for baseline factors. CONCLUSIONS: Persistent CD4+ T-cell activation and exhaustion may contribute to excess long-term mortality risk in women with HIV, independent of HIV disease progression.

Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha.

UNLABELLED: Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of liver-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150 Pa and increased to 1-6 kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α), whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase. In addition, blockade of the Rho/Rho-associated protein kinase pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. CONCLUSION: Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/Rho-associated protein kinase pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. (Hepatology 2016;64:261-275).

Association of the IFNL4-ΔG Allele With Impaired Spontaneous Clearance of Hepatitis C Virus.

Interferon lambda 4 protein can be generated in IFNL4-ΔG carriers but not IFNL4-TT homozygotes. We studied 890 anti-hepatitis C virus (HCV)-positive participants in the Women's Interagency HIV Study. Among blacks (n = 555), HCV was more often cleared for those with genotype IFNL4-TT/TT (32.6%; odds ratio [OR], 3.59; P = 3.3 × 10(-5)) than IFNL4-TT/ΔG (11.3%; OR, 0.95; P = .86) or IFNL4-ΔG/ΔG (11.9%; referent). Pooling these data with published results in blacks (n = 1678), ORs were 3.84 (P = 8.6 × 10(-14)) for IFNL4-TT/TT and 1.44 (P = .03) IFNL4-TT/ΔG, and the area under the curve was 0.64 for IFNL4-ΔG genotype and 0.61 for rs12979860 (IL28B). IFNL4-ΔG is strongly associated with impaired spontaneous HCV clearance.

Microbial translocation and liver disease progression in women coinfected with HIV and hepatitis C virus.

BACKGROUND: Microbial translocation has been implicated in the pathogenesis of liver fibrosis and cirrhosis. We sought to determine whether markers of microbial translocation are associated with liver disease progression during coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). METHODS: We measured serial plasma lipopolysaccharide (LPS), endotoxin core antibody, intestinal fatty acid-binding protein (I-FABP), soluble CD14 (sCD14), interleukin 6 (IL-6), interleukin 10, and tumor necrosis factor α (TNF-α) levels over a 5-year period in 44 HIV/HCV-coinfected women, 21 of whom experienced liver disease progression and 23 were nonprogressors. RESULTS: While LPS levels did not differ significantly over time between progressors and nonprogressors (P = .60), progressors had significantly higher plasma levels of sCD14, a marker of monocyte activation by LPS, at the first time point measured (P = .03) and throughout the study period (P = .001); progressors also had higher IL-6 and I-FABP levels over the 5-year study period (P = .02 and .03, respectively). The associations between progression and sCD14, I-FABP, and IL-6 levels were unchanged in models controlling for HIV RNA and CD4(+) T-cell count. CONCLUSIONS: Although LPS levels did not differ between liver disease progressors and nonprogressors, the association of sCD14, I-FABP, and IL-6 levels with liver disease progression suggests that impairment of gut epithelial integrity and consequent microbial translocation may play a role in the complex interaction of HIV and HCV pathogenesis.

Case Report: Kingella kingae causing prosthetic joint infection in an adult.

Introduction: Kingella kingae is a Gram-negative micro-organism that is rarely isolated as a pathogen in the adult population. Although widely reported to affect prosthetic heart valves, there have been no previously reported cases of K. kingae infecting prosthetic joints in adults. Case Presentation: A 61-year-old patient with a history of rheumatoid arthritis presented with insidious onset of pain and swelling in her right shoulder, which had progressed to a discharging sinus. The patient had undergone a total shoulder replacement 11 years previously and had not developed any prior post-operative infections. She had been taking anti-TNF medication for 5 years prior to review for her rheumatoid disease. The patient underwent a two-stage revision replacement procedure, including implant removal, sinus excision and debridement. Deep tissue samples grew K. kingae post-operatively. The patient was commenced on intravenous ceftriaxone for 14 days, followed by a further 28 days of oral ciprofloxacin. A second-stage custom shoulder replacement was undertaken 10 months following the first stage and the patient made a good functional recovery. Conclusion: The authors suggest that clinicians should be attuned to K. kingae as a potential pathogen for prosthetic joint infection, particularly in patients who are immunosuppressed. Two-stage revision procedures can ensure a favourable outcome and eradication of this pathogen from the joint. Beta lactams remain the principal antibiotic of choice.

