Potent antiretroviral therapy does more than just decrease viral load.
Explore the source record for details and available documents.
AIDS-Related Opportunistic Infections↗
Biomedical subjects
E S Daar
Publications and source records attributed to E S Daar.
Does the human immunodeficiency virus (HIV) RNA concentration in cerebrospinal fluid help clinicians diagnose or understand HIV-induced neurological disease?
Explore the source record for details and available documents.
AIDS Dementia Complex↗
Human immunodeficiency virus inhibits multilineage hematopoiesis in vivo.
Human immunodeficiency virus type 1 (HIV-1)-infected individuals often exhibit multiple hematopoietic abnormalities reaching far beyond loss of CD4(+) lymphocytes. We used the SCID-hu (Thy/Liv) mouse (severe combined immunodeficient mouse transplanted with human fetal thymus and liver tissues), which provides an in vivo system whereby human pluripotent hematopoietic progenitor cells can be maintained and undergo T-lymphoid differentiation and wherein HIV-1 infection causes severe depletion of CD4-bearing human thymocytes. Herein we show that HIV-1 infection rapidly and severely decreases the ex vivo recovery of human progenitor cells capable of differentiation into both erythroid and myeloid lineages. However, the total CD34+ cell population is not depleted. Combination antiretroviral therapy administered well after loss of multilineage progenitor activity reverses this inhibitory effect, establishing a causal role of viral replication. Taken together, our results suggest that pluripotent stem cells are not killed by HIV-1; rather, a later stage important in both myeloid and erythroid differentiation is affected. In addition, a primary virus isolated from a patient exhibiting multiple hematopoietic abnormalities preferentially depleted myeloid and erythroid colony-forming activity rather than CD4-bearing thymocytes in this system. Thus, HIV-1 infection perturbs multiple hematopoietic lineages in vivo, which may explain the many hematopoietic defects found in infected patients.
Adult↗
Virology and immunology of acute HIV type 1 infection.
Primary or acute human immunodeficiency virus type 1 (HIV-1) infection is the stage of disease when virus first disseminates throughout the body of newly infected individuals. This process results in the seeding of lymphoid tissue and the central nervous system, and the induction of a specific humoral and cellular immune response. The high level of viremia and associated immune response is often accompanied by an acute illness referred to as the acute retroviral syndrome. This syndrome often includes fever, myalgia, rash, sore throat, and lymphadenopathy. The diagnosis is confirmed by the presence of high levels of HIV in blood along with an undetectable or evolving humoral immune response. Identification of this syndrome allows for the interruption of transmission, early diagnosis and treatment, as well as the opportunity to analyze subjects at a time when the virus and immune system first interact. Studies of the virology and immunology of acute HIV infection, as well as the effect of therapy during this stage of disease has provided new insights into the pathogenesis of HIV infection. Moreover, these studies have advanced our understanding of the successes and failures of the immune response to HIV. Investigations of what constitutes an effective immune response to HIV will be vital to the success of vaccine development in the future.
Anti-HIV Agents↗
A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor.
The chemokine receptor CXCR4 is the major coreceptor used for cellular entry by T cell- tropic human immunodeficiency virus (HIV)-1 strains, whereas CCR5 is used by macrophage (M)-tropic strains. Here we show that a small-molecule inhibitor, ALX40-4C, inhibits HIV-1 envelope (Env)-mediated membrane fusion and viral entry directly at the level of coreceptor use. ALX40-4C inhibited HIV-1 use of the coreceptor CXCR4 by T- and dual-tropic HIV-1 strains, whereas use of CCR5 by M- and dual-tropic strains was not inhibited. Dual-tropic viruses capable of using both CXCR4 and CCR5 were inhibited by ALX40-4C only when cells expressed CXCR4 alone. ALX40-4C blocked stromal-derived factor (SDF)-1alpha-mediated activation of CXCR4 and binding of the monoclonal antibody 12G5 to cells expressing CXCR4. Overlap of the ALX40-4C binding site with that of 12G5 and SDF implicates direct blocking of Env interactions, rather than downregulation of receptor, as the mechanism of inhibition. Thus, ALX40-4C represents a small-molecule inhibitor of HIV-1 infection that acts directly against a chemokine receptor at the level of Env-mediated membrane fusion.
Anti-HIV Agents↗
Changes in plasma HIV RNA levels and CD4+ lymphocyte counts predict both response to antiretroviral therapy and therapeutic failure. VA Cooperative Study Group on AIDS.
