Early Stages Of HIV Infection Research Articles

P-PN033. Chronic inflammatory demyelinating polyneuropathy in HIV infected patient responding to plasmapheresis: A case report

Introduction . Chronic Inflammatory Demyelinating Polyradiculoneuropathy or CIDP is a neurological disorder characterized by chronic progressive weakness and impairment of sensory function of the limbs and arms, accompanied by decreased tendon reflexes. CIDP can occur in the setting of HIV, as are other immune-mediated neurologic disorders including a wide spectrum of neuropathies. Results . Male, 27 years old, with thick and tingling complaints in both feet and hands followed by ascending, symmetrical, progressive weakness of all four limbs for 3 months. Physical examination showed decreased muscle strength, areflexia, and hypoesthesia in the distal four extremities. In addition, there was oral candidiasis in the patient so there was a suspicion of an immunodeficiency condition. Repeat HIV antibody testing returned positive. The ENMG results shows demyelinating and axonopathy in peripheral nerve. Six sessions of plasmapheresis measures were performed in this patient as therapy. Muscle strength and complaints of numbness improved with therapy, patient was expected to continue to improve with intensive rehabilitation after discharge. The diagnosis of CIDP meets the EFNS clinical criteria and EFNS definite electrophysiologic criteria. This case can be distinguished from HIV-related distal sensory polyneuropathy because of motor nerve involvement. Conclusion . CIDP may occur in early stages of HIV infection, is probably autoimmune in etiology, clinically shows sensorimotor neuropathy and nerve conduction studies show demyelination. This case report shows HIV-infected patients with CIDP displayed a progressive course of sensorimotor involvement. Plasma exchange showed a good therapeutic response in this case.

Thymidylate synthase is essential for efficient HIV-1 replication in macrophages

Thymidylate synthase (TS) is a key enzyme in nucleotide biosynthesis. A study performed by our group on human monocyte-derived macrophages (MDMs) infected with HIV-1 showed that many enzymes related to the folate cycle pathway, such as TS, are upregulated in productively infected cells. Here, we suggest that TS is essential for an effective HIV-1 infection in MDMs. Indeed, a TS specific small interfering RNA (siRNA) as well as the TS specific inhibitor Raltitrexed (RTX) caused a reduction in productively infected cells. Quantitative PCR analysis showed that this treatment decreased the efficacy of the early steps of the viral cycle. The RTX inhibitory effect was counteracted by dNTP addition. These results suggest that TS is essential for the early stages of HIV-1 infection by providing optimal dNTP concentrations in MDMs. TS and its related pathway may thus be considered as a potential therapeutic target for HIV-1 treatment.

Association between obesity and combination antiretroviral therapy (cART) adherence among persons with early-stage HIV infection initiating cART.

BackgroundObesity is common among people living with HIV (PLWH) and early-stage infection, yet associations with combination antiretroviral (cART) adherence are unclear.MethodsAmong PLWH initiating cART in Uganda and South Africa, body mass index (BMI) was assessed at cART initiation, and cART adherence was monitored in real-time over 12 months. The association of obesity (BMI >=30kg/m2) with adherence was assessed among non-pregnant participants with CD4>350 cells/mm3 using fractional regression modeling.ResultsAmong 322 participants, median age was 32 years, 70% were female, and 54% were from Uganda. Prevalence of obesity was 12% in Uganda and 28% in South Africa. Mean overall cART adherence was 83% in Uganda and 66% in South Africa. Participants with obesity had higher adherence than those without obesity: +3.6% (p=0.44) in Uganda and +11.4% (p=0.02) in South Africa.ConclusionObesity at cART initiation was common and associated with higher adherence, although only significantly in South Africa.

