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HIV reverse transcriptase (RT) inhibitors are the important components of highly active antiretroviral therapies (HAARTs) for anti-HIV treatment and pre-exposure prophylaxis in clinical practice. Many RT inhibitors and their combination regimens have been approved in the past ten years, but a review on their drug discovery, pharmacology, and clinical efficacy is lacking. Here, we provide a comprehensive review of RT inhibitors (tenofovir alafenamide, rilpivirine, doravirine, dapivirine, azvudine and elsulfavirine) approved in the past decade, regarding their drug discovery, pharmacology, and clinical efficacy in randomized controlled trials. Novel RT inhibitors such as islatravir, MK-8504, MK-8507, MK8583, IQP-0528, and MIV-150 will be also highlighted. Future development may focus on the new generation of novel antiretroviral inhibitors with higher bioavailability, longer elimination half-life, more favorable side-effect profiles, fewer drug-drug interactions, and higher activities against circulating drug-resistant strains. ispartof: Acta Pharm Sin B vol:12 issue:4 pages:1567-1590 ispartof: location:Netherlands status: published

Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In the last 20 years, our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs, including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), thio-dihydro-alkoxy-benzyl-oxopyrimidine (S-DABO), diaryltriazine (DATA), diarylpyrimidine (DAPY) analogues, and their hybrid derivatives. Application of integrated modern medicinal strategies, including structure-based drug design, fragment-based optimization, scaffold/fragment hopping, molecular/fragment hybridization, and bioisosterism, led to the development of several highly potent analogues for further evaluations. In this paper, we review the development of NNRTIs in the last two decades using the above optimization strategies, including their structure–activity relationships, molecular modeling, and their binding modes with HIV-1 reverse transcriptase (RT). Future directions and perspectives on the design and associated challenges are also discussed., Graphical abstract Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In this review, we summarize the development of NNRTIs in our past two decades using the multiple optimization strategies.Image 1

Objective: To assess our adherence to treatment guidelines for diffuse large B-cell lymphoma (DLBCL) established by the American Society of Hematology in 2014 through implementation of a quality improvement initiative (QII) at our institution in 2015. Patients and Methods: Patients with newly diagnosed DLBCL treated from January 1, 2006, through December 31, 2017, were identified. Electronic medical records were reviewed for documentation of American Society of Hematology Practice Improvement Module quality measures (eg, key pathologic features of DLBCL, lymphoma staging, and screening for hepatitis B virus [HBV] infection in patients receiving rituximab-based chemotherapy). We also reviewed assessment of prognosis by revised International Prognostic Index score, testing for hepatitis C virus, HBV, and HIV, chemotherapy education, and the addition of rituximab in the treatment regimen of CD20+ DLBCL. Results: Following QII implementation, we saw improvements in most metrics, including reporting of key molecular features (fluorescence in situ hybridization for c-MYC, BCL2, and BCL6, from 45.5% [75 of 165 patients] before QII to 91.7% [22 of 24 patients] after QII; P

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed., Graphical abstract Unlabelled Image

Treatment of HIV has long faced the challenge of high mutation rates leading to rapid development of resistance, with ongoing need to develop new methods to effectively fight the infection. Traditionally, early HIV medications were designed to inhibit RNA replication and protein production through small molecular drugs. Peptide based therapeutics are a versatile, promising field in HIV therapy, which continues to develop as we expand our understanding of key protein-protein interactions that occur in HIV replication and infection. This review begins with an introduction to HIV, followed by the biological basis of disease, current clinical management of the disease, therapeutics on the market, and finally potential avenues for improved drug development., Graphical abstract This review discusses the biological basis of HIV, the current clinical management of the disease, the therapeutics developed to treat HIV, and the potential strategies for improving HIV drug development. It explores new methods for developing HIV therapeutics that aim to produce effective drugs in the treatment of HIV. Specifically, it looks at peptide inhibitors currently being researched that show promise for HIV treatment.Image 1, Highlights • HIV hard to control, manage, and infectious with billions spent on research for prevention and treatment. • This review summarizes the biological basis of HIV, current management, and improved drug development. • It explores peptide inhibitors as a promising new therapeutic for HIV treatment.