Protocol for CLASSIC PBB: comparison of lower airway sampling strategies in children with protracted bacterial bronchitis.

BACKGROUND: Protracted bacterial bronchitis (PBB) is an endobronchial infection and a the most common cause of chronic wet cough in young children. It is treated with antibiotics, which can only be targeted if the causative organism is known. As most affected children do not expectorate sputum, lower airway samples can only be obtained by bronchoalveolar lavage (BAL) samples taken during flexible bronchoscopy (FB-BAL). This is invasive and is therefore reserved for children with severe or relapsing cases. Most children with PBB are treated empirically with broad spectrum antibiotics. CLASSIC PBB will compare the pathogen yield from two less invasive strategies with that from FB-BAL to see if they are comparable. METHODS: 131 children with PBB from four UK centres referred FB-BAL will be recruited. When attending for FB-BAL, they will have a cough swab and an induced sputum sample obtained. The primary outcome will be the discordance of the pathogen yield from the cough swab and the induced sputum when compared with FB-BAL. Secondary outcomes will be the sensitivity of each sampling strategy, the success rate of the induced sputum in producing a usable sample and the tolerability of each of the three sampling strategies. DISCUSSION: If either or both of the two less invasive airway sampling strategies are shown to be a useful alternative to FB-BAL, this will lead to more children with PBB having lower airway samples enabling targeted antibiotic prescribing. It would also reduce the need for FB, which is known to be burdensome for children and their families. TRIAL REGISTRATION NUMBER: ISRCTN79883982.

Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell alpha interferon: implication for T-cell activation.

Plasmacytoid dendritic cells (pDC) contribute to antiviral immunity mainly through recognition of microbial products and viruses via intracellular Toll-like receptor 7 (TLR7) or TLR9, resulting in the production of type I interferons (IFNs). Although interferons reduce the viral burden in the acute phase of infection, their role in the chronic phase is unclear. The presence of elevated plasma IFN-alpha levels in advanced HIV disease and its association with microbial translocation in chronic HIV infection lead us to hypothesize that IFN-alpha could contribute to immune activation. Blocking of IFN-alpha production using chloroquine, an endosomal inhibitor, was tested in a novel in vitro model system with the aim of characterizing the effects of chloroquine on HIV-1-mediated TLR signaling, IFN-alpha production, and T-cell activation. Our results indicate that chloroquine blocks TLR-mediated activation of pDC and MyD88 signaling, as shown by decreases in the levels of the downstream signaling molecules IRAK-4 and IRF-7 and by inhibition of IFN-alpha synthesis. Chloroquine decreased CD8 T-cell activation induced by aldrithiol-2-treated HIV-1 in peripheral blood mononuclear cell cultures. In addition to blocking pDC activation, chloroquine also blocked negative modulators of the T-cell response, such as indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PDL-1). Our results indicate that TLR stimulation and production of IFN-alpha by pDC contribute to immune activation and that blocking of these pathways using chloroquine may interfere with events contributing to HIV pathogenesis. Our results suggests that a safe, well-tolerated drug such as chloroquine can be proposed as an adjuvant therapeutic candidate along with highly active antiretroviral therapy to control immune activation in HIV-1 infection.

Early immune senescence in HIV disease.

Non-AIDS-defining co-morbidities that occur despite viral suppression and immune reconstitution using antiretroviral therapy depict early aging process in HIV-infected individuals. During aging, a reduction in T-cell renewal, together with a progressive enrichment of terminally differentiated T cells, translates into a general decline of the immune system, gradually leading to immunosenescence. Inflammation is a hallmark of age-associated comorbidities, and immune activation is a hallmark of HIV disease. Constant stimulation of the immune system by HIV or due to co-infections activates the innate and adaptive immune system, resulting in release of mediators of inflammation. Immune activation coupled with lack of anti-inflammatory responses likely results in accelerated aging in HIV disease. Dysfunctional thymic output, along with HIV-mediated disruption of the gastrointestinal barrier leading to microbial translocation, contributes to the circulating antigenic load driving early senescence in HIV disease.