Psychiatric stigma in patients with comorbid hiv infection

IntroductionHIV-positive patients with schizophrenia spectrum disorders experience burden of double stigma. Comorbid pathology may alter structure of stigma and shall be considered in development of individual destigmatization programs.ObjectivesStudy of psychiatric stigma features in HIV-positive and HIV-negative patients with schizophrenic disorders.MethodsISMI (Ritsher et al., 2003), PDD (Link et al., 1991) – to study stigma in 70 patients divided into three groups with respect to their diagnosis (I — F20.x, II — F21.x, III— F2x+HIV); BPRS (Overall & Gorham, 1962) – to assess psychiatric status, RSAS (Eckblad et al., 1982) – to assess anhedonia. Dispersion analysis (Kruskal and Mann–Whitney tests), Spearman and Pearson correlation were used.ResultsPatients with comorbid HIV-infection showed increased level of perceived stigma, although they resisted the stigma internalization better than others did (Table 1).Patients with schizotypal disorders and patients at early stages of HIV infection experienced the most alienation and frailty to internalization of stigma (Tables 1, 2).Correlation relationship between social anhedonia and perceived stigma (r=0.5, p<0.05) observed in patients with HIV infection.ConclusionsComorbid HIV infection in psychiatric patients contributes to the psychiatric stigma structure. Differentiated approaches in rehabilitation of HIV-positive mental patients should be used.

Application of deep learning and molecular modeling to identify small drug-like compounds as potential HIV-1 entry inhibitors

A generative adversarial autoencoder for the rational design of potential HIV-1 entry inhibitors able to block CD4-binding site of the viral envelope protein gp120 was developed. To do this, the following studies were carried out: (i) an autoencoder architecture was constructed; (ii) a virtual compound library of potential anti-HIV-1 agents for training the neural network was formed by the concept of click chemistry allowing one to generate a large number of drug candidates by their assembly from small modular units; (iii) molecular docking of all compounds from this library with gp120 was made and calculations of the values of binding free energy were performed; (iv) molecular fingerprints of chemical compounds from the training dataset were generated; (v) training of the developed autoencoder was implemented followed by the validation of this neural network using more than 21 million molecules from the ZINC15 database. As a result, three small drug-like compounds that exhibited the high-affinity binding to gp120 were identified. According to the data from molecular docking, machine learning, quantum chemical calculations, and molecular dynamics simulations, these compounds show the low values of binding free energy in the complexes with gp120 similar to those calculated using the same computational protocols for the HIV-1 entry inhibitors NBD-11021 and NBD-14010, highly potent and broad anti-HIV-1 agents presenting a new generation of the viral CD4 antagonists. The identified CD4-mimetic candidates are suggested to present good scaffolds for the design of novel antiviral drugs inhibiting the early stages of HIV-1 infection. Communicated by Ramaswamy H. Sarma

Non-synonymous Substitutions in HIV-1 GAG Are Frequent in Epitopes Outside the Functionally Conserved Regions and Associated With Subtype Differences.

In 2019, 38 million people lived with HIV-1 infection resulting in 690,000 deaths. Over 50% of this infection and its associated deaths occurred in Sub-Saharan Africa. The West African region is a known hotspot of the HIV-1 epidemic. There is a need to develop an HIV-1 vaccine if the HIV epidemic would be effectively controlled. Few protective cytotoxic T Lymphocytes (CTL) epitopes within the HIV-1 GAG (HIV_gagconsv) have been previously identified to be functionally conserved among the HIV-1 M group. These epitopes are currently the focus of universal HIV-1 T cell-based vaccine studies. However, these epitopes’ phenotypic and genetic properties have not been observed in natural settings for HIV-1 strains circulating in the West African region. This information is critical as the usefulness of universal HIV-1 vaccines in the West African region depends on these epitopes’ occurrence in strains circulating in the area. This study describes non-synonymous substitutions within and without HIV_gagconsv genes isolated from 10 infected Nigerians at the early stages of HIV-1 infection. Furthermore, we analyzed these substitutions longitudinally in five infected individuals from the early stages of infection till after seroconversion. We identified three non-synonymous substitutions within HIV_gagconsv genes isolated from early HIV infected individuals. Fourteen and nineteen mutations outside the HIV_gagconsv were observed before and after seroconversion, respectively, while we found four mutations within the HIV_gagconsv. These substitutions include previously mapped CTL epitope immune escape mutants. CTL immune pressure likely leaves different footprints on HIV-1 GAG epitopes within and outside the HIV_gagconsv. This information is crucial for universal HIV-1 vaccine designs for use in the West African region.

