Progressive Human Immunodeficiency Virus Research Articles

Interventions during Early Infection: Opening a Window for an HIV Cure?

Although combination antiretroviral therapy (ART) has been a landmark achievement for the treatment of human immunodeficiency virus (HIV), an HIV cure has remained elusive. Elimination of latent HIV reservoirs that persist throughout HIV infection is the most challenging barrier to an HIV cure. The progressive HIV infection is marked by the increasing size and diversity of latent HIV reservoirs until an effective immune response is mobilized, which can control but not eliminate HIV infection. The stalemate between HIV replication and the immune response is manifested by the establishment of a viral set point. ART initiation during the early stage limits HIV reservoir development, preserves immune function, improves the quality of life, and may lead to ART-free viral remission in a few people living with HIV (PLWH). However, for the overwhelming majority of PLWH, early ART initiation alone does not cure HIV, and lifelong ART is needed to sustain viral suppression. A critical area of research is focused on determining whether HIV could be functionally cured if additional treatments are provided alongside early ART. Several HIV interventions including Block and Lock, Shock and Kill, broadly neutralizing antibody (bNAb) therapy, adoptive CD8+ T cell therapy, and gene therapy have demonstrated delayed viral rebound and/or viral remission in animal models and/or some PLWH. Whether or not their application during early infection can improve the success of HIV remission is less studied. Herein, we review the current state of clinical and investigative HIV interventions and discuss their potential to improve the likelihood of post-treatment remission if initiated during early infection.

SIV infection and ARV treatment reshape the transcriptional and epigenetic profile of naïve and memory T cells in vivo.

Human and simian immunodeficiency viruses (HIV and SIV) are lentiviruses that reverse transcribe their RNA genome with subsequent integration into the genome of the target cell. How progressive infection and administration of antiretrovirals (ARVs) longitudinally influence the transcriptomic and epigenetic landscape of particular T cell subsets, and how these may influence the genetic location of integration are unclear. Here, we use RNAseq and ATACseq to study the transcriptomics and epigenetic landscape of longitudinally sampled naïve and memory CD4+ and CD8+ T cells in two species of non-human primates prior to SIV infection, during chronic SIV infection, and after administration of ARVs. We find that SIV infection leads to significant alteration to the transcriptomic profile of all T cell subsets that are only partially reversed by administration of ARVs. Epigenetic changes were more apparent in animals with longer periods of untreated SIV infection and correlated well with changes in corresponding gene expression. Known SIV integration sites did not vary due to SIV status but did contain more open chromatin in rhesus macaque memory T cells, and the expression of proteasome-related genes at the pre-SIV timepoint correlated with subsequent viremia.IMPORTANCEChronic inflammation during progressive human and simian immunodeficiency virus (HIV and SIV) infections leads to significant co-morbidities in infected individuals with significant consequences. Antiretroviral (ARV)-treated individuals also manifest increased levels of inflammation which are associated with increased mortalities. These data will help guide rational development of modalities to reduce inflammation observed in people living with HIV and suggest mechanisms underlying lentiviral integration site preferences.

S2053 Iso Painful in My Belli

Introduction: The etiology of diarrhea in patients with human immunodeficiency virus (HIV) is broad. Causes include antiretroviral therapy adverse events, opportunistic infections, malignancies, and progressive HIV. CD4 count and HIV viral load are important risk-assessment tools for infection. Stool studies including gastrointestinal pathogen polymerase chain reaction (GI PCR), C. difficile, and ova and parasites testing are instrumental. Microsporidia and Isospora are 2 causes of diarrhea in HIV patients for which testing is not included on GI PCR and ova and parasite testing. We present a case of a 57-year-old male with uncontrolled HIV and diarrhea found to have Isospora belli. Case Description/Methods: A 57-year-old male with a medical history of HIV on Descovy and Prezcovix (CD4 90, VL 154K) presented to the hospital with a 5-week course of watery non-bloody diarrhea with intermittent nausea, vomiting, and a 20 lb weight loss. He reported having up to 5 watery diarrheal movements daily. His last colonoscopy was 2 years prior with no acute findings. On exam, he was afebrile with no abdominal tenderness. Prior to presentation, the patient was seen by his primary care physician for diarrhea, with 2 GI PCR panels and ova and parasite testing negative. Patient was prescribed ciprofloxacin and metronidazole by his physician with no improvement in symptoms. On hospital admission, labs were significant for Na/K/Cl of 130/3.3/110, venous blood gas with pH 7.27, CO2 31, HCO3 14.2, and WBC of 6.0. C-diff, CMV, Cryptococcus and repeat GI PCR were negative. Stool examination was positive for Isospora. Patient was initially treated with Bactrim 800-160 twice daily for 10 days with resolution of his diarrea. His HIV regimen was adjusted from Descovy and Prezcovix to Biktarvy for concern for resistance and nonadherence. Discussion: Patients with HIV who present with diarrhea should be extensively worked up as etiology can be multifaceted with consideration for opportunistic infections, medication side effects, and worsening HIV disease burden. Isospora is an opportunistic protozoan parasite that can cause significant diarrhea and weight loss in HIV patients. It is more common in developing countries such as India and sub-saharan Africa and is rarely diagnosed in the United States. Thus, Isospora is not commonly part of the regular stool ova and parasite culture set and should be tested for in patients with high clinical suspicion.

