Progressive Human Immunodeficiency Research Articles

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.

CD4 Tcells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection.

HIV/Mycobacterium tuberculosis (Mtb) co-infected individuals have an increased risk of tuberculosis prior to loss of peripheral CD4 Tcells, raising the possibility that HIV co-infection leads to CD4 Tcell depletion in lung tissue before it is evident in blood. Here, we use rhesus macaques to study the early effects of simian immunodeficiency virus (SIV) co-infection on pulmonary granulomas. Two weeks after SIV inoculation of Mtb-infected macaques, Mtb-specific CD4 Tcells are dramatically depleted from granulomas, before CD4 Tcell loss in blood, airways, and lymph nodes, or increases in bacterial loads or radiographic evidence of disease. Spatially, CD4 Tcells are preferentially depleted from the granuloma core and cuff relative to B cell-rich regions. Moreover, live imaging of granuloma explants show that intralesional CD4 Tcell motility is reduced after SIV co-infection. Thus, granuloma CD4 Tcells may be decimated before many co-infected individuals experience the first symptoms of acute HIV infection.

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.

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.

Macrophages in Progressive Human Immunodeficiency Virus/Simian Immunodeficiency Virus Infections.

The cells that are targeted by primate lentiviruses (HIV and simian immunodeficiency virus [SIV]) are of intense interest given the renewed effort to identify potential cures for HIV. These viruses have been reported to infect multiple cell lineages of hematopoietic origin, including all phenotypic and functional CD4 T cell subsets. The two most commonly reported cell types that become infected in vivo are memory CD4 T cells and tissue-resident macrophages. Though viral infection of CD4 T cells is routinely detected in both HIV-infected humans and SIV-infected Asian macaques, significant viral infection of macrophages is only routinely observed in animal models wherein CD4 T cells are almost entirely depleted. Here we review the roles of macrophages in lentiviral disease progression, the evidence that macrophages support viral replication in vivo, the animal models where macrophage-mediated replication of SIV is thought to occur, how the virus can interact with macrophages in vivo, pathologies thought to be attributed to viral replication within macrophages, how viral replication in macrophages might contribute to the asymptomatic phase of HIV/SIV infection, and whether macrophages represent a long-lived reservoir for the virus.

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.

Manganese-Enhanced Magnetic Resonance Imaging Reflects Brain Pathology During Progressive HIV-1 Infection of Humanized Mice.

Progressive human immunodeficiency viral (HIV) infection commonly leads to a constellation of cognitive, motor, and behavioral impairments. These are collectively termed HIV-associated neurocognitive disorders (HAND). While antiretroviral therapy (ART) reduces HAND severity, it does not affect disease prevalence. Despite decades of research, there remain no biomarkers for HAND and all potential comorbid conditions must first be excluded for a diagnosis to be made. To this end, we now report that manganese (Mn(2+))-enhanced magnetic resonance imaging (MEMRI) can reflect brain region-specific HIV-1-induced neuropathology in chronically virus-infected NOD/scid-IL-2Rγc(null) humanized mice. MEMRI diagnostics mirrors the abilities of Mn(2+) to enter and accumulate in affected neurons during disease. T1 relaxivity and its weighted signal intensity are proportional to Mn(2+) activities in neurons. In 16-week virus-infected humanized mice, altered MEMRI signal enhancement was easily observed in affected brain regions. These included, but were not limited to, the hippocampus, amygdala, thalamus, globus pallidus, caudoputamen, substantia nigra, and cerebellum. MEMRI signal was coordinated with levels of HIV-1 infection, neuroinflammation (astro- and micro-gliosis), and neuronal injury. MEMRI accurately demonstrates the complexities of HIV-1-associated neuropathology in rodents that reflects, in measure, the clinical manifestations of neuroAIDS as it is seen in a human host.

Progressive human immunodeficiency virus-associated vasculopathy: time to revise antiretroviral therapy guidelines?