Highlights • Presentation of a rare case of an Amyand’s hernia containing acute appendicitis and a perforated cecum. • Diagnosis was intraoperative and an ileocecectomy followed by Bassini hernia repair produced a favorable patient outcome. • Amyand’s hernias can contain a diverse range of features and presentations that can complicate diagnosis and treatment. • Our case underscores the importance of considering an Amyand’s and individualizing treatment based on operative findings., Introduction An Amyand's hernia is a heterogeneous clinical condition defined by the presence of the vermiform appendix within an inguinal hernia sac, which may or may not contain other abdominal contents or pathologic inflammatory changes. Herein we present an exceptionally rare case of an Amyand's hernia containing acute appendicitis and a perforated cecum. Presentation of case A 46-year-old male with a right inguinal hernia of 2–3 year duration presented to our Emergency Department complaining of acute onset abdominal and groin pain. The patient was diagnosed with an incarcerated right inguinal hernia and underwent emergent surgical repair. Intraoperatively a reactive fluid was found within the hernia sac that prompted an exploratory laparotomy for suspected bowel perforation. The hernia was then found to contain an inflamed gangrenous appendix with an inflamed and perforated cecum. An ileocecectomy and enteroenterostomy was performed and the hernia defect was repaired without mesh. Discussion With an estimated incidence of only 1%, Amyand's hernias are rare and lack a clear evidence-based management scheme. Moreover, they can contain a diverse range of pathologic features and presentations that can complicate diagnosis and treatment. To avoid potential morbidity and mortality, the surgeon must consider an Amyand's hernia on his or her differential when operating on inguinal hernias and be aware of the associated presentations, complications, and management schemes. Conclusion There is a paucity of reports describing simultaneous appendicitis and cecal perforation within an Amyand's hernia. In our case, ileocecectomy and Bassini hernia repair with close follow-up led to a favorable outcome.

In Africa, the HIV prevalence in rural areas has begun to reach levels estimated within urban settings, where women are also more at risk for both malaria and intestinal parasitic infections. The objective of this review is to assess whether concomitant infections with malaria and/or helminthic diseases have an impact on cervical disease progression in women on HAART. This scoping review was conducted in August 2018. To conduct this scoping review, we searched the relevant studies in electronic databases such as PUBMED, Global Health, EMBASE, CINAHL and SCOPUS published in the year between 1960 and 2018 using the following search terms HAART AND malaria OR Helminth and Female OR women. Eight studies qualified for this review. The literature underscores the need for women on HAART with multiple co-infections to use adjuncts to retain immune recovery and undetectable HIV viral load, to reduce risk of cervical disease progression. A trend for higher risk of CIN3+ in HIV+ women reporting recent malarial infection was observed in one study. Given the public health impact of synergistic interactions between malaria and helminthic infections in HIV/HPV co-infected women on HAART, it is urgent that these interactions are elucidated., Highlights • Women on HAART should use adjuncts to prevent cervical disease progression. • An association is found between HIV-HPV-malaria co-infected women and CIN3+. • Synergistic interactions in HIV/HPV co-infected women on HAART should be elucidated.

Background and objectives: Human immunodeficiency virus (HIV) in adolescents is a growing concern. Amid psychosocial challenges, adolescents must successfully transition into adult-centered care; however, little is known about outcome measurements within this period. We assessed the trend in adolescent HIV viral loads (VLs) in a community with a high HIV prevalence, allowing physicians to better recognize the challenges of transitioning adolescents with HIV to adult care. Patients and methods: All HIV RNA VLs from the Molecular Virology Lab at University Hospital in Newark, New Jersey, from 2007 to 2010 were obtained. Patients were divided into pediatric (25 years of age) age groups. Univariate and multivariate analyses assessed characteristics of patients by age and gender. Results: A minimum of 40 pediatric, 178 adolescent, and 1335 adult patients were identified per year. There was a statistically significant increase in VLs of adolescents when compared to pediatric patients (P