Landscape of T Cells Transcriptional and Metabolic Modules During HIV Infection Based on Weighted Gene Co-expression Network Analysis.

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS). HIV infection affects the functions and metabolism of T cells, which may determine the fate of patients; however, the specific pathways activated in different T-cell subtypes (CD4+ and CD8+ T cells) at different stages of infection remain unclear. We obtained transcriptome data of five individuals each with early HIV infection, chronic progressive HIV infection, and no HIV infection. Weighted gene co-expression network analysis was used to evaluate changes in gene expression to determine the antiviral response. An advanced metabolic algorithm was then applied to compare the alterations in metabolic pathways in the two T-cell subtypes at different infection stages. We identified 23 and 20 co-expressed gene modules in CD4+ T and CD8+ T cells, respectively. CD4+ T cells from individuals in the early HIV infection stage were enriched in genes involved in metabolic and infection-related pathways, whereas CD8+ T cells were enriched in genes involved in cell cycle and DNA replication. Three key modules were identified in the network common to the two cell types: NLRP1 modules, RIPK1 modules, and RIPK2 modules. The specific role of NLRP1 in the regulation of HIV infection in the human body remains to be determined. Metabolic functional analysis of the two cells showed that the significantly altered metabolic pathways after HIV infection were valine, leucine, and isoleucine degradation; beta-alanine metabolism; and PPAR signaling pathways. In summary, we found the core gene expression modules and different pathways activated in CD4+ and CD8+ T cells, along with changes in their metabolic pathways during HIV infection progression. These findings can provide an overall resource for establishing biomarkers to facilitate early diagnosis and potential guidance for new targeted therapeutic strategies.

Indoleamine 2, 3-Dioxygenase-Mediated Tryptophan Catabolism: A Leading Star or Supporting Act in the Tuberculosis and HIV Pas-de-Deux?

Progression from latency to active Tuberculosis (TB) disease is mediated by incompletely understood host immune factors. The definitive characteristic of progressive human immunodeficiency virus (HIV) disease is a severe loss in number and function of T lymphocytes. Among the many possible mediators of T lymphocyte loss and ineffective function is the activity of the immune-modulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO is the rate-limiting enzyme converting tryptophan to kynurenine. IDO activity was initially recognized to mediate tolerance at the foeto-maternal interface. Recently, IDO activity has also been noted to play a critical role in immune tolerance to pathogens. Studies of host immune and metabolic mediators have found IDO activity significantly elevated in HIV and TB disease. In this review, we explore the link between IDO-mediated tryptophan catabolism and the presence of active TB disease in HIV-infected patients. We draw attention to increased IDO activity as a key factor marking the progression from latent to active TB disease in HIV-infected patients.

A Feasibility RCT Evaluating a Play-Informed, Caregiver-Implemented, Home-Based Intervention to Improve the Play of Children Who Are HIV Positive.