Cardiovascular abnormalities were appreciated early in the epidemic of the acquired immunodeficiency syndrome (AIDS), even before the aetiological agent, human immunodeficiency virus (HIV) was isolated and characterised. The aetiology and pathogenesis of cardiovascular disease in HIV infection is still the subject of intense speculation, and is likely multi-factorial. HIV affects every aspect of the cardiac axis, causing pericarditis, myocarditis, cardiomyopathy, coronary artery disease and microvascular dysfunction, valvular heart disease, pulmonary vascular disease and pulmonary hypertension, stroke and peripheral vascular disease. HIV-associated vasculopathy is an increasingly recognised clinical entity, causing high morbidity and increasing mortality in southern Africa, particularly from stroke and cardiovascular disease. HIV causes disease of the vascular tree, either by a direct effect on vascular or perivascular tissue, or indirectly via immune complex-mediated mechanisms, associated opportunistic infections and malignancies. As a result, highly active antiretroviral therapy (HAART) may have an important role in controlling disease progression. We report a case of histologically defined primary HIV vasculopathy in which the chance to start HAART was initially missed and in which the patient progressed to require bilateral amputations, but obtained disease quiescence upon commencement of HAART.

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.

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.

Monocyte Chemotactic Protein-1 Regulates Voltage-Gated K+ Channels and Macrophage Transmigration

Progressive human immunodeficiency virus (HIV)-1 infection and virus-induced neuroinflammatory responses effectuate monocyte-macrophage transmigration across the blood-brain barrier (BBB). A key factor in mediating these events is monocyte chemotactic protein-1 (MCP-1). Upregulated glial-derived MCP-1 in HIV-1-infected brain tissues generates a gradient for monocyte recruitment into the nervous system. We posit that the inter-relationships between MCP-1, voltage-gated ion channels, cell shape and volume, and cell mobility underlie monocyte transmigration across the BBB. In this regard, MCP-1 serves both as a chemoattractant and an inducer of monocyte-macrophage ion flux affecting cell shape and mobility. To address this hypothesis, MCP-1-treated bone marrow-derived macrophages (BMM) were analyzed for gene and protein expression, electrophysiology, and capacity to migrate across a laboratory constructed BBB. MCP-1 enhanced K+ channel gene (KCNA3) and channel protein expression. Electrophysiological studies revealed that MCP-1 increased outward K+ currents in a dose-dependent manner. In vitro studies demonstrated that MCP-1 increased BMM migration across an artificial BBB, and the MCP-1-induced BMM migration was blocked by tetraethylammonium, a voltage-gated K+ channel blocker. Together these data demonstrated that MCP-1 affects macrophage migratory movement through regulation of voltage-gated K+ channels and, as such, provides a novel therapeutic strategy for neuroAIDS.

Emergence of polyfunctional CD8+ T cells after prolonged suppression of human immunodeficiency virus replication by antiretroviral therapy.

Progressive human immunodeficiency virus type 1 (HIV-1) infection is often associated with high plasma virus load (pVL) and impaired CD8(+) T-cell function; in contrast, CD8(+) T cells remain polyfunctional in long-term nonprogressors. However, it is still unclear whether CD8(+) T-cell dysfunction is the cause or the consequence of high pVLs. Here, we conducted a longitudinal functional and phenotypic analysis of virus-specific CD8(+) T cells in a cohort of patients with chronic HIV-1 infection. During the initiation and maintenance of successful antiretroviral therapy (ART), we assessed whether the level of pVL was associated with the degree of CD8(+) T-cell dysfunction. Under viremic conditions, HIV-specific CD8(+) T cells were dysfunctional with respect to cytokine secretion (gamma interferon, interleukin-2 [IL-2], and tumor necrosis factor alpha), and their phenotype suggested limited potential for proliferation. During ART, cytokine secretion by HIV-specific CD8(+) T cells was gradually restored, IL-7Ralpha and CD28 expression increased dramatically, and PD-1 levels declined. Thus, prolonged ART-induced reduction of viral replication and, hence, presumably antigen exposure in vivo, allows a significant functional restoration of CD8(+) T cells with the appearance of polyfunctional cells. These findings indicate that the level of pVL as a surrogate for antigen load has a dominant influence on the phenotypic and functional profile of virus-specific CD8(+) T cells.