Stochastic investigation of HIV infection and the emergence of drug resistance.

Drug-resistant HIV-1 has caused a growing concern in clinic and public health. Although combination antiretroviral therapy can contribute massively to the suppression of viral loads in patients with HIV-1, it cannot lead to viral eradication. Continuing viral replication during sub-optimal therapy (due to poor adherence or other reasons) may lead to the accumulation of drug resistance mutations, resulting in an increased risk of disease progression. Many studies also suggest that events occurring during the early stage of HIV-1 infection (i.e., the first few hours to days following HIV exposure) may determine whether the infection can be successfully established. However, the numbers of infected cells and viruses during the early stage are extremely low and stochasticity may play a critical role in dictating the fate of infection. In this paper, we use stochastic models to investigate viral infection and the emergence of drug resistance of HIV-1. The stochastic model is formulated by a continuous-time Markov chain (CTMC), which is derived based on an ordinary differential equation model proposed by Kitayimbwa et al. that includes both forward and backward mutations. An analytic estimate of the probability of the clearance of HIV infection of the CTMC model near the infection-free equilibrium is obtained by a multitype branching process approximation. The analytical predictions are validated by numerical simulations. Unlike the deterministic dynamics where the basic reproduction number R0 serves as a sharp threshold parameter (i.e., the disease dies out if R0<1 and persists if R0>1), the stochastic models indicate that there is always a positive probability for HIV infection to be eradicated in patients. In the presence of antiretroviral therapy, our results show that the chance of clearance of the infection tends to increase although drug resistance is likely to emerge.

HIV capsid and productive infection: taking steps in the right direction

The Human Immunodeficiency Virus Type-1, the causative agent of AIDS, reaches its site of replication by trafficking through the cytoplasm towards the nucleus, benefiting from an active nuclear import through the nuclear pore in order to integrate in the genome of the host cell. Although it is generally accepted that the viral genome remains within the viral capsid for some time after cell entry, the mechanisms responsible for controlled uncoating, which is essential for productive infection, remain poorly understood. Numerous studies now show that the integrity of the viral capsid is essential for transport towards the nucleus, for reverse transcription and nuclear import, and to prevent sensing by innate immune receptors. This review aims to report recent developments in our understanding of the early stages of HIV infection, from entry into the cell to integration, highlighting the cellular partners of the HIV-1 capsid that promote or antagonize infection, as well as the different techniques that are developed for fundamental research and the identification of potential therapeutic targets.

Longitudinal Analysis of Peripheral and Colonic CD161+ CD4+ T Cell Dysfunction in Acute HIV-1 Infection and Effects of Early Treatment Initiation.

CD161 expression on CD4+ T cells is associated with a Th17 functional phenotype, as well as with an innate capacity to respond to interleukin (IL)-12 and IL-18 without T cell receptor (TCR) stimulation. Chronic HIV-1 infection is associated with loss of the CD161+ CD4 T cell population, and non-human primate studies suggest that their depletion is associated with disease progression. However, the dynamics of the CD161+ CD4+ T cell population during acute HIV-1 infection remains unknown. In this study, we characterize peripheral blood CD161+ CD4+ T cells in detail, and examine how they are affected during the earliest stages of HIV-1 infection. Unbiased surface proteome screening and principal component analysis indicated that CD161+ CD4+ T cells are relatively phenotypically homogeneous between donors, and are intermediates between conventional CD4 T cells and innate-like T cells. In acute untreated HIV-1 infection, the circulating CD161+ CD4+ T cell population decreased in frequency, as did absolute cell counts starting from peak viral load, with elevated levels of activation and exhaustion markers expressed throughout acute HIV-1 infection. The capacity of these cells to respond to stimulation with IL-12 and IL-18 was also reduced. Early initiation of anti-retroviral treatment (ART) during acute HIV-1 infection restored the functionality of peripheral blood CD161+ CD4+ T cells, but not their frequency. In contrast, early ART initiation prevented the decline of colonic CD161+ CD4+ T cells that otherwise started during acute infection. Furthermore, loss of peripheral and colonic CD161+ CD4+ T cells in untreated infection was associated with levels of viral load. These results suggest that acute HIV-1 infection has profound effects on the CD161+ CD4+ T cell population that could not be completely prevented by the initiation of ART.