Mounting evidence demonstrates that CYP2B6 plays a much larger role in human drug metabolism than was previously believed. The discovery of multiple important substrates of CYP2B6 as well as polymorphic differences has sparked increasing interest in the genetic and xenobiotic factors contributing to the expression and function of the enzyme. The expression of CYP2B6 is regulated primarily by the xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) in the liver. In addition to CYP2B6, these receptors also mediate the inductive expression of CYP3A4, and a number of important phase II enzymes and drug transporters. CYP2B6 has been demonstrated to play a role in the metabolism of 2%–10% of clinically used drugs including widely used antineoplastic agents cyclophosphamide and ifosfamide, anesthetics propofol and ketamine, synthetic opioids pethidine and methadone, and the antiretrovirals nevirapine and efavirenz, among others. Significant inter-individual variability in the expression and function of the human CYP2B6 gene exists and can result in altered clinical outcomes in patients receiving treatment with CYP2B6-substrate drugs. These variances arise from a number of sources including genetic polymorphism, and xenobiotic intervention. In this review, we will provide an overview of the key players in CYP2B6 expression and function and highlight recent advances made in assessing clinical ramifications of important CYP2B6-mediated drug–drug interactions., Graphical abstract CYP2B6 is a highly inducible and polymorphic enzyme which plays a significant role in human drug metabolism. Variations in the expression and function of CYP2B6 significantly alter the metabolism and pharmacokinetics of many drugs. These alterations may result in significant drug–drug interactions which may lead to improved therapy or toxicity. fx1

Graphical abstract, Highlights • Highly active antiretroviral therapy (HAART) associated nephrotoxicity is characterized by tubular necrosis with glomerular hypertrophy. • Derangements of the cytoarchitectural patterns of the kidney were seen as a result of treatment with HAART regimen (triplavar). • Co-administration of M. charantia and HAART mitigates the intensive histopathological changes of the rat kidney. • Nephrotoxicity is associated with increased oxidative stress which stems from increased reactive oxygen species (ROS) generation in tissues. • M. charantia possesses phytochemical properties which are powerful counter measures against oxidative stress tissue damage., Momordica charantia (M. charantia) is known for its antioxidant and antidiabetic properties. The aim of this study is to investigate the renoprotective effects of M. charantia in rats following treatment with highly active antiretroviral therapy (HAART) regimen triplavar. Adult male Sprague-Dawley rats weighing 178.1–220.5 g (n = 36) were divided into six groups (A–F) with each group comprising of six (n = 6) rats. The drugs and extract were administered via oral gavage. The therapeutic dose of triplavar was adjusted using the human therapeutic dose equivalent for the rat model. Animals were euthanized on the tenth week with kidneys removed for examination and blood obtained via cardiac puncture. Levels of oxidative stress enzymes (superoxide dismutase-SOD, catalase-CAT, and reduced glutathione-GSH) were significantly lowered in all groups not receiving M. charantia. The levels of thiobarbituric acid reactive substances (TBARS) were increased resulting in free radical formation via auto-oxidation. Renal parameters showed no albuminuria, normal blood urea nitrogen (BUN), serum creatinine (SCr) and electrolytes in groups treated with M. charantia. HAART treated (Group B) showed severe albuminuria, a significantly (p

