Current HIV Research - Volume 17, Issue 3, 2019

Uracil-DNA glycosylase-2 (UNG2) is a DNA repair protein that removes uracil from single and double-stranded DNA through a basic excision repair process. UNG2 is packaged into new virions by interaction with integrase (IN) and is needed during the early stages of the replication cycle. UNG2 appears to play both a positive and negative role during HIV-1 replication; UNG2 improves the fidelity of reverse transcription but the nuclear isoform of UNG2 participates in the degradation of cDNA and the persistence of the cellular genome by repairing its uracil mismatches. In addition, UNG2 is neutralized by Vpr, which redirects it to the proteasome for degradation, suggesting that UNG2 may be a new cellular restriction factor. So far, we have not understood why HIV-1 imports UNG2 via its IN and why it causes degradation of endogenous UNG2 by redirecting it to the proteasome via Vpr. In this review, we propose to discuss the ambiguous role of UNG2 during the HIV-1 replication cycle.

Background: Socioeconomic and demographic statuses are associated with adherence to the treatment of patients with several chronic diseases. However, there is a controversy regarding their impact on adherence among HIV/AIDS patients. Thus, we performed a systematic review of the evidence regarding the association of socioeconomic and demographic statuses with adherence to antiretroviral therapy (ART) among HIV/AIDS patients. Methods: The PubMed database was used to search and identify studies concerning about socioeconomic and demographic statuses and HIV/AIDS patients. Data were collected on the association between adherence to ART and varies determinants factors of socioeconomic (income, education, and employment/occupation) and socio-demographic (sex and age). Findings: From 393 potentially-relevant articles initially identified, 35 original studies were reviewed in detail, which contained data that were helpful in evaluating the association between socioeconomic/ demographic statuses and adherence to ART among HIV patients. Two original research study has specifically focused on the possible association between socioeconomic status and adherence to ART. Income, level of education, and employment/occupational status were significantly and positively associated with the level of adherence in 7 studies (36.8%), 7 studies (28.0%), and 4 studies (23.5%) respectively out of 19, 25, and 17 studies reviewed. Sex (being male), and age (per year increasing) were significantly and positively associated with the level of adherence in 5 studies (14.3%), and 9 studies (25.7%) respectively out of 35 studies reviewed. However, the determinant of socioeconomic and demographic statuses was not found to be significantly associated with adherence in studies related to income 9(47.4%), education 17(68.0%), employment/ occupational 10(58.8%), sex 27(77.1%), and age 25(71.4%). Conclusion: The majority of the reviewed studies reported that there is no association between socio- demographic and economic variables and adherence to therapy. Whereas, some studies show that age of HIV patients (per year increasing) and sex (being male) were positively associated with adherence to ART. Among socio-economic factors, the available evidence does not provide conclusive support for the existence of a clear association with adherence to ART among HIV patients. There seems to be a positive trend between socioeconomic factors and adherence to ART in some of the reviewed studies.

Background: Non-alcoholic Fatty Liver Disease (NAFLD) is common in HIV-infected individuals. Liver biopsy remains the gold-standard procedure for the diagnosis of liver fibrosis, but both Transient Elastography (TE) and Non-invasive Biomarkers (NIBMs) have emerged as alternatives. Objectives: Our study’s aim was to validate commonly used NIBMs for the assessment of liver fibrosis in a cohort of Greek HIV-mono-infected patients. Methods: Inclusion criteria were confirmed HIV-infection and age>18 years and exclusion criteria HBV or HCV seropositivity, liver disease other than NAFLD, alcohol abuse, ascites, transaminases levels>4xULN(upper limit of normal) and Body-Mass index(BMI)>40. Liver stiffness (LS) measurement with TE and thorough laboratory work up and medical history were acquired at study entry. FIB-4, APRI, NFS, BARD, Forns and Lok scores were calculated for each patient. Results: A total of 157 patients were eligible for this study. Significant liver fibrosis, compatible with Metavir score of F3-F4, was found in only 11(7%) patients. These findings were in accordance with those of the NIBMs; the BARD score constituting the only exception, allocating 102(65%) patients as having significant liver fibrosis. In order to obtain a balance between sensitivity and specificity new cut-offs for each NIBM were calculated; FIB-4 score yielded the best results, since by changing the cut-off to 1.49 a sensitivity and specificity balanced for both close to 85% was achieved. Conclusion: Our findings suggest that NIBMs can be used for the evaluation of liver fibrosis in HIV mono-infected patients. New cut-offs for NIBMs should probably be calculated, to help distinguishing patients with significant from those with mild/no fibrosis.

Objectives: The aim of the study was to investigate if the supplementation with multistrain probiotics may be able to modulate T cell response in HIV-1 infected patients and to evaluate the anti-HIV activity of probiotic by studying fecal water (FW) samples. Methods: Three HIV-1-positive patients (Pt1, Pt2 and Pt3) on long-term suppressive combined antiretroviral therapy (cART) received a specific multi-strain probiotic supplementation (Vivomixx ®), for six months (T6). Levels of T cell subsets were evaluated by flow cytometry. Anti- HIV activity of FW samples was evaluated in vitro. Results: CD4+ T cells levels increased in all HIV-1 infected patients whereas activation markers (CD38 and HLA-DR) were decreased both on CD4+ and CD8+ T cells. FW samples presented an increased inhibitory activity against HIV-1 compared to T0 (FW-Pt1: T0 =40%, T6 = 65% of reduction; FW Pt2: T0 = 26%, T6 = 46% of reduction; FW Pt3: T0 = 47%, T6 = 94% of reduction). Discussion: Our data suggest that the administration of the specific probiotic formulation improves the antiviral status of people living with HIV-1 under cART, also modulating T cell response. Conclusion: Anti-HIV activity of FW may have several public health and social implications for sexually transmitted diseases that need to be further explored.