Background/aim In South Africa, contextual factors have been identified as barriers to outdoor, unstructured play. The human immunodeficiency virus (HIV) and resulting progressive HIV encephalopathy (PHE) is a pandemic in this area, associated with development delays that are not addressed by highly active antiretroviral treatment (HAART). This study aimed to describe the playfulness in children with HIV and PHE on HAART living in challenging socioeconomic areas in South Africa aged 6 months to 8 years and to evaluate the feasibility and preliminary effectiveness of a play-informed, caregiver-implemented, home-based intervention (PICIHBI) for improving play. Methods A feasibility randomized control trial allowed for comparison of PICIHBI and conventional one-on-one occupational therapy interventions. Children were filmed playing pre-, mid-, and postintervention, using the Test of Playfulness (ToP) to assess playfulness. The PICIHBI comprised of 10 monthly sessions facilitated by an occupational therapist, involving group discussions with caregivers and periods of experiential play. Results Twenty-four children with HIV and/or PHE were randomized into one of the two intervention groups. Overall, the group (n = 24) had a median score of 0 (lowest item score) on nine of 24 ToP items and only had a median score of 3 (highest score) on two items. Pre- to postintervention overall ToP scores improved marginally for the PICIHBI group (n = 12) and the conventional group (n = 12). Between-group differences were not significant. The PICIHBI group demonstrated a significant increase in one ToP item score at midassessment. No significant ToP item changes were found in the conventional group. Conclusion Children with HIV were found to have the most difficulty on ToP items relating to the play elements of internal control and freedom from constraints of reality. The PICIHBI did not significantly improve children's play and was not more effective than the conventional intervention. Considerations for feasibility and effectiveness, including barriers to attendance, are discussed.

Systemic HIV-1 infection produces a unique glial footprint in humanized mouse brains.

ABSTRACTStudies of innate glial cell responses for progressive human immunodeficiency virus type one (HIV-1) infection are limited by a dearth of human disease-relevant small-animal models. To overcome this obstacle, newborn NOD/SCID/IL2Rγc−/− (NSG) mice were reconstituted with a humanized brain and immune system. NSG animals of both sexes were transplanted with human neuroglial progenitor cells (NPCs) and hematopoietic stem cells. Intraventricular injection of NPCs symmetrically repopulated the mouse brain parenchyma with human astrocytes and oligodendrocytes. Human glia were in periventricular areas, white matter tracts, the olfactory bulb and the brain stem. HIV-1 infection led to meningeal and perivascular human leukocyte infiltration into the brain. Species-specific viral-neuroimmune interactions were identified by deep RNA sequencing. In the corpus callosum and hippocampus of infected animals, overlapping human-specific transcriptional alterations for interferon type 1 and 2 signaling pathways (STAT1, STAT2, IRF9, ISG15, IFI6) and a range of host antiviral responses (MX1, OAS1, RSAD2, BST2, SAMHD1) were observed. Glial cytoskeleton reorganization, oligodendrocyte differentiation and myelin ensheathment (MBP, MOBP, PLP1, MAG, ZNF488) were downregulated. The data sets were confirmed by real-time PCR. These viral defense-signaling patterns paralleled neuroimmune communication networks seen in HIV-1-infected human brains. In this manner, this new mouse model of neuroAIDS can facilitate diagnostic, therapeutic and viral eradication strategies for an infected nervous system.

Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome.

Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression.

Destabilization of the gut microbiome marks the end-stage of simian immunodeficiency virus infection in wild chimpanzees.

Enteric dysbiosis is a characteristic feature of progressive human immunodeficiency virus type 1 (HIV-1) infection but has not been observed in simian immunodeficiency virus (SIVmac)-infected macaques, including in animals with end-stage disease. This has raised questions concerning the mechanisms underlying the HIV-1 associated enteropathy, with factors other than virus infection, such as lifestyle and antibiotic use, implicated as playing possible causal roles. Simian immunodeficiency virus of chimpanzees (SIVcpz) is also associated with increased mortality in wild-living communities, and like HIV-1 and SIVmac, can cause CD4+ T cell depletion and immunodeficiency in infected individuals. Given the central role of the intestinal microbiome in mammalian health, we asked whether gut microbial constituents could be identified that are indicative of SIVcpz status and/or disease progression. Here, we characterized the gut microbiome of SIVcpz-infected and -uninfected chimpanzees in Gombe National Park, Tanzania. Subjecting a small number of fecal samples (N = 9) to metagenomic (shotgun) sequencing, we found bacteria of the family Prevotellaceae to be enriched in SIVcpz-infected chimpanzees. However, 16S rRNA gene sequencing of a larger number of samples (N = 123) failed to show significant differences in both the composition and diversity (alpha and beta) of gut bacterial communities between infected (N = 24) and uninfected (N = 26) chimpanzees. Similarly, chimpanzee stool-associated circular virus (Chi-SCV) and chimpanzee adenovirus (ChAdV) identified by metagenomic sequencing were neither more prevalent nor more abundant in SIVcpz-infected individuals. However, fecal samples collected from SIVcpz-infected chimpanzees within 5 months before their AIDS-related death exhibited significant compositional changes in their gut bacteriome. These data indicate that SIVcpz-infected chimpanzees retain a stable gut microbiome throughout much of their natural infection course, with a significant destabilization of bacterial (but not viral) communities observed only in individuals with known immunodeficiency within the last several months before their death. Am. J. Primatol. 80:e22515, 2018. © 2015 Wiley Periodicals, Inc.