Graphical abstract, Highlights • Induction and action of IFN during acute and chronic HIV-1 infection. • Host and viral factors influencing IFN response in HIV-1 infected patients. • Type I IFN and IFNα subtypes signatures and their antiviral activity during HIV-1 infection. • The microbiome and intestinal IFN responses relationship in HIV-1 infection and disease., Type I interferon (IFN) response initially limits HIV-1 spread and may delay disease progression by stimulating several immune system components. Nonetheless, persistent exposure to type I IFN in the chronic phase of HIV-1 infection is associated with desensitization and/or detrimental immune activation, thereby hindering immune recovery and fostering viral persistence. This review provides a basis for understanding the complexity and function of IFN pleiotropic activity in HIV-1 infection. In particular, the dichotomous role of the IFN response in HIV-1 immunopathogenesis will be discussed, highlighting recent advances in the dynamic modulation of IFN production in acute versus chronic infection, expression signatures of IFN subtypes, and viral and host factors affecting the magnitude of IFN response during HIV-1 infection. Lastly, the review gives a forward-looking perspective on the interplay between microbiome compositions and IFN response.

Several pathological mutations have been identified in human POLG gene, encoding for the catalytic subunit of Pol γ, the solely mitochondrial replicase in animals and fungi. However, little is known regarding non-pathological polymorphisms found in this gene. Here we studied, in the yeast model Saccharomyces cerevisiae, eight human polymorphisms. We found that most of them are not neutral but enhanced both mtDNA extended mutability and the accumulation of mtDNA point mutations, either alone or in combination with a pathological mutation. In addition, we found that the presence of some SNPs increased the stavudine and/or zalcitabine-induced mtDNA mutability and instability., Highlights • We studied the effects of 8 human polymorphisms in Pol γ in the model system yeast. • Most polymorphisms increase mtDNA extended and point mutability. • Treatment with NRTIs determines mtDNA instability in wt and mutant strains. • Some polymorphisms make Mip1 more sensitive to NRTIs-induced mtDNA toxicity.

A 30-year-old gravid, African-American womanwith multidrug-resistant HIV based on genotypetesting presented to the Department of Dermatologywith a 10-year history of asymptomatic hyperpigmen-tationofthegingivaandlip,whichhaddarkenedoverthe course of her current pregnancy. Physical exam-ination found an asymmetric, ill-defined, 3-cm darkbrown and black plaque with irregular bordersinvolving the vermillion and mucosal lip, gingiva,and hard palate (Fig 1). There was no cervicaladenopathy.Initialpunchbiopsyfromtherightuppermucosal lip found a melanoma in situ involving thelateral margins. Subsequent incisional biopsy foundinvasive mucosal lentiginous melanoma with aBreslowdepthof1.45mm(Fig2).Pertinentlaboratoryfindings included a decreased CD4 count of 177 cellsper cubic millimeter anda viral load of624copies permilliliter.Aftermultidisciplinaryconsensuswithotolar-yngology and surgical oncology, the patient under-went wide resection with 1-cm margins after delivery.Sentinellymphnodebiopsyresultswerenegative.Thepatient is disease free 21 months after resection andhas required no further adjuvant treatment.

The elimination of oxidatively modified proteins is a crucial process in maintaining cellular homeostasis, especially during stress. Mitochondria are protein-dense, high traffic compartments, whose polypeptides are constantly exposed to superoxide, hydrogen peroxide, and other reactive species, generated by ‘electron leakage’ from the respiratory chain. The level of oxidative stress to mitochondrial proteins is not constant, but instead varies greatly with numerous metabolic and environmental factors. Oxidized mitochondrial proteins must be removed rapidly (by proteolytic degradation) or they will aggregate, cross-link, and cause toxicity. The Lon Protease is a key enzyme in the degradation of oxidized proteins within the mitochondrial matrix. Under conditions of acute stress Lon is highly inducible, possibly with the oxidant acting as the signal inducer, thereby providing increased protection. It seems that under chronic stress conditions, however, Lon levels actually decline. Lon levels also decline with age and with senescence, and senescent cells even lose the ability to induce Lon during acute stress. We propose that the regulation of Lon is biphasic, in that it is up-regulated during transient stress and down-regulated during chronic stress and aging, and we suggest that the loss of Lon responsiveness may be a significant factor in aging, and in age-related diseases.