Macrophage‐induced inflammation affects hippocampal plasticity and neuronal development in a murine model of HIV‐1 encephalitis

Cognitive, behavioral, and motor impairments, during progressive human immunodeficiency virus type 1 (HIV-1) infection, are linked to activation of brain mononuclear phagocytes (MP; perivascular macrophages and microglia). Activated MPs effect a giant cell encephalitis and neuroinflammatory responses that are mirrored in severe combined immunodeficient (SCID) mice injected with human monocyte-derived macrophages (MDM). Whether activated human MDMs positioned in the basal ganglia affect hippocampal neuronal plasticity, the brain subregion involved in learning and memory, is unknown. Thus, immunohistochemical techniques were used for detection of newborn neurons (polysialylated neuronal cell adhesion molecule [PSA-NCAM]) and cell proliferation (Ki-67) to assay MDM effects on neuronal development in mouse models of HIV-1 encephalitis. Immunodeficient (C.B.-17/SCID and nonobese diabetic/SCID, NOD/SCID) and immune competent (C.B.-17) mice were injected with uninfected or HIV-1-infected MDM. Sham-operated or unmanipulated mice served as controls. Neuronal plasticity was evaluated in the hippocampal dentate gyrus (DG) at days 7 and 28. By day 7, increased numbers of Ki-67+ cells, PSA-NCAM+ cells and dendrites in DG were observed in sham-operated animals. In contrast, significant reductions in neuronal precursors and altered neuronal morphology paralleled increased microglial activation in both HIV-1-infected and uninfected MDM-injected animals. DG cellular composition was restored at day 28. We posit that activated MDM induce inflammation and diminish DG neuronal plasticity. These data provide novel explanations for the cognitive impairments manifested during advanced HIV-1 infection.

Changing the Prognosis of Pulmonary Arterial Hypertension: Impact of Medical Therapy

Pulmonary arterial hypertension (PAH) is a progressive arteriopathy of the pulmonary circulation that can affect a wide group of patients. Presentation and natural history of PAH are intimately linked to progressive right ventricular failure. Historically, survival in PAH has been poor, especially for patients with PAH associated with progressive systemic sclerosis and human immunodeficiency virus. Oral, subcutaneous, and intravenous therapies that have emerged during the last decade can improve symptoms and hemodynamics. This review explores the impact of these therapies on prognosis in PAH, which ultimately rests on the ability to reverse the pulmonary arteriopathy and preserve right ventricular function.

Persistent recognition of autologous virus by high-avidity CD8 T cells in chronic, progressive human immunodeficiency virus type 1 infection.

