Current HIV Research - Volume 20, Issue 2, 2022

Purpose of Review: There have been significant developments in the treatment of people living with HIV-1/AIDS with current antiretroviral therapies; however, these developments have not been able to achieve a functional or sterilizing cure for HIV-1. While there are multiple barriers, one such barrier is the existence of pharmacological sanctuaries and viral reservoirs where the concentration of antiretrovirals is suboptimal, which includes the gut-associated lymphoid tissue, central nervous system, lymph nodes, and myeloid cells. This review will focus on illustrating the significance of these sanctuaries, specific barriers to optimal antiretroviral concentrations in each of these sites, and potential strategies to overcome these barriers. Recent Findings: Research and studies have shown that a uniform antiretroviral distribution is not achieved with current therapies. This may allow low-level replication associated with low antiretroviral concentrations in these sanctuaries/reservoirs. Many methods are being investigated to increase antiretroviral concentrations in these sites, such as blocking transporting enzymes functions, modulating transporter expression and nanoformulations of current antiretrovirals. While these methods have been shown to increase antiretroviral concentrations in the sanctuaries/reservoirs, no functional or sterilizing cure has been achieved due to these approaches. Summary: New methods of increasing antiretroviral concentrations at the specific sites of HIV-1 replication has the potential to target cellular reservoirs. In order to optimize antiretroviral distribution into viral sanctuaries/reservoirs, additional research is needed.

Antiretroviral therapy (ART) can effectively suppress HIV-1 replication, improving quality of life and restoring the lifespan of persons living with HIV (PLWH) to near-normal levels. However, after standardized ART, a low level of HIV-1 RNA, i.e., low-level viremia (LLV), may still be identified in 3% to 10% of the patients. LLV is capable of impacting the immunological and clinical outcomes of patients and serves as a risk factor for transmission. The underlying mechanism of LLV is not yet certain, and the effects of LLV on patient outcomes remain under evaluation. Understanding LLV will allow effective prevention and control strategies to be designed for the benefit of PLWH.

Objective: It has been reported that approximately 90 % of patients infected with the human immunodeficiency virus (HIV) have various cutaneous symptoms related to the virus. This study aims to describe the cutaneous disorders that have developed in HIV-infected patients and to investigate the factors that may be related, such as relationships to drug use and CD4 counts. Methods: This cross-sectional study included people living with HIV and being followed by our hospital’s infectious diseases clinic after being referred to the dermatology clinic because of skin lesions. These patients had been diagnosed with HIV by enzyme-linked immunosorbent assay tests and were included in the study if they were older than 18 years and had agreed to participate. Findings from detailed dermatological examinations were recorded, along with the patients’ CD4 counts, the durations of their illnesses, and the treatments they received. Results: 144 patients were included in the study. The most common mucocutaneous manifestation was seborrheic dermatitis, at 28.5 % (n = 41). The mean CD4 count was 607.1 (min-max = 10.6- 1982). The CD4 counts were divided into three groups in the study as follows: 22 (15.3 %) patients with <200, 35 (24.3 seborrheic dermatitis) patients between 200 and 500, and 87 (60.4 %) patients with >500. There were no statistical differences between these groups in terms of dermatological findings. Nevertheless, the highest rate of patients with three or more dermatological conditions was found among those with CD4 counts <200 (n = 11.50 %). Conclusion: Skin manifestations are common in patients who are HIV-positive; however, many skin disorders can be seen in HIV/acquired immunodeficiency syndrome (AIDS) patients whatever CD4 cell counts of these patients are.

