As a result of successful antiretroviral treatment over the last 20 years, HIV has become more of a chronic disease for practitioners to manage, requiring careful, but routine, clinical monitoring. Laboratory markers, such as the HIV-1 RNA viral load and CD4 cell count, are regularly used for patient management in addition to predicting disease progression and/or treatment outcomes. The HIV viral load is considered to be the gold standard for evaluating treatment success, although it is often limited by the cost. Furthermore, in certain cases, there is a mismatch between an undetectable viral load (<50 copies/ml) and the absence of immune reconstitution, which can be confusing to both the treatment provider and patient. In this review, the utility of the CD4 count as a predictor for HIV disease progression in patients not on therapy is evaluated, as well as a method for monitoring a patient’s response to therapy. Its use in predicting immune reconstitution in patients initiating antiretrovirals is also identified. We hope to aid the clinician by examining the most recent literature and discussing the added value of the CD4 count in the management of a person with HIV infection.
Background:Recently, we discovered a new glucogenic and centrally acting orexigenic hormone – asprosin. Asprosin is elevated in metabolic syndrome (MS) patients, and its genetic loss results in reduced appetite, leanness, and blood glucose burden, leading to protection from MS.Methods:We generated three independent monoclonal antibodies (mAbs) that recognize unique asprosin epitopes and investigated their preclinical efficacy and tolerability in the treatment of MS.Results:Anti-asprosin mAbs from three distinct species lowered appetite and body weight, and reduced blood glucose in a dose-dependent and epitope-agnostic fashion in three independent MS mouse models, with an IC50 of ~1.5 mg/kg. The mAbs displayed a half-life of over 3days in vivo, with equilibrium dissociation-constants in picomolar to low nanomolar range.Conclusions:We demonstrate that anti-asprosin mAbs are dual-effect pharmacologic therapy that targets two key pillars of MS – over-nutrition and hyperglycemia. This evidence paves the way for further development towards an investigational new drug application and subsequent human trials for treatment of MS, a defining physical ailment of our time.Funding:DK118290 and DK125403 (R01; National Institute of Diabetes and Digestive and Kidney Diseases), DK102529 (K08; National Institute of Diabetes and Digestive and Kidney Diseases), Caroline Wiess Law Scholarship (Baylor College of Medicine, Harrington Investigatorship Harrington Discovery Institute at University Hospitals, Cleveland); Chao Physician Scientist Award (Baylor College of Medicine); RP150551 and RP190561 (Cancer Prevention and Research Institute of Texas [CPRIT]).
Background: Nuclear factor-kB (NF-kB) is a key transcriptional regulator of inflammatory bowel disease (IBD). Aim: To investigate the therapeutic potential of a locally administered ''non-viral'' nuclear factor-kB decoy (NFkBD) in multiple experimental models of IBD. Methods: A fully phosphorothioated decoy oligonucleotide with improved stability that specifically binds NFkB and blocks inflammatory mediators regulated by this transcription factor without the help of viral envelopeassisted delivery was developed. The therapeutic effects of NFkBD were studied in the trinitrobenzene sulphonic acid, oxazolone and dextran sodium sulphate induced colitis models. Results: Intracolonic administration of NFkBD results in the delivery of NFkBD to inflammatory cells and a reduction of NF-kB heterodimers. In the T helper cell 1-driven trinitrobenzene sulphonic acid-induced colitis model, mice receiving NFkBD treatment exhibit a dose-dependent reduction in disease severity and a more rapid recovery to normal body weight, similar to a clinically relevant dose of budesonide. Clinical efficacy was corroborated by considerable reductions in colitis pathology and tissue levels of several proinflammatory markers, including tumour necrosis factor a, interleukin 6, interleukin 1b and monocyte chemotactic protein 1. NFkBD also mitigates disease activity in the T helper cell 2-like oxazolone colitis and epithelial injury-related acute dextran sodium sulphate colitis models. Interestingly, restoration of tissue homeostasis is observed in NFkBD-treated animals with the rapid re-emergence of functional goblet cells and a return to normal patterns of cell proliferation in the mucosal epithelium and smooth muscle cell layers. Conclusions: These data support the potential use of ''naked'' NFkBD as a cross-functional therapeutic in IBD, and show for the first time that it can facilitate the restoration of colon homeostasis and function.
Seminal plasma HIV-1 RNA level is an important determinant of the risk of HIV-1 sexual transmission. We investigated potential associations between seminal plasma cytokine levels and viral concentration in the seminal plasma of HIV-1-infected men. This was a prospective, observational study of paired blood and semen samples from 18 HIV-1 chronically infected men off antiretroviral therapy. HIV-1 RNA levels and cytokine levels in seminal plasma and blood plasma were measured and analyzed using simple linear regressions to screen for associations between cytokines and seminal plasma HIV-1 levels. Forward stepwise regression was performed to construct the final multivariate model. The median HIV-1 RNA concentrations were 4.42 log 10 copies/ml (IQR 2.98, 4.70) and 2.96 log 10 copies/ml (IQR 2, 4.18) in blood and seminal plasma, respectively. In stepwise multivariate linear regression analysis, blood HIV-1 RNA level ( p < 0.0001) was most strongly associated with seminal plasma HIV-1 RNA level. After controlling for blood HIV-1 RNA level, seminal plasma HIV-1 RNA level was positively associated with interferon (IFN)-c ( p = 0.03) and interleukin (IL)-17 ( p = 0.03) and negatively associated with IL-5 ( p = 0.0007) in seminal plasma. In addition to blood HIV-1 RNA level, cytokine profiles in the male genital tract are associated with HIV-1 RNA levels in semen. The Th1 and Th17 cytokines IFN-c and IL-17 are associated with increased seminal plasma HIV-1 RNA, while the Th2 cytokine IL-5 is associated with decreased seminal plasma HIV-1 RNA. These results support the importance of genital tract immunomodulation in HIV-1 transmission.
Mucosal immunity is central to sexual transmission and overall pathogenesis of HIV-1 infection, but the ability of vaccines to induce immune responses in mucosal tissue compartments is poorly defined. Because macaque vaccine studies suggest that inguinal (versus limb) vaccination may better target sexually-exposed mucosa, we performed a randomized, double-blinded, placebo-controlled Phase I trial in HIV-1-uninfected volunteers, using the recombinant Canarypox (CP) vaccine vCP205 delivered by different routes. 12 persons received vaccine and 6 received placebo, divided evenly between deltoid-intramuscular (deltoid-IM) or inguinal-subcutaneous (inguinal-SC) injection routes. The most significant safety events were injection site reactions (Grade 3) in one inguinal vaccinee. CP-specific antibodies were detected in the blood of all 12 vaccinees by Day 24, while HIV-1-specific antibodies were observed in the blood and gut mucosa of 1/9 and 4/9 evaluated vaccinees respectively, with gut antibodies appearing earlier in inguinal vaccinees (24–180 versus 180–365 days). HIV-1-specific CD8+ T lymphocytes (CTLs) were observed in 7/12 vaccinees, and blood and gut targeting were distinct. Within blood, both deltoid and inguinal responders had detectable CTL responses by 17–24 days; inguinal responders had early responses (within 10 days) while deltoid responders had later responses (24–180 days) in gut mucosa. Our results demonstrate relative safety of inguinal vaccination and qualitative or quantitative compartmentalization of immune responses between blood and gut mucosa, and highlight the importance of not only evaluating early blood responses to HIV-1 vaccines but also mucosal responses over time.Trial RegistrationClinicalTrials.gov NCT00076817
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