The advent of highly active antiretroviral therapy (HAART), which constitutes HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors, has dramatically reduced the morbidity and mortality associated with human immunodeficiency virus (HIV) infection in resource-rich countries. However, this disease still kills several million people each year. Though the reason for therapeutic failure is multi-factorial, an important concern is the treatment and control of HIV within the central nervous system (CNS). Due to the restricted entry of anti-HIV drugs, the brain is thought to form a viral sanctuary site. This not only results in virological resistance, but also is often associated with the development of complications such as HIV-associated dementia. The CNS delivery of anti-HIV drugs is limited by the blood–brain and blood–CSF interfaces due to a combination of restricted paracellular movement, powerful metabolic enzymes and numerous transporters including members of the ATP binding cassette (ABC) and solute carrier (SLC) superfamilies. A better appreciation of the transporters present at the brain barriers will prove a valuable milestone in understanding the limited brain penetration of anti-HIV drugs in HIV and also aid the development of new anti-HIV drugs and drug combinations, with enhanced efficacy in the CNS. This review aims to summarise current knowledge on the transport of anti-HIV drugs across the blood–brain barrier and the choroid plexus, as well as provide recommendations for future research.

Antiviral agents are drugs approved by the Food and Drug Administration (FDA) for the treatment or control of viral infections. Available antiviral agents mainly target stages in the viral life cycle. The target stages in the viral life cycle are; viral attachment to host cell, uncoating, synthesis of viral mRNA, translation of mRNA, replication of viral RNA and DNA, maturation of new viral proteins, budding, release of newly synthesized virus, and free virus in body fluids. At least half of available antiviral agents are for the treatment of human immunodeficiency virus (HIV) infections. The others are used mainly for the management of herpesviruses, hepatitis B virus (HBV), hepatitis C virus (HCV), and respiratory viruses. Antiviral agents can be used for prophylaxis, suppression, preemptive therapy, or treatment of overt disease. Two important factors that can limit the utility of antiviral drugs are toxicity and the development of resistance to the antiviral agent by the virus. In addition, host phenotypic behaviors toward antiviral drugs because of either genomic or epigenetic factors could limit the efficacy of an antiviral agent in an individual. This article summarizes the most relevant pharmacologic and clinical properties of current antiviral agents, and targets for novel antiviral agents.

The intrasplenic injection of human peripheral blood mononuclear cells (PBMCs) into severely immune deficient NOD/SCID mice, causes a massive and transient dominant expansion of human B cells in the spleen. This permits the easy isolation of human monoclonal antibodies specific for different antigens by a Kohler and Milstein-based method. Here we studied the human HIV-specific antibody response in the circulation of mice after intrasplenic transfer of PBMC from untreated HIV-infected patients with detectable to high viral load as well as from HAART-treated and from untreated patients, who kept an undetectable viral load (the latter referred to as “natural suppressors”). Excellent B cell expansion was obtained for all PBMC. High level replication of virus was observed after transfer of PBMC of untreated viremic patients only. A strong and multispecific HIV-specific antibody response was observed after transfer of PBMC of untreated viremic patients and natural suppressors. In contrast, only a weak and pauci-specific antibody response was detected in mice reconstituted with PBMC from successfully treated patients. Based on these observations we conclude that the use of the intraspleen mouse model confirmed a) the presence of HIV-specific circulating memory B cells in untreated patients and natural suppressors; b) the nearly complete absence of circulating memory B cells in patients receiving highly active antiretroviral therapy. Using the intraspleen model we generated large numbers of immortalized B cells and isolated two anti-p24 human monoclonal antibodies. We further conclude that the intraspleen huPBL NOD/SCID model is a small animal model useful for the analysis of the antibody response against HIV found in patients.

Viral diseases continue to pose some of the greatest challenges to modern medicine. For many viral diseases, prophylactic vaccines are unlikely to be developed in the near future. Fortunately, effective antiviral therapies have been developed for many of these viruses. In this review, I will focus on antiviral therapy for herpes simplex virus, human immunodeficiency virus, hepatitis C virus, and human papillomavirus. The development of compounds targeting these viruses illustrates many of the principles driving current antiviral development. It is likely that our increasing understanding of viral replication and the virus-host interaction will lead to more rapid development of new antivirals in the future.