Follow-up study of HIV-infected patients with prior cerebral toxoplasmosis

To assess follow-up study results in human immunodeficiency virus (HIV)-infected patients with prior cerebral toxoplasmosis (CT). Follow-up study results were assessed in HIV-infected patients with prior CT. The fate of only 97 out of 137 (66% of the hospitalized) patients discharged from hospital is known, as 40 convalescents have been lost to follow up. Thereafter, relapses developed in 19 patients, of whom 6 died. Eleven more patients with HIV infection died due to its progression and development of other secondary lesions. Five more patients died from narcotic overdose, staphylococcal sepsis, and acute pancreatic necrosis. The main peak of fatal outcomes was within the first 2 years after discharge. 3.5-year survival rates after TC were 75%. The causes of recurrent and progressive HIV infection were non-compliance with secondary prevention of CT and low adherence to an antiretroviral therapy regimen, the blame of which fell not only on the patients, but also their attending physicians and specialists who had advised how to enhance treatment motivation. Further follow-up of convalescent CT patients calls for closer attention to the possible development of recurrences within the first three years after discharge in particular, regardless of CD4 cell counts.

Neuroimmune Dysregulation in HIV-Associated Neurocognitive Disorders

CME Educational Objectives 1. Identify three of the major cells involved in cellular immune dysregulation in HIV. 2. Discuss monocyte activation in central nervous system (CNS) HIV. 3. Discuss CD8+ T-lymphocyte activation in CNS HIV. Human immunodeficiency virus (HIV) is a global epidemic, directly infecting approximately 0.8% of people in the world, and indirectly affecting countless others. 1 Chronic immune activation, measured by cell proliferation, metabolic activity, or changed chemokine/cytokine or proteome profiles, is a hallmark of progressive HIV infection and predicts systemic disease progression more accurately than plasma viral load. 2,3 The neuropathophysiology of HIV infection appears to be driven in part by this chronic peripheral immune activation, resulting in an independent central immune dysregulation involving alteration in macrophage, T-lymphocyte, B-lymphocyte, microglial, and/or astrocyte functional capabilities.

Cytokine production and dysregulation in HIV pathogenesis: Lessons for development of therapeutics and vaccines

Numerous studies have characterized the cytokine modulation observed in human immunodeficiency virus (HIV) infected individuals, from initial infection through chronic disease. Progressive and non-progressive HIV infection models show the cytokine milieu differs in terms of production and responsiveness in these two groups, suggesting an understanding of the role cytokines play during infection is necessary for directing the immune response toward viral control. This review will cover cytokine induction and dysfunction during HIV pathogenesis, with a focus on the interplay between cytokines and transcription factors, T cell activation, and exhaustion. We highlight cytokines that have either vaccine adjuvant or therapeutic potential and discuss the need to identify key factors required for prevention of progression, clearance of infection, or protection from acquisition.