Immune recovery in HIV-1 infected patients with sustained viral suppression under long-term antiretroviral therapy in Ethiopia.

BackgroundThere is very little data on long-term immune recovery responses in patients on suppressive antiretroviral therapy (ART) in the setting of sub-Saharan Africa (SSA). Thus, we sought to determine CD4+ T-cell, CD8+ T-cell and CD4/CD8 ratio responses in a cohort of HIV infected individuals on sustained suppressive ART followed up for more than a decade.MethodsThe cohort comprised adult patients who started ART between 2001 and 2007 and followed for up to 14 years. Trends in median CD4+ T-cells, CD8+ T-cells and CD4/CD8 ratio were reviewed retrospectively. Poisson regression models were used to identify factors associated with achieving normalized T-cell biomarkers. Kaplan-Meier curves were used to estimate the probability of attaining normalized counts while on suppressive ART.ResultsA total of 227 patients with a median duration of follow-up on ART of 12 (IQR: 10.5–13.0) years were included. CD4 cell count increased from baseline median of 138 cells (IQR: 70–202) to 555 cells (IQR: 417–830). CD4 cell increased continuously up until 5 years, after which it plateaued up until 14 years of follow up. Only 69.6% normalized their CD4 cell count within a median of 6.5 (IQR: 3.0–10.5) years. In addition, only 15.9% of the cohort were able to achieve the median reference CD4+ T-cell threshold count in Ethiopians (≈760 cells/μL). CD8+ T-cell counts increased initially until year 1, after which continuous decrease was ascertained. CD4/CD8 ratio trend revealed continuous increase throughout the course of ART, and increased from a median baseline of 0.14 (IQR: 0.09–0.22) to a median of 0.70 (IQR: 0.42–0.95). However, only 12.3% normalized their ratio (≥ 1.0) after a median of 11.5 years. In addition, only 8.8% of the cohort were able to achieve the median reference ratio of healthy Ethiopians.ConclusionDetermination of both CD4+ and CD8+ T-cells, along with CD4/CD8 ratio is highly relevant in long-term follow-up of patients to assess immune recovery. Monitoring ratio levels may serve as a better biomarker risk for disease progression among patients on long-term ART. In addition, the findings emphasize the relevance of initiation of ART at the early stage of HIV-1 infection.

Deep Profiling Identifies Selection of Nonsynonymous Amino Acid Substitutions in HIV-1 Envelope During Early Infection.

Understanding the evolutionary dynamics of the viruses within an individual at or near the moment of transmission can provide critical inputs for the design of an effective vaccine for HIV infection. In this study, high-throughput sequencing technology was employed to analyze the evolutionary rate in viruses obtained at a single time point from drug-naive recently infected infants and adults in the chronic stage of disease. Gene-wise nonsynonymous (pN) and synonymous (pS) mutation rates were estimated and compared between the two groups. Significant differences were observed in the evolutionary rates between viruses in the early and late stages of infection. Higher rates of adaptive mutations in the HIV-1 envelope gene (env) were found in the chronic viruses as compared with those in the early stages of HIV infection. Conversely, percentage of nonsynonymous substitutions in env was found to be higher in recently transmitted viruses. In addition, a positive correlation was found between mutation and the evolutionary rate, and infectivity titer in recent infection. Despite the small sample size, the study identified useful information about viral evolution on transmission-associated bottlenecks. The effect of intraindividual HIV-1 evolution at the population level was highly contemporary, and the higher percentage of nonsynonymous substitutions seen in env during recent HIV-1 infection has suggested a pattern of convergent evolution leading to a positive selection for survival fitness and disease progression.

HIV-1 capsids mimic a microtubule regulator to coordinate early stages of infection.