HIV and aging: role of the microbiome.

PURPOSE OF REVIEW: The purpose of this article is to review age-associated alterations in microbiota composition, diversity and functional features in context of immune senescence, chronic inflammation and comorbidities associated with HIV infection. The overall goal is to assess whether modulating the microbiome will likely improve resilience of the immune system and augment return to health. RECENT FINDINGS: Alteration in the gut microbiota composition diversity and function occur in HIV and aging. Importantly, butyrate producing bacteria are reduced in both HIV and aging individuals. There is increasing relevance of studying metabolomics in the context of HIV-associated non-AIDS comorbidities and aging. Interventional prospects of probiotics, prebiotics and fecal microbiota transplantation in HIV and aging will provide novel therapeutic approaches. SUMMARY: Increasing evidence suggests a significant link in changes in the composition, diversity and functional aspects of intestinal microbiome with normal aging and HIV infection. Data on association of metabolites produced by the microbiome with HIV-associated non-AIDS comorbidities is mounting. The impact of the microbiome alterations on inflammation, immune and organ senescence and mechanisms by which bio-behavioral pathways will exacerbate these outcomes needs to be further evaluated.

Macrophage Activation and the Tumor Necrosis Factor Cascade in Hepatitis C Disease Progression Among HIV-Infected Women Participating in the Women's Interagency HIV Study.

BACKGROUND: HIV/hepatitis C-coinfected persons experience more rapid liver disease progression than hepatitis C virus (HCV) monoinfected persons, even in the setting of potent antiretroviral therapy. METHODS: We sought to articulate the role of macrophage activation and inflammation in liver disease progression by measuring serial soluble markers in HIV/HCV-coinfected women. We compared markers measured during retrospectively defined periods of rapid liver disease progression to periods where little or no liver disease progression occurred. Liver disease progression was defined by liver biopsy, liver-related death or the serum markers AST-to-platelet ratio index and FIB-4. Soluble CD14, sCD163, lipopolysaccharide (LPS), tumor necrosis factor (TNF) receptor II, interleukin-6, and chemokine ligand 2 (CCL 2) were measured at 3 time points over 5 years. RESULTS: One hundred six time intervals were included in the analysis: including 31 from liver disease progressors and 75 from nonprogressors. LPS, sCD14, interleukin-6, and CCL2 levels did not differ in slope or quantity over time between rapid liver disease progressors and nonprogressors. TNFRII and sCD163 were significantly higher in liver disease progressors at (P = 0.002 and <0.0001 respectively) and preceding (P = 0.01 and 0.003 respectively) the liver fibrosis outcome in unadjusted models, with similar values when adjusted for HIV RNA and CD4 count. CONCLUSIONS: In women with HIV/HCV coinfection, higher sCD163 levels, a marker of macrophage activation, and TNFRII levels, implying activation of the TNF-α system, were associated with liver disease progression. Our results provide an addition to the growing body of evidence regarding the relationship between macrophage activation, inflammation, and liver disease progression in HIV/HCV coinfection.

A whole blood assay to assess peripheral blood dendritic cell function in response to Toll-like receptor stimulation.

We report a practical technique to assess peripheral blood dendritic cell (DC) maturation and function in whole blood (WB), which requires minimal blood volumes and minimizes ex vivo manipulations of clinical specimens. We determined optimal conditions for flow cytometric analysis of markers of DC maturation, including CCR7, CD25, CD80 and CD83, and of the intracellular cytokines, tumor necrosis factor-alpha (TNF-alpha) and interferon-alpha (IFN-alpha), in both myeloid (mDC) and plasmacytoid (pDC) lineages. We demonstrate concentration-dependent production of these cytokines by DC following short-term stimulation with ligands to Toll-like receptors (TLRs) 2/1, 3, 4, 7, 8 and 9. Kinetic studies revealed maximal TNF-alpha and IFN-alpha protein expression at 2 to 3 h after stimulation with certain TLR ligands. Finally, utilizing cells from a cohort of eight healthy donors, we compared DC responses to TLR activation in WB, freshly isolated peripheral blood mononuclear cells (PBMC) and cryopreserved PBMC. We found that TNF-alpha responses were essentially preserved, but IFN-alpha responses were profoundly diminished or entirely abrogated following cryopreservation. In conclusion, we propose that WB analysis of peripheral DC function is a rapid, reliable and simple method to evaluate TLR function in clinical specimens, which obviates artifact-prone cell purification. The major impact of cryopreservation on some DC responses further strengthens the case for a rapid method that uses fresh blood.