Yet Another Reason to Treat HIV Infection

Antiretroviral therapy (ART) has allowed a cohort of children who were perinatally infected with human immunodeficiency virus (HIV) to reach early adulthood, but their risk of death, non-AIDS-defining infections, cancers and organ failure remain elevated compared with uninfected populations [1]. Although ART dramatically improves the survival of infants [2] and children [1] and appears to improve the growth and neurologic function when initiated in older children [3, 4], less is known about the optimal time to initiate ART in older, asymptomatic children to prevent indolent HIV-associated morbidities, including loss of cognitive functions. The recommended CD4 cell count at which to start ART in adults and adolescents has been progressively revised upward [5]; however, this threshold remains controversial, and resulted in the split judgment by the 2011 Department of Health and Human Services panel on whether to recommend ART for all adults [5]. Current World Health Organization guidelines recommend the use of adult immunologic criteria (CD4 cell count, ,350 cells/lL) to determine when to initiate ART in children .5 years of age [6]. This leaves many relatively asymptomatic HIV-infected children with moderately decreased CD4 T-cell counts untreated, which could place them at risk for HIV-associated morbidity. (Normal CD4 cell counts in children 5–12 years of age range from 980 to 1200 cells/lL [7, 8]). In this issue of Clinical Infectious Diseases, Ruel et al [9] present a casecontrol study that demonstrates neurocognitive and motor dysfunction in ‘‘asymptomatic’’ HIV-infected children 6–12 years of age who do not qualify for ART. Their findings suggest that the World Health Organization guidelines do not capture early neurologic disease and provide a rationale to explore whether earlier ART would benefit these children. In children, progressive HIV encephalopathy (PHE) is a severe, potentially fatal, AIDS-defining illness that was common in the pre-ART era. It is defined as failure to achieve developmental milestones, or loss of previously acquired developmental milestones, impaired brain growth, and acquired symmetrical motor deficits (manifested by $2 of the following: paresis, pathologic reflexes, ataxia or gait disturbance) [10]. In the pre-ART era, the prevalence of PHE was 30%–50% [11]. With the use of ART, symptoms of those affected by PHE generally have improved, fatalities have become uncommon, and the incidence of PHE has dropped 10-fold [4, 11]. The study by Ruel et al carefully assessed neurocognitive and motor function in HIV-infected African children who did not qualify for ART and who were not considered encephalopathic by their referring physicians. The study used neurocognitive tests (Test of Variables of Attention [TOVA]; the Kaufman Assessment Battery for Children, 2nd edition [KABC-2]; and the Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition [BOT-2]) to detect impairments in attention deficit and impulsivity, cognition, and motor function, respectively. The study does not provide an estimate of the prevalence of neurocognitive impairment but identifies subtle population-level differences between HIV-infected and uninfected children. This study is noteworthy because it suggests that, unlike PHE, which is rare in the era of ART, subtle neurocognitive and motor impairments affect a significant proportion of apparently asymptomatic HIV-infected children who do not yet qualify for ART. Unfortunately, the large-scale administration of the neurocognitive tests used by Ruel et al to prompt ART initiation is unrealistic in low resource settings owing to the time, space, and trained personnel needed for testing. Ideally, biomarkers and/or simple tests would identify early symptoms of neuropathology and serve as tools to monitor children who do not qualify for ART. Received 1 December 2011; accepted 9 December 2011. Correspondence: Lisa M. Frenkel, MD, Department of Pediatrics, Laboratory Medicine and Global Health, University of Washington, Children's Hospital and Research Institute, 1900 Ninth Avenue, Seattle, WA 98101-1304 (lfrenkel@uw.edu). Clinical Infectious Diseases The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@ oup.com. DOI: 10.1093/cid/cir1041

Modeling HIV-associated neurocognitive disorders in mice: new approaches in the changing face of HIV neuropathogenesis

It is well established that infection with the human immunodeficiency virus (HIV) leads to immune suppression. Less well known is the fact that long-term, progressive HIV disease is associated with the development of cognitive deficits. Since the introduction of combined antiretroviral therapy (cART), the clinical presentation of HIV infection has evolved into a chronic illness with very low levels of viral replication and chronic immune activation, with compliant affected individuals surviving for decades with a high quality of life. Despite these advances, many HIV-infected individuals develop some degree of neurodegeneration and cognitive impairment. The underlying pathophysiological mechanisms are not well understood, and there are no effective treatments. Thus, there is an unmet need for animal models that enable the study of HIV-associated neurocognitive disorders (HAND) and the testing of new therapeutic approaches to combat them. Here, we review the pros and cons of existing mouse models of HIV infection for addressing these aims and propose a detailed strategy for developing a new mouse model of HIV infection.