While the microtubule end-binding protein, EB1 facilitates early stages of HIV-1 infection, how it does so remains unclear. Here, we show that beyond its effects on microtubule acetylation, EB1 also indirectly contributes to infection by delivering the plus-end tracking protein (+TIP), cytoplasmic linker protein 170 (CLIP170) to the cell periphery. CLIP170 bound to intact HIV-1 cores or invitro assembled capsid-nucleocapsid complexes, while EB1 did not. Moreover, unlike EB1 and several other +TIPs, CLIP170 enhanced infection independently of effects on microtubule acetylation. Capsid mutants and imaging revealed that CLIP170 bound HIV-1 cores in a manner distinct from currently known capsid cofactors, influenced by pentamer composition or curvature. Structural analyses revealed an EB-like +TIP-binding motif within the capsid major homology region (MHR) that binds SxIP motifs found in several +TIPs, and variability across this MHR sequence correlated with the extent to which different retroviruses engage CLIP170 to facilitate infection. Our findings provide mechanistic insights into the complex roles of +TIPs in mediating early stages of retroviral infection, and reveal divergent capsid-based EB1 mimicry across retroviral species.

The Analysis of Urological Morbidity in HIV-Infected Patients of the Vladivostok City District

Introduction: HIV infection, the disease that develops as a result of infection with the human immunodeficiency virus, has moved from the category of fatal diseases to indolent manageable infections. Urologic diseases are a common complication observed already in the early stages of HIV infection, and the prevalence of kidney disease in HIV patients ranges from 5% to 30%. Our objective was to analyze urological morbidity in HIV-infected patients hospitalized for emergency and planned indications in the Urology Department of Vladivostok Clinical Hospital No. 2 (VCB No. 2) and to identify the main nosological forms of urological pathology in this cohort. Methods: For the analysis of epidemiological, immunological and virological characteristics of 91 HIV-infected patients admitted to the Urology Department from June 2016 to December 2019 we reviewed inpatient and outpatient medical histories, structured HIV-infected patients by urological nosologies, assessed stages of HIV infection and values of viral load and CD4+ T-lymphocytes, and established the presence of coinfections. Results: The analysis revealed the prevalence of acute infectious and inflammatory diseases of the urinary system (pyelonephritis, prostatitis, orchiepidymitis, kidney abscess) and urolithiasis, which in some cases required the immediate initiation of empirical antibiotic therapy and emergency drainage of the renal cavity system. Our findings are consistent with the results of studies previously conducted on a different population of HIV-infected patients. Conclusions: Since the Urology Department of Vladivostok Clinical Hospital No. 2 is the main hospital that provides both emergency and planned urology care, our data fully reflect urological morbidity of HIV-infected patients in the city district and can be used for optimization of medical care for this cohort of patients.

The Role of p24 Immunohistochemistry to Identify HIV Lymphadenitis

Introduction : That was a difficulty to diagnose the early stage of HIV while the symptoms was only enlargement of the lymph nodes, so that the pattern A of HIV lymphadenitis that presented on histopathological examination is expected to be a determinant of early-stage. Although the staining of p24 antibody has already be used to detect HIV infection in the tissue, but the positivity of p24 in pattern A HIV lymphadenitis has not been investigated. &#x0D; Aim of study : To identify pattern A of HIV lymphadenitis on histopathological examination and to identify p24 antibody to be a determinant of early-stage HIV infection.&#x0D; Methods : This is a retrospective descriptive study. We collected 64 cases of non spesific lymphadenitis from the Anatomical Pathology archive, Cipto Mangunkusumo hospital and examined these cases by using the criteria of pattern A HIV lymphadenitis in the tissue specimen. Then we performed the staining of p24 antibody by immunohistochemistry.&#x0D; Results : There were twelve by sixty four (12/64) cases of that have pattern A HIV lymphadenitis on microscopic evaluation. Only three cases was clinically noted as Acquired Immunodeficiency Syndrome (AIDS) by clinician, while 11 of 12 cases showed immunohistochemistry positive for p24 antibody.&#x0D; Conclusion : Most of the patten A HIV lymphadenitis (11/12) showed the positive staining for p24 antibody. In patients who had received Anti Retro Viral (ARV) therapy, the staining of p24 antibody was negative. This study still needs more samples, the serologic data of the patient to be more reliable.

A longitudinal study of brain volume changes in rhesus macaque model infected with SIV.