Background: Evidence of lymphopoiesis, exhaustion, and premature aging in Chinese patients with human immunodeficiency virus (HIV) is very limited. Objective: To assess biological aging and immune senescence in Chinese healthy controls (HC) and ART-naïve HIV-infected men who have sex with men (MSM). Methods: This case-control study was conducted in Beijing Ditan Hospital from March 2018 to June 2019. The percentages of naïve (TN), central memory (TCM), effector memory (TEM), and terminally differentiated memory (TemRA) subsets of CD4 and CD8 T cells were studied, along with markers of senescence (CD28-CD57+) and activation (HLA-DR+). Telomere length of naïve (CD45RA+) and memory (CD45RO+) CD8 T cells were quantified by real-time PCR. Results: A total of 26 HIV-infected and 20 age-matched HC MSM were included. Compared to the HC group, the CD4/CD8 ratio of the HIV-infected group was significantly reduced (0.30 vs. 1.70, P<0.001); significant differences emerged among all CD8 but not CD4 T cell subsets (all P<0.05). In the HIV-infected group, the percentages of senescent cells (CD28-CD57+) in TN, TCM, TEM, and TemRA subsets of CD8 T cells were higher (all P<0.05); while a significant difference was only found in naïve CD4 T cells (P<0.05). HLA-DR expression was increased significantly in all CD4 and CD8 T cell subsets. Both naïve (CD45RA+) and memory (CD45RO+) CD8 T cells in this population had significantly shorter telomere lengths (P<0.01) compared to the HC group. Conclusion: HIV-infected MSM exhibit signs of accelerated immune senescence and biological aging, which particularly affects the CD8 T-cell subsets.

Background: Rates of cardiovascular disease are higher in people living with HIV. Early detection of high-risk subjects (applying cardiovascular risk equations) would allow preventive actions. D:A:D, ASCVD, and FRS:CVD equations are the most recommended. However, controversies surround these equations and cut-points, which have the greatest capacity to discriminate high-risk subjects. Objectives: The study aims (i) to assess the association/agreement between cardiovascular risk levels obtained with D:A:D and fifteen other cardiovascular risk equations, (ii) to detect cardiovascular risk equation’s capability to detect high-risk subjects, and (iii) to specify the optimal cardiovascular risk equation´s cut points for the prediction of carotid plaque presence, as a surrogate of high cardiovascular risk. Methods: 86 adults with HIV were submitted to the clinical, laboratory, and cardiovascular risk evaluation (including carotid ultrasound measurements). Cardiovascular risk was evaluated through multiple risk equations (e.g., D.A.D, ASCVD, and FRS equations). Association and agreement between equations (Correlation, Bland-Altman, Williams´test) and equation’s capacity to detect plaque presence (ROC curves, sensitivity, specificity) were evaluated. Results: Cardiovascular risk equations showed a significant and positive correlation with plaque presence. Higher high-cardiovascular risk detection capability was obtained for ASCVD and D:A:D. Full D:A:D5y>0.88 %, ASCVD>2.80 %, and FRS:CVD>2.77 % correspond to 80 % sensitivity. Conclusion: All cardiovascular risk equations underestimate the true risk in HIV subjects. The cut-- points for high cardiovascular risk were found to vary greatly from recommended in clinical guidelines.

Background: Entry inhibitors prevent the binding of human immunodeficiency virus protein to the chemokine receptor CXCR4 and are used along with conventional anti-HIV therapy. They aid in restoring immunity and can prevent the development of HIV-TB co-infection. Aims: In the present study, various thiazolidinone-pyrazine derivatives earlier studied for NNRT inhibition activity were gauged for their entry inhibitor potential. Objective: The objective of the study is to perform molecular docking, ADME, toxicity studies of some thiazolidinone-pyrazine derivatives as entry inhibitors targeting CXCR4 co-receptors. Methods: In-silico docking studies were performed using AutoDock Vina software and compounds were further studied for ADME and toxicity using SwissADME and pkCSM software, respectively. Results: Taking into consideration the docking results, pharmacokinetic behaviour and toxicity profile, four molecules (compounds 1, 9, 11, and 16) have shown potential as entry inhibitors. Conclusion: These compounds have shown potential as both NNRTI and entry inhibitors and hence can be used in management of immune compromised diseases like TB-HIV coinfection.