Proteomic analyses of monocytes obtained from Hispanic women with HIV‐associated dementia show depressed antioxidants

Monocyte ingress into the brain during progressive human immunodeficiency virus (HIV-1) infection parallels the severity of cognitive impairments. Although activated monocyte phenotypes emerge in disease, the functional correlates of these cells remain unresolved. To this end, we studied the proteome of blood-derived monocytes obtained from Hispanic women with the most severe form of HIV-associated neurocognitive disorders, HIV-associated dementia (HAD). Monocytes isolated from peripheral blood mononuclear cells by CD14+ immunoaffinity column chromatography were >95% pure. Cells were recovered from four patients without evidence of cognitive impairment and five with HAD and analyzed by 2-D DIGE and tandem MS. Importantly, ADP ribosylhydrolase, myeloperoxidase, thioredoxin, peroxiredoxin 3, NADPH, and GTPase-activating protein were all downregulated in HAD. In regards to myeloperoxidase, thioredoxin, and peroxiredoxin 3, these changes were validated in an additional cohort of 30 patients by flow cytometry. We conclude that deficits in monocyte antioxidants lead to neuronal damage through the loss of hydrogen peroxide scavenging capabilities; thus exposing neurons to apoptosis-inducing factors. Altered monocyte functions therefore may contribute to the development and progression of cognitive impairment.

Palliative Care Program For Human Immunodeficiency Virus-Infected Patients: Rebuilding of an Academic Urban Program

palliative care is extremely important for human immunodeficiency virus (HIV)-infected clientele. The impact of HIV infection is significant in the city of New Orleans. As of September 2009, a cumulative total of 29 548 HIV/acquired immunodeficiency syndrome (AIDS) cases and 12 267 HIV-related deaths were reported in Louisiana. retrospective review of charts of patients enrolled in our palliative care program. as of September 2009, there were around 1800 active patients in our HIV outpatient clinic. A total of 5 (22%) patients had multidrug-resistant AIDS infection. Three (13%) referred patients had AIDS dementia. Progressive multifocal leukoencephalopathy (PML) and advanced HIV nephropathy were also reasons for referral (13% and 4% of referred patients, respectively). Around 9% of patients had advanced liver cancer with metastases. In all, 22% of patients had rapidly deteriorating functional status. The rest of the patients (26%) complained of cancer-related nausea and vomiting and progressive and nonresponsive weight loss. In terms of psychosocial assessment, the majority of referred patients had problems in areas such as social functioning, mood swings, unstable moods, problems with controlling temper, outbursts of anger, violence, and disturbing or unreal thoughts and beliefs. palliative care is extremely important in the care of patients with HIV/AIDS. More research is needed to elaborate on best palliative care practices in the care of HIV-infected patients. Interesting to note is that there is significant proportion of patients with mental issues (substance abuse, psychiatric problems, depression, and despair) for which better resources are needed. Integration of services among clinical, mental, and palliative care providers might be needed to better serve this population.

Nanoformulated antiretroviral drug combinations extend drug release and antiretroviral responses in HIV-1-infected macrophages: implications for neuroAIDS therapeutics.

We posit that improvements in pharmacokinetics and biodistributions of antiretroviral therapies (ART) for human immunodeficiency virus type one-infected people can be achieved through nanoformulationed drug delivery systems. To this end, we manufactured nanoparticles of atazanavir, efavirenz, and ritonavir (termed nanoART) and treated human monocyte-derived macrophages (MDM) in combination therapies to assess antiretroviral responses. This resulted in improved drug uptake, release, and antiretroviral efficacy over monotherapy. MDM rapidly, within minutes, ingested nanoART combinations, at equal or similar rates, as individual formulations. Combination nanoART ingested by MDM facilitated individual drug release from 15 to >20 days. These findings are noteworthy as a nanoART cell-mediated drug delivery provides a means to deliver therapeutics to viral sanctuaries, such as the central nervous system during progressive human immunodeficiency virus type one infection. The work brings us yet another step closer to realizing the utility of nanoART for virus-infected people.