Hepatic fibrosis and immune phenotype vary by HCV viremia in HCV/HIV co-infected subjects: A Women's interagency HIV study.

HCV and HIV independently lead to immune dysregulation. The mechanisms leading to advanced liver disease progression in HCV/HIV coinfected subjects remain unclear.In this cross-sectional study, we assessed the association of HCV viremia, liver fibrosis, and immune response patterns in well-characterized HIV phenotypes: Elite controllers (Elites), HIV controlled (ARTc), and HIV uncontrolled (ARTuc) matched by age and race. Groups were stratified by HCV RNA status. Regulatory T-cell frequencies, T-cell activation (HLADR+CD38+), apoptosis (Caspase-3+), and intracellular cytokines (interferon-γ, IL-2, IL-17) were assessed using multiparametric flow-cytometry. Liver fibrosis was scored by AST to platelet ratio index (APRI).We found liver fibrosis (APRI) was 50% lower in Elites and ARTc compared to ARTuc. Higher liver fibrosis was associated with significantly low CD4+ T cell counts (P < 0.001, coefficient r = -0.463). Immune activation varied by HIV phenotype but was not modified by HCV viremia. HCV viremia was associated with elevated CD8 T-cell Caspase-3 in Elites, ARTuc, and HIV- except ARTc. CD8 T-cell Caspase-3 levels were significantly higher in HCV RNA+ Elites (P = 0.04) and ARTuc (P = 0.001) and HIV- groups (P = 0.02) than ARTc. Importantly, ARTuc HCV RNA+ had significantly higher CD4 T-cell interleukin-17 levels than ARTuc HCV RNA- (P = 0.005).HIV control was associated with lower liver fibrosis in HCV/HIV co-infected women. HCV viremia is associated with an inflammatory CD4 TH-17 phenotype in absence of HIV control and higher frequency of pro-apoptosis CD8 T-cells critical to avert progression of HIV and HCV disease that is attenuated in ART controllers. Elite controllers with HCV viremia are more prone to CD8 T-cell apoptosis than ART controllers, which could have negative consequences over time, highlighting the importance of ART control in HCV/HIV coinfected individuals.

Systemic Cytokine Levels Do Not Predict CD4(+) T-Cell Recovery After Suppressive Combination Antiretroviral Therapy in Chronic Human Immunodeficiency Virus Infection.

Background. Subjects on suppressive combination antiretroviral therapy (cART) who do not achieve robust reconstitution of CD4(+) T cells face higher risk of complications and death. We studied participants in the Women's Interagency HIV Study with good (immunological responder [IR]) or poor (immunological nonresponder [INR]) CD4(+) T-cell recovery after suppressive cART (n = 50 per group) to determine whether cytokine levels or low-level viral load correlated with INR status. Methods. A baseline sample prior to viral control and 2 subsequent samples 1 and 2 years after viral control were tested. Serum levels of 30 cytokines were measured at each time point, and low-level human immunodeficiency virus (HIV) viral load and anti-HIV antibody levels were measured 2 years after viral suppression. Results. There were minimal differences in cytokine levels between IR and INR subjects. At baseline, macrophage inflammatory protein-3ß levels were higher in IR subjects; after 1 year of suppressive cART, soluble vascular endothelial growth factor-R3 levels were higher in IR subjects; and after 2 years of suppressive cART, interferon gamma-induced protein 10 levels were higher in INR subjects. Very low-level HIV viral load and anti-HIV antibody levels did not differ between IR and INR subjects. Conclusions. These results imply that targeting residual viral replication might not be the optimum therapeutic approach for INR subjects.