BACKGROUND: Markers are needed for assessing response to antiretroviral therapy over time. The CD4+ lymphocyte count is one such surrogate, but it is relatively weak. OBJECTIVE: To assess the association of changes in plasma human immunodeficiency virus (HIV) RNA level and CD4+ lymphocyte count with progression to the acquired immunodeficiency syndrome (AIDS). DESIGN: Analysis of data from a subset of patients in a multicenter, randomized, clinical trial. SETTING: Six Veterans Affairs medical centers and one U.S. Army medical center. PATIENTS: 270 symptomatic HIV-infected patients from the Veterans Affairs Cooperative Study on AIDS. INTERVENTION: Patients were randomly assigned to receive zidovudine or placebo initially; a cross-over protocol was established for patients receiving placebo who had disease progression. MEASUREMENTS: Reverse transcriptase polymerase chain reaction on cryopreserved plasma samples, previously obtained CD4+ lymphocyte counts, and clinical events. RESULTS: For each decrease of 0.5 log10 copies/mL in plasma HIV RNA level, averaged over the 6 months after randomization, the relative risk (RR) for progression to AIDS was 0.67 (P < 0.001). In a subset of 70 treated patients with long-term follow-up, a return to baseline plasma HIV RNA levels within 6 months of randomization was associated with progression to AIDS (RR, 4.28; P = 0.004). Plasma HIV RNA levels or CD4+ lymphocyte counts over time were more strongly associated with progression to AIDS than were baseline levels or counts. CONCLUSIONS: An adequate virologic response after initiation of antiretroviral therapy seems to require a decrease in plasma HIV RNA level of at least 0.5 log10 copies/mL that is sustained for at least 6 months. The independent relation between plasma HIV RNA level and CD4+ lymphocyte count over time and clinical outcome suggests that the measurement of plasma HIV RNA level, in addition to the CD4+ lymphocyte count, has a role in guiding the management of antiretroviral therapy.
Acquired Immunodeficiency Syndrome↗
Utility of fungal blood cultures for patients with AIDS.
This study was designed to define the clinical utility of fungal blood cultures for human immunodeficiency virus type 1-infected individuals. A retrospective chart review was performed for all patients admitted to an inpatient AIDS unit who had evidence of an invasive fungal infection. During a 25-month period, 1,162 fungal blood cultures were performed for 322 patients. These cultures, along with bacterial blood cultures, resulted in the isolation of fungi from 26 patients; 15 of these isolates were considered true pathogens. Routine blood cultures were positive for the fungal isolates in all 15 cases: Candida species and Candida glabrata (6 cases), Cryptococcus neoformans (7), Coccidioides immitis (1), and Histoplasma capsulatum (1). All invasive fungal infections were diagnosed by other means before fungal blood cultures were reported as positive. The results of this study suggest that the routine performance of such cultures in clinical practice should be reevaluated.
AIDS-Related Opportunistic Infections↗
HIV/AIDS. Assessment, testing, and natural history.
Physicians need to screen all patients for HIV risk and provide education to reduce risk. If a careful history and physical examination suggest the possibility of HIV infection, physicians should provide informed consent, counsel appropriately, and perform testing. For patients testing positive, knowledge of HIV pathogenesis helps physicians devise rational plans for treatment and patient education. The nonspecific symptoms of primary HIV infection cause it to be underrecognized and frequently not evaluated appropriately. Therapeutic intervention during primary infection may present a unique opportunity to attenuate disease caused by HIV.
Anti-HIV Agents↗
Recombinant human growth hormone in patients with HIV-associated wasting. A randomized, placebo-controlled trial. Serostim Study Group.
BACKGROUND: Body wasting, particularly loss of body cell mass, is an increasingly prevalent acquired immunodeficiency syndrome (AIDS)-defining condition and is an independent risk factor for death in patients infected with the human immunodeficiency virus (HIV). Treatment with growth hormone for 7 days resulted in weight gain and nitrogen retention, but the long-term effects of this treatment in patients with HIV-associated wasting are not known. OBJECTIVE: To evaluate the long-term effect of treatment with growth hormone on weight, body composition, functional performance, and quality of life in patients with HIV-associated wasting. DESIGN: Randomized, double-blind, placebo-controlled, multicenter trial. SETTING: Outpatient university and community-based patient care facilities. PATIENTS: 178 HIV-infected patients with documented unintentional weight loss of at least 10% or weight less than 90% of the lower limit of ideal body weight. INTERVENTION: Patients were randomly assigned to receive either recombinant human growth hormone, 0.1 mg/kg of body weight per day (average dosage, 6 mg/d) (n = 90) or placebo (n = 88) for 12 weeks. MEASUREMENTS: Weight; body fat, lean body mass, and bone mineral content (measured by dual-energy x-ray absorptiometry); total body water (by deuterium oxide dilution); extracellular water (by sodium bromide dilution); work output (by treadmill exercise); quality of life; and safety of treatment. RESULTS: Treatment with growth hormone resulted in a sustained and statistically significant increase in weight (mean increase +/- SD, 1.6 +/- 3.7 kg [P < 0.001]) and lean body mass (3.0 +/- 3.0 kg [P < 0.001]), accompanied by a decrease in body fat (-1.7 +/- 1.7 kg [P < 0.001]). In contrast, in patients receiving placebo, weight (increase, 0.1 +/- 3.1 kg), lean body mass (decrease, 0.1 +/- 2.0 kg), and body fat (decrease, 0.3 +/- 2.2 kg) did not change significantly from baseline. Differences between groups at week 12 were statistically significant (P = 0.011 for body weight and P < 0.001 for lean body mass and body fat). A greater increase in treadmill work output was noted in the group receiving growth hormone (increase, 99 +/- 293 kg. m/min) compared with the group receiving placebo (increase, 20 +/- 233 kg.m/min)(P = 0.039). Health status (quality of life) scores did not differ between groups at baseline or after treatment. Days of disability and use of medical resources were the same for both groups. Treatment was was well tolerated; no significant differences were seen between groups in clinical events, progression of AIDS, CD4+ or CD8+ cell counts, or viral burden. CONCLUSION: Treatment with growth hormone increases body weight, lean body mass, and treadmill work output and appears to be a safe and potentially effective therapy in patients with HIV-associated wasting.