Given the current lack of understanding of brain volume changes caused by HIV infection, this study aimed to longitudinally assess the changes in regional brain tissue volume following HIV infection and to explore its relationship with peripheral blood absolute CD4+ lymphocyte count (CD4+), the percentage of monocytes in plasma(MON%) and cerebrospinal fluid viral load (CFVL).Four adult male rhesus monkeys were examined in healthy status and following infection with simian immunodeficiency virus using high-resolution 3D T1-weighted sagittal whole brain magnetic resonance imaging. DPABI and SPM were used to process and record changes in brain tissue volume. Correlation analyses were then used to explore the above relationships. Compared with brain tissue volume during the healthy stage, there was no change at 12 and 24weeks postinoculation (12wpi, 24wpi). At 36wpi, 48wpi, and 60wpi, basal ganglia, left inferior temporal gyrus, left occipital gyrus, and left superior frontal gyrus exhibited varying degrees of atrophy. There was no association found between CD4+, MON%, CFVL, and brain volume loss in any brain region. Our research demonstrated that in the early stage of HIV infection, local brain tissue atrophy can be demonstrated by MRI technique; furthermore, MRI can identify the earliest site of atrophy as well as the most severely affected site. Although there was no significant correlation between brain tissue volume loss and CD4+, MON%, and CFVL, our findings provided some evidence in the application of volumetric MR imaging in the early diagnosis and treatment follow-up of patients with HIV infection.

In Silico Selection of Gp120 ssDNA Aptamer to HIV-1.

Nucleic acid aptamers that specifically bind to other molecules are mostly obtained through the systematic evolution of ligands by exponential enrichment (SELEX). Because SELEX is a time-consuming procedure, the in silico design of specific aptamers has recently become a progressive approach. HIV-1 surface glycoprotein gp120, which is involved in the early stages of HIV-1 infection, is an attractive target for RNA and DNA aptamer selection. In this study, four single-stranded DNA aptamers, referred to as HD2, HD3, HD4, and HD5, that had the ability of HIV-1 inhibition were designed in silico. In a proposed non-SELEX approach, some parts of the B40 aptamer sequence, which interacted with gp120, were isolated and considered as a separate aptamer sequence. Then, to obtain the best docking scores of the HDOCK server and Hex software, some modifications, insertions, and deletions were applied to each selected sequence. Finally, the cytotoxicity and HIV inhibition of the selected aptamers were evaluated experimentally. Results demonstrated that the selected aptamers could inhibit HIV-1 infection by up to 80%, without any cytotoxicity. Therefore, this new non-SELEX approach could be considered a simple, fast, and efficient method for aptamer selection.

Cervicovaginal and Alveolar Macrophage responses of Rhesus Macaques following Mucosal Adenovirus-SIV recombinant priming and systemic SIV envelope boosting

Abstract Vaccine strategies targeting the earliest stages of HIV infection at the mucosal portal of entry may prevent acquisition. Thus, understanding the immune profiles of mucosal cells after immunization is important for vaccine design. We vaccinated rhesus macaques with replicating Ad5hr-SIVenv/gag/nef or empty Ad5hr vector orally/intranasally and intra-tracheally, followed by intramuscular gp120 boosts in alum or alum only. Macaques were repeatedly challenged intravaginally with low doses of SIVmac251. We evaluated cervicovaginal macrophage (CM) responses to Ad5hr 3d post-immunization, and alveolar macrophage (AM) responses in BAL, as initial immunization was to the upper respiratory tract. CM showed significantly increased expression of the chemokines CCL3 (p&amp;lt;0.01), CCL4, CCL5 and CXCL8 (p&amp;lt;0.0001 for all) after the first prime, which decreased post-2nd boost. CD4+ T-cell frequency in the cervical mucosa was unchanged. CD16 expression was significantly increased post 2nd Ad and positively correlated with the number of challenges needed for infection (r=0.6763; p=0.0051). Immunization also increased expression of CD16 on AMs up to the 1st boost time point. Activation of AMs was evident by increased expression of CD40 and CD80 post-2nd Ad compared to naïve macaques. APRIL expression also significantly increased post-2nd Ad compared to naive levels and correlated with B cell frequency in BAL (r=0.7329; p=0.0019) and total IgG in BAL-Fluid (r=0.525; p=0.0471). These data indicate that the vaccine regimen did not induce recruitment of susceptible cells to the vaginal mucosa but increased CM CD16 expression associated with delayed SIV acquisition, and further induced AM cytokine expression that may be associated with B cell help.

