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A case-cohort study was used to determine the effect of baseline nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance, as assessed by viral genotyping, on the response to efavirenz-containing regimens in AIDS Clinical Trials Group A5095. The sample included a random cohort of efavirenz-treated subjects plus unselected subjects who experienced virologic failure. Of 220 subjects in the random cohort, 57 (26%) had virologic failure. The prevalence of baseline NNRTI resistance was 5%. The risk of virologic failure for subjects with baseline NNRTI resistance was higher than that for subjects without such resistance (hazard ratio 2.27 [95% confidence interval], 1.15-4.49; P = .018). These results support resistance testing before starting antiretroviral therapy. Copyright © 2008 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Background. Few studies have prospectively evaluated the impact of highly active antiretroviral therapy (HAART) on body weight and lean body mass (LBM) or explored the impact of baseline immunologic or virological changes on these parameters. Methods. Adult AIDS Clinical Trials Group (ACTG) protocol 892 was a prospective, 48-week, multisite observational study of body composition conducted during 1997-2000 among 224 antiretroviral-naive and antiretroviral-experienced subjects controlled into various adult ACTG antiretroviral studies. Assessments included human immunodeficiency virus type 1 (HIV-1) RNA load (by polymerase chain reaction); T lymphocyte subset analysis; Karnofsky score; height (baseline only); weight, LBM, and fat (by bioelectrical impedance analysis); and functional performance (by questionnaire). Results. Overall, only modest median increases in body weight (1.9 kg) and LBM (0.6 kg) occurred after 16 weeks of therapy. Significantly greater median increases in body weight (2.1 vs. 0.5 kg; P = .045) occurred in subjects who achieved virological suppression (HIV- 1 RNA load, <500 copies/mL) at week 16 than in subjects who did not. Subjects who were antiretroviral naive at baseline gained more weight (median increase in body weight, 2.6 vs. 0.0 kg; Pc .001) and LBM (1.0 vs. 0.1 kg; P = .002) after 16 weeks of treatment than did subjects who were antiretroviral experienced. Subjects with lower baseline CD4 cell counts (<200 cells/mm³) and subjects with higher baseline HIV-1 RNA loads &ges;100,000 copies/mL) were more likely to show increases in LBM of >1.5 kg (P = .013 and P = .005, respectively). Conclusions. HAART had modestly favorable effects on body composition, particularly in patients with greater pretreatment immuno compromise and virological compromise. The difference between antiretroviral-naive and antiretroviral-experienced subjects with regard to the ability to achieve increased body weight and LBM requires more study. [ABSTRACT FROM AUTHOR]

Twenty-two children (median age 14 months) were treated for a minimum of three days with ceftizoxime (50–100 mg/kg/day). Infections included soft tissue cellulitis, adenitis, haemophilus septicaemia and urinary tract infections. Satisfactory clinical responses occurred in 21 of 22 children. The drug was well tolerated, mild eosinophilia and elevations of liver and muscle enzymes were observed most frequently. Infections due to Gram-negative pathogens (Haemophilus influenzae and Escherichia coli) responded well. Further evaluation is needed to define the role of ceftizoxime in infections due to staphylococci. [ABSTRACT FROM PUBLISHER]

We describe a 50-year-old Caucasian man with a family history of myoclonic epilepsy associated with ragged red fibers (MERRF) and a diagnosis of Human Immunodeficiency Virus (HIV). The patient had multiple risk factors for contracting HIV and was being followed in our clinic at the time of his diagnosis. Initial testing following seroconversion revealed a baseline CD4+ T-lymphocyte count of 652×106cells/l and a HIV-1 RNA of 14,781copies/ml. He reported exercise intolerance and had mild neurologic deficits, which worsened around the time of HIV seroconversion. These symptoms led to his subsequent diagnosis of MERRF by the detection of the A8344G point mutation in the tRNALys gene of mitochondrial DNA (mtDNA). The baseline estimated proportion of mutant genome was 39%. He showed a rapid course of HIV disease progression with a CD4+ T-lymphocyte nadir of 174×106cells/l associated with a HIV-1 RNA of 238,178copies/ml, within 17 months following HIV seroconversion. To avoid further mitochondrial insult, which could result from the use of a standard nucleoside reverse transcriptase inhibitor-containing regimen, a protease inhibitor regimen consisting of hard-gel saquinavir (Invirase™), and lopinavir/ritonavir (Kaletra™) was chosen for this patient. The patient''s CD4+ T-lymphocyte count increased to 282×106cells/l and his viral load became undetectable 7 months following the initiation of antiretroviral therapy. His neurologic symptoms did not worsen on this antiretroviral regimen. When initiating HIV therapy in individuals with metabolic myopathies related to mitochondrial dysfunction, it may be important to design an antiviral regimen that minimizes mitochondrial damage, yet effectively maintains durable viral suppression. [Copyright &y& Elsevier]