Biocompatibility and characterization of a peptide amphiphile hydrogel for applications in peripheral nerve regeneration.

Peripheral nerve injury is a debilitating condition for which new bioengineering solutions are needed. Autografting, the gold standard in treatment, involves sacrifice of a healthy nerve and results in loss of sensation or function at the donor site. One alternative solution to autografting is to use a nerve guide conduit designed to physically guide the nerve as it regenerates across the injury gap. Such conduits are effective for short gap injuries, but fail to surpass autografting in long gap injuries. One strategy to enhance regeneration inside conduits in long gap injuries is to fill the guide conduits with a hydrogel to mimic the native extracellular matrix found in peripheral nerves. In this work, a peptide amphiphile (PA)-based hydrogel was optimized for peripheral nerve repair. Hydrogels consisting of the PA C16GSH were compared with a commercially available collagen gel. Schwann cells, a cell type important in the peripheral nerve regenerative cascade, were able to spread, proliferate, and migrate better on C16GSH gels in vitro when compared with cells seeded on collagen gels. Moreover, C16GSH gels were implanted subcutaneously in a murine model and were found to be biocompatible, degrade over time, and support angiogenesis without causing inflammation or a foreign body immune response. Taken together, these results help optimize and instruct the development of a new synthetic hydrogel as a luminal filler for conduit-mediated peripheral nerve repair.

Interferon Lambda 4 Genotype Is Not Associated with Recurrence of Oral or Genital Herpes.

IFNL4-ΔG/TT (rs368234815) genotype is associated with hepatitis C virus clearance and may play a role in other infections. IFN-λ4 protein is generated only in individuals who carry the IFNL4-ΔG allele. The IFNL4 rs12979860-T allele, which is in strong linkage disequilibrium with IFNL4-ΔG, was recently reported to be associated with more frequent and severe oral herpes episodes. We investigated the association of IFNL4-ΔG/TT with herpes simplex virus (HSV)-related outcomes among 2,192 African American and European American participants in the Women's Interagency HIV Study (WIHS). WIHS is a prospective cohort study of human immunodeficiency virus (HIV)-infected and at-risk women that began in 1994. This report includes follow-up through 2013. Available data included: HSV-1 and HSV-2 antibodies at study entry; bi-annually ascertained episodes of (self-reported) oral herpes, (self-reported) genital sores and (clinician-observed) genital ulcers; HSV-2 DNA in cervicovaginal lavage (CVL) specimens. IFNL4-ΔG/TT genotyping was determined by TaqMan. We compared women with IFNL4-ΔG/ΔG or IFNL4-TT/ΔG genotypes (i.e., IFNL4-ΔG carriers) to those with the IFNL4-TT/TT genotype, adjusting for age, race and HIV status. For outcomes with repeated measurements, the adjusted odds ratio (aOR), 95% confidence interval [CI] and p-value were determined using a generalized estimating equations approach. Median participant age at enrollment was 36 years; 81% were African American, 74% were HIV-infected. Among 1,431 participants tested for antibodies, 72.8% were positive for HSV-1 and 79.0% were positive for HSV-2. We observed no association between IFNL4-ΔG/TT genotype and any outcome: HSV-1 or HSV-2 antibody prevalence (p>0.1, all comparisons); oral herpes (aOR, 1.2; p = 0.35); genital sores (aOR, 1.0; p = 0.71); genital ulcers (aOR, 1.1; p = 0.53); detectable HSV-2 DNA in CVL (N = 322; aOR, 0.71; p = 0.49); HSV-2 DNA level (p = 0.68). In this large prospective study, IFNL4-ΔG/TT genotype was not associated with HSV-related outcomes, including episodes of oral or genital herpes.

T-cell activation, both pre- and post-HAART levels, correlates with carotid artery stiffness over 6.5 years among HIV-infected women in the WIHS.