Background: Effective global antiretroviral vaccines and therapeutic strategies depend on the diversity, evolution, and epidemiology of their various strains as well as their transmission and pathogenesis. Most viral disease-causing particles are clustered into a taxonomy of subtypes to suggest pointers toward nucleotide-specific vaccines or therapeutic applications of clinical significance sufficient for sequence-specific diagnosis and homologous viral studies. These are very useful to formulate predictors to induce cross-resistance to some retroviral control drugs being used across study areas. Objective: This research proposed a collaborative framework of hybridized (Machine Learning and Natural Language Processing) techniques to discover hidden genome patterns and feature predictors for HIV-1 genome sequences mining. Methods: 630 human HIV-1 genome sequences above 8500 bps were excavated from the National Center for Biotechnology Information (NCBI) database (https://www.ncbi.nlm.nih.gov) for 21 countries across different continents, except for Antarctica. These sequences were transformed and learned using a self-organizing map (SOM). To discriminate emerging/new sub-strain(s), the HIV-1 reference genome was included as part of the input isolates/samples during the training. After training the SOM, component planes defining pattern clusters of the input datasets were generated for cognitive knowledge mining and subsequent labeling of the datasets. Additional genome features, including dinucleotide transmission recurrences, codon recurrences, and mutation recurrences, were finally extracted from the raw genomes to construct output classification targets for supervised learning. Results: SOM training explains the inherent pattern diversity of HIV-1 genomes as well as interand intra-country transmissions in which mobility might play an active role, as corroborated by the literature. Nine sub-strains were discovered after disassembling the SOM correlation hunting matrix space attributed to disparate clusters. Cognitive knowledge mining separated similar pattern clusters bounded by a certain degree of correlation range, as discovered by the SOM. Kruskal-Wallis ranksum test and Wilcoxon rank-sum test showed statistically significant variations in dinucleotide, codon, and mutation patterns. Conclusion: Results of the discovered sub-strains and response clusters visualizations corroborate the existing literature, with significant haplotype variations. The proposed framework would assist in the development of decision support systems for easy contact tracing, infectious disease surveillance, and studying the progressive evolution of the reference HIV-1 genome.

Background and Objective: Integrase strand transfer inhibitors (INSTIs) are currently the standard of practice for first-line HIV therapy for most patients. We evaluated the mutations associated with INSTI resistance in naive HIV-1 infected patients and treated them with antiretrovirals (ART). Methods: The study, conducted in the 2018 - 2020 period, included 50 ART-naïve patients, 69 INSTI free ART-experienced patients, and 82 INSTI-experienced patients. INSTI resistance mutations were interpreted using the Stanford University HIVdb Program algorithm. Results: INSTI resistance was not detected in ART naïve patients. At least one INSTI resistance mutation was detected in 10% of the INSTI-free patients and 29% of the INSTI-treated patients. Major INSTI-mutations E138K, Y143R, S147G, Q148R, N155H, and E157Q were found in raltegravir. Additional mutations, E92Q, E138K, G140A, S147G, and Q148R were found in elvitegravir; E192Q, E138K/T, G140A/S, S147G, Q148H/R, N155H, E157Q were found in dolutegravir (DTG) experienced patients. According to all drug classes, drug resistance mutation prevalences were determined at the rate of 60%, 46%, and 46% in the RAL, EVG, and DTG groups, respectively. Conclusion: Our findings provide data for treatment and resistance management of INSTIs and may provide feedback for INSTIs resistance surveillance consensus-building efforts. In viral rebound under INSTI treatment, INSTI-resistant mutations follow typical INSTI resistance pathways and high resistance rates. INSTI resistance genotypic analysis should be considered before any DTG-based regimes can be initiated in the future, and reduced DTG susceptibility should be carefully monitored and investigated.

Background: Multilocular thymic cysts (MTCs) in adults with human immunodeficiency virus (HIV) are rarely reported. Case Presentation: We describe a case of symptomatic MTC in a male with untreated HIV. A presumptive diagnosis was established based on radiographic imaging and biopsy. Pathologic diagnosis and exclusion of malignancy were ultimately confirmed following thymectomy. In conjunction with starting antiretroviral therapy, the patient recovered well post-operatively with a resolution of his presenting symptoms. Conclusion: Our case report and review of the literature serve to highlight MTCs as an important clinical entity occurring in persons with HIV.