Background: People living with HIV (PLWH) have higher rates of chronic kidney disease (CKD) compared with HIV-uninfected individuals. The pathogenesis of CKD in HIV remains poorly understood but is likely from a combination of various factors, such as traditional comorbidities, prolonged antiretroviral therapy, immune dysregulation, and direct HIV effect on the kidneys. We evaluated plasma galectin-3 (Gal-3), a circulating marker of fibrosis, and its association with renal function., Methods: Estimated glomerular filtration rate (eGFR) was assessed by CKD-EPI. Plasma galectin-3 was obtained from banked specimens by ELISA. Factors associated with eGFR were analyzed using step-wise multiple linear regression., Results: A total of 45 PLWH and 58 HIV-uninfected participants were included with similar demographic parameters. Among PLWH, majority had undetectable plasma HIV RNA (82.2%). Gal-3 was significantly higher in PLWH than in HIV-uninfected participants (6.4 [IQR 4.0, 8.5] ng/mL and 4.5 [IQR 2.3, 6.5] ng/mL, respectively; p  = 0.020) while a trend towards lower eGFR was found in PLWH compared to the HIV-uninfected cohort (86.8 [IQR 71.3, 91.8] and 89.0 [IQR 78.6, 97.4] mL/min/1.73 m 2 , respectively; p  = 0.071). In univariable analysis, HIV status was marginally associated with decreased eGFR (β coefficient= -0.035, p  = 0.051). In the final multivariable regression model adjusted for traditional risk factors of CKD, Gal-3 independently predicted a decrease in eGFR (unstandardized B= -0.008, p  < 0.001) while HIV status did not demonstrate any significant association., Conclusion: Gal-3 was higher in PLWH compared with HIV-uninfected participants. In multivariable adjusted analyses, Gal-3, but not HIV status, was associated with decreased eGFR. The role of Gal-3 as a biomarker of kidney function needs to be further elucidated.

The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ injury including testicular inflammation, reduced testosterone, and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells, however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury could be initiated by direct virus infection or exposure to systemic inflammatory mediators or viral antigens. We characterized SARS-CoV-2 infection in different human testicular 2D and 3D culture systems including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not productively infect any testicular cell type. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma decreased cell viability and resulted in the death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 Envelope protein caused inflammatory response and cytopathic effects dependent on TLR2, while Spike 1 or Nucleocapsid proteins did not. A similar trend was observed in the K18-hACE2 transgenic mice which demonstrated a disrupted tissue architecture with no evidence of virus replication in the testis that correlated with peak lung inflammation. Virus antigens including Spike 1 and Envelope proteins were also detected in the serum during the acute stage of the disease. Collectively, these data strongly suggest that testicular injury associated with SARS-CoV-2 infection is likely an indirect effect of exposure to systemic inflammation and/or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Giannakopoulos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Siglec-9 is an MHC-independent inhibitory receptor expressed on a subset of natural killer (NK) cells. Siglec-9 restrains NK cytotoxicity by binding to sialoglycans (sialic acid-containing glycans) on target cells. Despite the importance of Siglec-9 interactions in tumor immune evasion, their role as an immune evasion mechanism during HIV infection has not been investigated. Using in vivo phenotypic analyses, we found that Siglec-9+ CD56dim NK cells, during HIV infection, exhibit an activated phenotype with higher expression of activating receptors and markers (NKp30, CD38, CD16, DNAM-1, perforin) and lower expression of the inhibitory receptor NKG2A, compared to Siglec-9- CD56dim NK cells. We also found that levels of Siglec-9+ CD56dim NK cells inversely correlate with viral load during viremic infection and CD4+ T cell-associated HIV DNA during suppressed infection. Using in vitro cytotoxicity assays, we confirmed that Siglec-9+ NK cells exhibit higher cytotoxicity towards HIV-infected cells compared to Siglec-9- NK cells. These data are consistent with the notion that Siglec-9+ NK cells are highly cytotoxic against HIV-infected cells. However, blocking Siglec-9 enhanced NK cells' ability to lyse HIV-infected cells, consistent with the known inhibitory function of the Siglec-9 molecule. Together, these data support a model in which the Siglec-9+ CD56dim NK subpopulation is highly cytotoxic against HIV-infected cells even whilst being restrained by the inhibitory effects of Siglec-9. To harness the cytotoxic capacity of the Siglec-9+ NK subpopulation, which is dampened by Siglec-9, we developed a proof-of-concept approach to selectively disrupt Siglec/sialoglycan interactions between NK and HIV-infected cells. We achieved this goal by conjugating Sialidase to several HIV broadly neutralizing antibodies. These conjugates selectively desialylated HIV-infected cells and enhanced NK cells' capacity to kill them. In summary, we identified a novel, glycan-based interaction that may contribute to HIV-infected cells' ability to evade NK immunosurveillance and developed an approach to break this interaction., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Reduced estimated glomerular filtration rate (eGFR) is associated with increased risk of cardiovascular disease among people living with HIV (PLWH). It is unclear whether eGFR equations incorporating cystatin C (CysC) measurements are more predictive of preclinical cardiovascular disease than those using only creatinine (Cr)., Objectives: The study aimed to determine which of the 3 Chronic Kidney Disease Epidemiology (CKD-EPI) eGFR equations is most associated with carotid intima media thickness (CIMT) and coronary artery calcium (CAC) score., Methods: This cross-sectional analysis of pooled data from 3 large cohorts compared the associations between the 3 CKD-EPI eGFR equations (Cr, CysC, and Cr-CysC) with CIMT and CAC score using multivariable regression analysis. eGFR and CIMT were analyzed as continuous variables. CAC scores were analyzed as a binary variable (detectable calcification versus nondetectable) and as a log10 Agatston score in those with detectable CAC., Results: Thousand four hundred eighty-seven participants were included, and of these 910 (562 HIV+ and 348 HIV-) had CIMT measurements and 366 (296 HIV+ and 70 HIV-) had CAC measurements available. In HIV- participants, GFR estimated by any CKD-EPI equation did not significantly correlate with CIMT or CAC scores. When PLWH were analyzed separately including HIV-specific factors, only GFR estimated using Cr-Cys C correlated with CIMT [β= -0.90, 95% CI: (-1.67 to -0.13) μm; P = 0.023]. Similarly, eGFR correlated with Agatston scores only when using cystatin C-based eGFR [β= -8.63, 95% CI: (-16.49 to -0.77) HU; P = 0.034]. Associations between other eGFR formulas and CAC did not reach statistical significance., Conclusions: In PLWH, preclinical atherosclerosis may be more closely correlated with eGFR using formulae that incorporate CysC measurements than Cr alone.