CD8 T-cell responses are thought to be crucial for control of viremia in human immunodeficiency virus (HIV) infection but ultimately fail to control viremia in most infected persons. Studies in acute infection have demonstrated strong CD8-mediated selection pressure and evolution of mutations conferring escape from recognition, but the ability of CD8 T-cell responses that persist in late-stage infection to recognize viruses present in vivo has not been determined. Therefore, we studied 24 subjects with advanced HIV disease (median viral load = 142,000 copies/ml; median CD4 count = 71/ micro l) and determined HIV-1-specific CD8 T-cell responses to all expressed viral proteins using overlapping peptides by gamma interferon Elispot assay. Chronic-stage virus was sequenced to evaluate autologous sequences within Gag epitopes, and functional avidity of detected responses was determined. In these subjects, the median number of epitopic regions targeted was 13 (range, 2 to 39) and the median cumulative magnitude of CD8 T-cell responses was 5,760 spot-forming cells/10(6) peripheral blood mononuclear cells (range, 185 to 24,700). On average six (range, one to 8) proteins were targeted. For 89% of evaluated CD8 T-cell responses, the autologous viral sequence was predicted to be well recognized by these responses and the majority of analyzed optimal epitopes were recognized with medium to high functional avidity by the contemporary CD8 T cells. Withdrawal of antigen by highly active antiretroviral therapy led to a significant decline both in breadth (P = 0.032) and magnitude (P = 0.0098) of these CD8 T-cell responses, providing further evidence that these responses had been driven by recognition of autologous virus. These results indicate that strong, broadly directed, and high-avidity gamma-interferon-positive CD8 T-cells directed at autologous virus persist in late disease stages, and the absence of mutations within viral epitopes indicates a lack of strong selection pressure mediated by these responses. These data imply functional impairment of CD8 T-cell responses in late-stage infection that may not be reflected by gamma interferon-based screening techniques.

Plasma levels of soluble CD14 and tumor necrosis factor-alpha type II receptor correlate with cognitive dysfunction during human immunodeficiency virus type 1 infection.

The relationship between monocyte immune responses and cognitive impairment during progressive human immunodeficiency virus type 1 (HIV-1) infection was investigated in 28 subjects receiving highly active antiretroviral therapy. The mean+/-SEM CD4(+) T lymphocyte count and virus load for all patients were 237+/-41 cells/mm(3) and 77,091+/-195,372 HIV-1 RNA copies/mL, respectively. Levels of soluble tumor necrosis factor-alpha type II receptor (sTNF-RII) and soluble CD14 (sCD14) were measured in plasma by ELISA and were correlated with results from neuropsychological, magnetic resonance imaging, and magnetic resonance spectroscopy tests. Plasma sCD14 and sTNF-RII levels were elevated in subjects with cognitive impairment and in those with brain atrophy. Furthermore, both factors were correlated with spectroscopic choline:creatine ratios. These findings support the idea that peripheral immune responses are linked to cognitive dysfunction during advanced HIV-1 disease.

Severe, rapidly progressive human immunodeficiency virus type 1 disease in newborns with coinfections

To describe a severe form of rapidly progressive HIV-1 infection manifesting in the neonatal period. Prospective cohort study, King Edward VIII Hospital, Durban, South Africa. HIV-1-exposed neonates with hepatosplenomegaly, lymphadenopathy or persistent pneumonia within the first 28 days of life were investigated for perinatal infections. Confirmation of neonatal HIV-1 infection, HIV-1 subtype and clinical outcomes were studied. Twenty-three (72%) of 32 symptomatic HIV-1-exposed neonates recruited at a mean of 15.2 days were HIV-1-infected. HIV-1 infection was detected in 5 patients who were tested within 48 h of birth, confirming congenital infection. Congenital infection was not excluded in any case. Median neonatal viral load at recruitment was 471,932 copies/ml and median CD4 was 777 cells/mm3. The predominant clinical presentation was growth retardation and prematurity. Perinatal infections detected included: tuberculosis (8), syphilis (6) and cytomegalovirus (10). All of the neonates with perinatal tuberculosis were HIV-1-coinfected. Maternal and neonatal viral load and CD4 at recruitment were not statistically different between the groups with tuberculosis vs. other coinfections. Gag gene sequence analysis confirmed closely aligned HIV-1 subtype C in mothers and neonates. Nineteen (83%) died by 9 months, with a mean age at death of 3.5 months. A distinct group of HIV-1-infected babies may clinically manifest in the neonatal period with perinatal coinfections, subsequent rapidly progressive HIV-1 and early death.