OBJECTIVE: T-cell activation is a major pathway driving HIV disease progression. Little is known regarding the impact of T-cell activation on HIV-associated atherosclerosis and cardiovascular disease, a common comorbidity in HIV infection. We hypothesized that T-cell activation will predict vascular stiffness, a measure of subclinical atherosclerosis. DESIGN: Linear regression models evaluated the covariate-adjusted association of T-cell activation with vascular stiffness. METHODS: CD38 and HLA-DR expression on CD4⁺ and CD8⁺ T cells was assessed by flow cytometry among 59 HIV-negative and 376 HIV-infected (185 hepatitis C coinfected) women in the Women's Interagency HIV Study. T-cell activation was defined by CD8⁺CD38⁺DR+ and CD4⁺CD3⁺8DR+. Multiple activation assessments over 6.5 years were averaged. In 140 women, T-cell activation was measured before and after highly active antiretroviral therapy (HAART) initiation. Carotid artery ultrasounds were completed a median of 6.5 years after last measurement of T-cell activation and carotid artery stiffness including distensibility and elasticity were calculated. RESULTS: Percentages of CD4⁺ and CD8⁺ T-cell activation were significantly higher in HIV- infected compared with HIV-negative women. Among HIV-negative women, T-cell activation was not associated with carotid artery stiffness. Among HIV-infected women, higher CD4⁺ T-cell activation levels significantly predicted increased arterial stiffness independent of CD4⁺ cell count and HIV RNA. The association was stronger among HIV/hepatitis C-coinfected women compared with HIV-monoinfected women; however, the difference was not statistically significant (P for interaction >0.05). Pre- and post-HAART levels of CD4⁺ T-cell activation significantly predicted carotid artery stiffness. CONCLUSIONS: Persistent T-cell activation, even after HAART initiation, can contribute to structural and/or functional vascular damage accelerating atherogenesis in HIV infection. These results need to be confirmed in a longitudinal prospective study.

HIV RNA levels in plasma and cervical-vaginal lavage fluid in elite controllers and HAART recipients.

OBJECTIVES: The introduction of HAART leads to control of HIV replication to less than 50 copies/ml, similar to levels in 'elite controllers'. Low-level viral replication may be one of the contributing factors to persistent immune activation/inflammation in HAART-treated individuals. There are still gaps in our knowledge of whether low-level replication persists in systemic versus mucosal sites. DESIGN AND METHODS: Participants for this study were recruited from the Women's Interagency HIV Study. We evaluated 33 'elite controllers' who naturally controlled HIV replication and 33 matched HAART-suppressed recipients. This study employed a sensitive target-capture transcription-mediated-amplification assay to compare low-level virus concentrations in plasma and cervical-vaginal lavage (CVL) samples from HIV-positive HAART recipients and 'elite controllers'. RESULTS: The median (interquartile range) plasma viral load signal/cut-off (S/Co) for 'elite controllers' was 10.5 (3.9-21.1), which was significantly (P < 0.001) higher than the S/Co for HAART recipients [2.0 (1-4.9)]. The majority of CVL samples from both groups had undetectable HIV RNA and the proportion of CVL samples with a cut-off more than 1.0 was not different between 'elite controllers' and HAART-suppressed recipients. CONCLUSION: This study demonstrated persistent low-level HIV replication in 'elite controllers', suggesting potential value of HAART treatment for these individuals. Absent or very low levels of HIV RNA in CVL indicate very low risk of secondary sexual transmission for both groups.

The relation of plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) with HPV persistence in HIV-infected and HIV-uninfected women.

Other than CD4+ count, the immunologic factors that underlie the relationship of HIV/AIDS with persistent oncogenic HPV (oncHPV) and cervical cancer are not well understood. Plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) are of particular interest. pDCs have both effector and antigen presenting activity and, in HIV-positive patients, low pDC levels are associated with opportunistic infections. Tregs downregulate immune responses, and are present at high levels in HIV-positives. The current pilot study shows for the first time that low pDC and high Treg levels may be significantly associated with oncHPV persistence in both HIV-positive and HIV-negative women. Larger studies are now warranted.