Background: HIV infection is a chronic disease for which therapeutic adherence and tolerance require particular attention. Objective: This study aimed to assess whether and when therapeutic drug monitoring (TDM) could be associated with a benefit in routine practice. Methods: All HIV-infected patients who underwent at least one TDM at the University Hospital of Dijon (France) between 1st January 2009 and 31st December 2012 were retrospectively included. Compliance with the recommendations, the results (antiretroviral concentrations), any subsequent therapeutic modifications, and the virological results at 4-8 months were analysed each time TDM was performed. TDM was defined as “practically relevant” when low or high antiretroviral concentrations led to a change in therapy. Results: Of the 571 patients who followed-up, 43.4% underwent TDM. TDM complying with recommendations (120 patients) was associated with a higher proportion of antiretroviral concentrations outside the therapeutic range (p=0.03). Antiretroviral treatment was modified after TDM in 22.6% of patients. Protease inhibitors, non-nucleoside reverse transcriptase inhibitors and raltegravir were more significantly modified when the measured concentration was outside the therapeutic range (p=0.008, p=0.05 and p=0.02, respectively). Overall, 11.7% of TDM was considered “practically relevant”, though there was no significant correlation between subsequent changes in antiretroviral treatment and undetectable final HIV viral load. Conclusion: TDM may be a useful tool in the management of HIV infection in specific situations, but the overall benefit seems moderate in routine practice. TDM cannot be systematic and/or a decision tool per se, but should be included in a comprehensive approach in certain clinical situations.

Background: Fibroblast growth factor (FGF) 23 is a well-known phosphaturic hormone produced mainly by bone cells to maintain phosphate and mineral homeostasis. Serum FGF23 levels are elevated in patients with chronic kidney disease (CKD), and elevated FGF23 might increase the risk of cardiovascular disease (CVD). Several reports have documented an increased incidence of risk factors for osteopenia, CKD, and CVD in people living with HIV (PLWH). However, few reports related to FGF23 in PLWH have been published. Methods: Male HIV patients who presented to the outpatient clinic of Teikyo University Hospital, Tokyo, Japan, in 2015 and were treated with antiretroviral therapy (ART) for > 6 months were enrolled in the study. In addition to serum FGF23 measurements, the clinical factors assessed included age, ART regimens, and laboratory data. Spearman correlation and multiple regression analysis were performed to determine factors significantly associated with FGF23. Results: In total, 67 patients were enrolled in the present study. The median age was 43.7 years, the median CD4 count was 529 cells/μL, and the median serum FGF23 level was 36.0 pg/mL. Based on correlation and multiple regression analyses, serum FGF23 levels were significantly correlated with HIV RNA > 50 copies (correlation analysis: t = 3.4259, P = 0.0011 / multiple regression analysis: P = 0.00106) or abacavir (ABC)/lamivudine (3TC) use (t = 2.8618, P = 0.0057 / P = 0.02704). Conclusion: Factors significantly associated with elevated serum FGF23 levels included poor virologic control and ABC/3TC use.

Background: Increasing age of HIV-1 infected population brought about the risk of frailty as comorbidity, whose prevalence is higher in low and middle-income countries (LMICs). Indonesia as an LMIC also bears a major burden of HIV-1 epidemic with a similarly aging population, but the prevalence of frailty and its predictors are unknown. Objectives: To identify the prevalence of frailty and analyze its associated factors, among HIV-1 infected adults under antiretroviral therapy in Indonesia. Methods: A cross-sectional study was conducted among HIV-infected individuals with inclusion criteria of age ≥30 years old and underwent ART for at least 6 months. The main assessment was done using Fried’s frailty phenotype score, which categorizes subjects into non-frail, pre-frail, or frail. Factors associated with frailty were characterized and multiple logistic regression analysis was performed. Results: A total of 164 subjects were recruited; male subjects were 118 (72%), the median age was 40.5 years old, and the median CD4 nadir was 53 cells/μl. Frailty was identified among 90 (54.9%) subjects with 84 (51.2%) identified as pre-frail and 6 (3.7%) as frail, with dominant frailty phenotype was weakness in grip strength. The multivariate model showed that depression was the only factor significantly correlated with pre-frailty and frailty (OR 2.14; 95% CI 1.04-4.43, p=0.036). Conclusion: Frailty is a common occurrence among HIV-infected patients under ART, with depression as an independent predictive factor.

Background: Although major efforts have been devoted to the effective treatment of HIV-1 infection, it has remained one of the leading causes of deaths around the world. So, development of anti-HIV-1 agents featuring novel structure is essential. Objective: To synthesize novel quinazolinone derivatives and evaluate their anti-HIV-1 activity. Method: In this study, we designed and synthesized a series of novel 2,3-diaryl-4-quinazolinone derivatives using a one-pot multicomponent reaction. Then, the resulting derivatives were evaluated for anti-HIV-1 activity using Hela cell-based single-cycle replication assay. Results: Most of the compounds showed efficacy against HIV-1 replication and the compound 9c exhibited the highest activity with EC50 value of 37 μM. Docking studies indicated that synthesized compounds can interact with the key residues of the HIV-1 integrase active site. Binding of the most active compound was consistent with the HIV-1 integrase inhibitors. Conclusion: Based on our results, these derivatives represent novel lead compounds for the development of new promising anti-HIV-1 agents.