T-cell progenitor function during progressive human immunodeficiency virus-1 infection and after antiretroviral therapy

AbstractImpairment of T-cell renewal has been proposed as contributing to CD4+ T-cell depletion in persons infected with human immunodeficiency virus-1. We analyzed the T-cell development capacity of progenitors using fetal thymus organ culture. Those who progressed to AIDS had a dramatic loss in T-cell development capacity shortly after seroconversion. In contrast, long-term nonprogressors retained progenitor capacity 8 years after seroconversion. Approximately 70% of patients experienced an improvement in T-cell development capacity after receiving 6 months of potent antiretroviral therapy. Improvement in T-cell development in fetal thymus organ culture correlated with an increase in the number of naive CD4+ T cells in peripheral blood. Numbers of progenitors in blood and bone marrow after seroconversion or during therapy did not correlate with the change observed in T-cell development capacity. These data provide evidence that HIV-1 infection can interfere with T-cell renewal at the level of the progenitor cell. Interference with T-cell renewal may contribute to CD4+ T-cell depletion.

T-cell progenitor function during progressive human immunodeficiency virus-1 infection and after antiretroviral therapy

Impairment of T-cell renewal has been proposed as contributing to CD4(+) T-cell depletion in persons infected with human immunodeficiency virus-1. We analyzed the T-cell development capacity of progenitors using fetal thymus organ culture. Those who progressed to AIDS had a dramatic loss in T-cell development capacity shortly after seroconversion. In contrast, long-term nonprogressors retained progenitor capacity 8 years after seroconversion. Approximately 70% of patients experienced an improvement in T-cell development capacity after receiving 6 months of potent antiretroviral therapy. Improvement in T-cell development in fetal thymus organ culture correlated with an increase in the number of naive CD4(+) T cells in peripheral blood. Numbers of progenitors in blood and bone marrow after seroconversion or during therapy did not correlate with the change observed in T-cell development capacity. These data provide evidence that HIV-1 infection can interfere with T-cell renewal at the level of the progenitor cell. Interference with T-cell renewal may contribute to CD4(+) T-cell depletion.

Respiratory disease trends in the Pulmonary Complications of HIV Infection Study cohort. Pulmonary Complications of HIV Infection Study Group.

We examined trends in the incidence of specific respiratory disorders in a multicenter cohort with progressive human immunodeficiency virus (HIV) disease during a 5-yr period. Individuals with a wide range of HIV disease severity belonging to three transmission categories were evaluated at regular intervals and for episodic respiratory symptoms using standard diagnostic algorithms. Yearly incidence rates of respiratory diagnoses were assessed in the cohort as a whole and according to CD4 count or HIV transmission category. The most frequent respiratory disorders were upper respiratory tract infections, but the incidence of lower respiratory tract infections increased as CD4 counts declined. Specific lower respiratory infections followed distinctive patterns according to study-entry CD4 count and transmission category. Acute bronchitis was the predominant lower respiratory infection of cohort members with entry CD4 counts > or = 200 cells/mm3. In cohort members with entry CD4 counts of 200 to 499 cells/mm3, the incidence of bacterial and Pneumocystis carinii pneumonia each increased an average of 40% per year. In members with entry CD4 counts < 200 cells/mm3, acute bronchitis, bacterial pneumonia, and P. carinii pneumonia occurred at high rates without discernible time trends, despite chemoprophylaxis in more than 80% after Year 1, and the rate of other pulmonary opportunistic infections increased over time. Each year, injecting drug users had a higher incidence of bacterial pneumonia than did homosexual men. The yearly rate of tuberculosis was < 3 episodes/100 person-yr in each entry CD4 and HIV-transmission group. We conclude that the time trends of HIV-associated respiratory disorders are determined by HIV disease stage and influenced by transmission category. Whereas acute bronchitis is prevalent during all stages of HIV infection, incidence rates of bacterial pneumonia and P. carinii pneumonia rise continuously during progression to advanced disease. In advanced disease, the incidence of acute bronchitis, bacterial pneumonia and P. carinii pneumonia is high despite widespread chemoprophylaxis.