Quantitation of parvalbumin+ neurons and human immunodeficiency virus type 1 (HIV-1) regulatory gene expression in the HIV-1 transgenic rat: effects of vitamin A deficiency and morphine

Vitamin A (VA) deficiency in human immunodeficiency virus (HIV) infection has been associated with more progressive HIV disease, which may be enhanced by opioid use. In these studies, we examined the effects of VA deficiency and morphine on frontal cortex neuronal numbers in the HIV-1 transgenic (Tg) rat. These studies showed that total numbers of neurons were similar for rats on the VA-deficient diet as for rats on the normal diet and these numbers were not affected by treatment with morphine. In contrast, numbers of neurons that expressed the calcium-binding protein parvalbumin, which is a marker interneurons that express the inhibitory neurotransmitter gamma-aminobutyric acid (GABAergic neurons) were decreased for wild-type (Wt) rats on the VA-deficient diet and for Wt rats treated with morphine. In addition, parvalbumin+ neurons were also decreased for Tg rats on a normal diet but increased to normal levels when these animals were placed on the VA-deficient diet and treated with morphine. Analysis of expression of the genes that code for the HIV regulatory proteins vif, vpr, nef, and tat in frontal cortex and adjacent subcortical white matter showed that tat expression was increased in the morphine-treated Tg rat on the VA-deficient diet as compared to untreated Tg rats on the normal diet and untreated VA-deficient rats. These studies therefore suggest that VA deficiency, opioid exposure, and HIV infection alone and in combination may potentially alter neuronal metabolic activity and induce cellular stress, resulting in the observed changes in levels of parvalbumin expression. The specific mechanisms that underlie these effects require further study.

Distinct Phenotype of Unrestricted Cytotoxic T lymphocytes from Human Immunodeficiency Virus-infected Individuals

Human immunodeficiency virus (HIV)-infected individuals have CD8(+) cytotoxic T lymphocytes (CTL) that kill activated uninfected T lymphocytes. These CTL are independent of class Ia human histocompatibility-linked leukocyte antigens (HLA-Ia). To further characterize these CTL, we investigated their possible restriction to non-classical class Ib HLA-E molecules and their expression of natural killer cell receptors (NKR) that are often affected in HIV infection. We found no role for HLA-E in CTL-mediated killing of activated uninfected T lymphocytes. The non-HLA-restricted CTL did not express NKG2A, an inhibitory NKR that binds HLA-E, nor CD56, a prominent marker on previously described non-HLA-restricted CTL. This NKG2A(-)CD56(-) phenotype of HLA-unrestricted CTL that kill uninfected activated T lymphocytes matches generalized changes on CD8(+) T lymphocytes that occur in progressive HIV infection, suggesting these phenotypic changes may reflect pathogenic evolution of the CD8(+) T cell repertoire. These CTL represent a unique phenotypic and functional subset with potential relevance to HIV pathogenesis.

Papular pruritic eruptions: A marker of progressive HIV disease in children: Experience from eastern India

Papular pruritic eruptions (PPEs) are a commonly seen dermatological manifestation in children with Human Immunodeficiency Virus (HIV) stage 2 disease, whereas recurrent upper respiratory tract infection (URTI) (<2 episodes in 6 months) is the most common presenting illness in this category. Papular pruritic eruptions has been associated with progressive HIV disease in adults though it is categorized in early stage. To evaluate PPE as a clinical marker for progressive pediatric HIV. In Pediatric HIV/AIDS clinic, Medical College, Kolkata, a prospective longitudinal hospital-based observational study was carried out. A total of 108 children in WHO stage 2 HIV disease aged between 2 and 12 years were selected, of which 58 had recurrent URTI without PPE and another 50 had PPE with or without secondary bacterial infection. Clinico-immunological deterioration was compared between the groups in terms of progression to undernutrition, WHO clinical stage 4 disease, severe immunodeficiency, need for initiation of Highly Active Anti Retroviral Therapy (HAART) and mortality over a period of 2 years. SPSS statistical software version 10 was used. P value, relative risk (RR) with 95% Confidence Interval (CI), sensitivity and specificity was estimated. P < 0.05 was considered significant. Significantly higher incidence (P < 0.001) of clinico-immunological progression of disease at a significantly shorter time period (P < 0.05) was found in those with PPE in comparison to those without PPE. Papular pruritic eruption has high sensitivity, specificity and positive predictive value as a clinical marker for severe immunodeficiency. Papular pruritic eruption could be a useful clinical marker of progressive HIV disease in children.