Development of a generative adversarial neural network for identification of potential HIV-1 inhibitors by deep learning methods

A generative adversarial autoencoder for the rational design of potential HIV-1 entry inhibitors able to block the region of the viral envelope protein gp120 critical for the virus binding to cellular receptor CD4 was developed using deep learning methods. The research were carried out to create the architecture of the neural network, to form virtual compound library of potential anti-HIV-1 agents for training the neural network, to make molecular docking of all compounds from this library with gp120, to calculate the values of binding free energy, to generate molecular fingerprints for chemical compounds from the training dataset. The training the neural network was implemented followed by estimation of the learning outcomes and work of the autoencoder. The validation of the neural network on a wide range of compounds from the ZINC database was carried out. The use of the neural network in combination with virtual screening of chemical databases was shown to form a productive platform for identifying the basic structures promising for the design of novel antiviral drugs that inhibit the early stages of HIV infection.

Influences on Adherence to Antiretroviral Therapy (ART) in Early-Stage HIV Disease: Qualitative Study from Uganda and South Africa.

Realization of optimal treatment and prevention benefits in the era of universal antiretroviral therapy (ART) and "U=U" (undetectable=untransmittable) requires high adherence at all stages of HIV disease. This article draws upon qualitative interview data to characterize two types of influences on ART adherence for 100 Ugandans and South Africans initiating ART during early-stage HIV infection. Positive influences are: (a) behavioral strategies supporting adherence; (b) preserving health through adherence; (c) support from others; and (d) motivating effect of adherence monitoring. "De-stabilizing experiences" (mobility, loss, pregnancy) as barriers are posited to impact adherence indirectly through intervening consequences (e.g. exacerbation of poverty). Positive influences overlap substantially with adherence facilitators described for later-stage adherers in previous research. Adherence support strategies and interventions effective for persons initiating ART later in HIV disease are likely also to be helpful to individuals beginning treatment immediately upon confirmation of infection. De-stabilizing experiences merit additional investigation across varying populations.

Regional brain volumetric changes despite 2 years of treatment initiated during acute HIV infection.

To assess changes in regional brain volumes after 24 months among individuals who initiated combination antiretroviral therapy (cART) within weeks of HIV exposure. Prospective cohort study of Thai participants in the earliest stages of HIV-1infection. Thirty-four acutely HIV-infected individuals (AHI; Fiebig I-V) underwent brain magnetic resonance (MR) imaging and MR spectroscopy at 1.5 T and immediately initiated cART. Imaging was repeated at 24 months. Regional brain volumes were quantified using FreeSurfer's longitudinal pipeline. Voxel-wise analyses using tensor-based morphometry (TBM) were conducted to verify regional assessments. Baseline brain metabolite levels, blood and cerebrospinal fluid biomarkers assessed by ELISA, and peripheral blood monocyte phenotypes measured by flow cytometry were examined as predictors of significant volumetric change. Participants were 31 ± 8 years old. The estimated mean duration of infection at cART initiation was 15 days. Longitudinal analyses revealed reductions in volumes of putamen (P < 0.001) and caudate (P = 0.006). TBM confirmed significant atrophy in the putamen and caudate, and also in thalamic and hippocampal regions. In exploratory post-hoc analyses, higher baseline frequency of P-selectin glycoprotein ligand-1 (PSGL-1)-expressing total monocytes correlated with greater caudate volumetric decrease (ρ = 0.67, P = 0.017), whereas the baseline density of PSGL-1-expressing inflammatory (CD14CD16) monocytes correlated with putamen atrophy (ρ = 0.65, P = 0.022). Suppressive cART initiated during AHI may not prevent brain atrophy. Volumetric decrease appears greater than expected age-related decline, although examination of longitudinal change in demographically similar HIV-uninfected Thai individuals is needed. Mechanisms underlying progressive HIV-related atrophy may include early activation and enhanced adhesive and migratory capacity of circulating monocyte populations.