Viral quasispecies may possess a molecular memory of their past evolutionary history, imprinted on minority components of the mutant spectrum. Here we report experimental evidence and a theoretical model for memory in retroviral quasispecies in vivo. Apart from replicative memory associated with quasispecies dynamics, retroviruses may harbour a “cellular” or “anatomical” memory derived from their integrative cycle and the presence of viral reservoirs in body compartments. Three independent sets of data exemplify the two kinds of memory in human immunodeficiency virus type 1 (HIV-1). The data provide evidence of re-emergence of sequences that were hidden in cellular or anatomical compartments for extended periods of infection, and recovery of a quasispecies from pre-existing genomes. We develop a three-component model that incorporates the essential features of the quasispecies dynamics of retroviruses exposed to selective pressures. Significantly, a numerical study based on this model is in agreement with the experimental data, further supporting the existence of both replicative and reservoir memory in retroviral quasispecies.

Diarrhea in patients with acquired immune deficiency syndrome (AIDS) has proven to be both a diagnostic and treatment challenge since the discovery of the human immunodeficiency virus (HIV) virus more than 30 years ago. Among the main etiologies of diarrhea in this group of patients are infectious agents that span the array of viruses, bacteria, protozoa, parasites, and fungal organisms. In many instances, highly active antiretroviral therapy remains the cornerstone of therapy for both AIDS and AIDS-related diarrhea, but other targeted therapies have been developed as new pathogens are identified; however, some infections remain treatment challenges. Once identifiable infections as well as other causes of diarrhea are investigated and excluded, a unique entity known as AIDS enteropathy can be diagnosed. Known as an idiopathic, pathogen-negative diarrhea, this disease has been investigated extensively. Atypical viral pathogens, including HIV itself, as well as inflammatory and immunologic responses are potential leading causes of it. Although AIDS enteropathy can pose a diagnostic challenge so too does the treatment of it. Highly active antiretroviral therapy, nutritional supplementation, electrolyte replacements, targeted therapy for infection if indicated, and medications for symptom control all are key elements in the treatment regimen. Importantly, a multidisciplinary approach among the gastroenterologist, infectious disease physician, HIV specialists, oncology, and surgery is necessary for many patients.

In the 2 decades since the first reports of the acquired immunodeficiency syndrome (AIDS), the human immunodeficiency virus (HIV)-1 pandemic has surpassed the European-centered bubonic plague of the 14th century in magnitude and number of deaths. Originating in chimpanzees in central Africa, 1 AIDS reached epidemic proportions in the 1980s in the United States and Europe, where the vast majority of infections were acquired through homosexual contact. Subsequently, the epidemic spread to heterosexual populations, and by 1998, 35 million people were estimated to be infected with HIV-1 and 20 million to have died of the consequences of HIV-1 infection worldwide. In contrast to the initial focus of the epidemic in developed countries, today 70% of infected persons live in sub-Saharan Africa; in some countries, an astonishing 25% of the population is infected with HIV-1. 2 Today, the virus is transmitted by heterosexual contact in 75%‐ 85% of cases. 3 As a consequence of heterosexual transmission, the passage of HIV-1 from mother to fetus, neonate, and nursing infant (vertical transmission) has emerged as a devastating public health problem, particularly in developing countries. Coinciding with these changes in the epidemiology of HIV-1 infection, important new information has emerged regarding the role of the gastrointestinal tract in HIV-1 infection. This information is derived from an array of epidemiologic, basic, and clinical investigations. Here, we review the key findings from these investigations and present the emerging concepts regarding the role of the gastrointestinal tract mucosa in HIV-1 transmission and pathophysiology and the effect of highly active antiretroviral therapy (HAART) on the epidemiology, morbidity, and treatment of gastrointestinal infections.