Adult↗
Neutralization of HIV type 1 infectivity by serum antibodies from a subset of autoimmune patients with mixed connective tissue disease.
Mixed connective tissue disease (MCTD) is a rheumatic disorder with clinical similarities to HIV-1 infection, and with characteristic autoimmune anti-RNP antibodies specific for the U1 snRNP splicing complex. Anti-RNP antibodies cross-react with the HIV-1 surface, owing to multiple homologies between the gp120/41 envelope complex and the 70K protein of U1 snRNP. A key epitope of 70K, its RNA-binding site, is homologous to a dominant B and T cell epitope in the third variable loop (V3) of gp120. In this study, we tested the ability of anti-RNP sera to inhibit HIV-1 infectivity in vitro. Of nine sera tested, five were 70-99% effective in neutralizing one or more HIV-1 strains. One serum was > 99% effective in neutralizing HIV-1MN, and 86 and 77% effective against the primary isolates HIV-1(CO) and HIV-1(JR-FL), respectively, an efficacy equal to that of a pool of broadly neutralizing antibodies from HIV-1-infected subjects (HIVIG). The mean neutralizing titer of anti-RNP sera against HIV-1(JR-FL) was 3.9-fold higher than that of HIVIG. Neutralizing potency was associated with high reactivity to gp120 by ELISA, and with the presence of serum rheumatoid factor, known to enhance antibody neutralization of other viruses. The current findings provide further evidence that individuals unexposed to HIV-1 may develop immunologic resistance by alternative mechanisms, possibly including molecular mimicry, or exposure to as yet unidentified retroviruses. Thus MCTD, which involves both B and T cell reactivity to self-epitopes homologous to HIV-1, may elucidate new strategies for generating protective immunity to this virus.
Antibodies, Antinuclear↗
Rapid evolution of human immunodeficiency virus strains with increased replicative capacity during the seronegative window of primary infection.
The relationship between host and virus was examined during the initial stages of human immunodeficiency virus type 1 (HIV) infection in a volunteer from the Multicenter AIDS Cohort Study (MACS). The individual was asymptomatic and unaware of his infection during an initial donation of blood and inguinal lymphoid tissue. Proviral DNA, however, was present in cells from both sources, HIV RNA was detected in the plasma, and CD4+ cell levels were reduced by approximately 50% compared with previous donations in the MACS. In a second blood donation 12 days later, plasma HIV RNA increased 200-fold in tandem with viral isolates with an increased growth phenotype in vitro. HIV burden was ultimately suppressed upon seroconversion and the emergence of HIV-specific CD8+ cytotoxic T lymphocytes. These observations provide further evidence that the potential benefits of early treatment may be maximized during the early stages of infection, when viral fitness may be low but is unopposed by immune responses.
CD4-Positive T-Lymphocytes↗
Sequential determination of viral load and phenotype in human immunodeficiency virus type 1 infection.
Detailed studies of HIV viral load and phenotype were performed on sequentially cryopreserved peripheral blood mononuclear cells (PBMCs) from eight infected individuals followed in the Los Angeles Multicenter AIDS Cohort Study. Three individuals remained clinically and immunologically stable over a 5- to 8-year period, three demonstrated precipitous and two gradual declines in CD4+ T lymphocytes. Viral load in PBMCs was quantitated by limiting dilution culture and DNA PCR, while minimally passaged viral isolates were studied for their ability to induce syncytium formation in vitro and, when relevant, sensitivity to zidovudine (ZDV). Viral burden remained relatively low in those who remained clinically and immunologically stable, while increasing substantially in all five individuals who experienced a decline in CD4+ T lymphocytes. Two subjects were noted to have a switch from non-syncytium-inducing (NSI) to syncytium-inducing (SI) isolates immediately preceding a precipitous decline in CD4+ T lymphocytes, while the third individual who experienced such a decline and the two who had gradual declines did not develop SI isolates. Moreover, of the three subjects who experienced a decrease in CD4+ T lymphocyte number and were given ZDV during the study period, none were noted to develop resistance to this agent. In summary, the virology in clinically and immunologically stable individuals was characterized by relatively low viral burden in PBMCs and a predominance of NSI isolates.(ABSTRACT TRUNCATED AT 250 WORDS)
Acquired Immunodeficiency Syndrome↗
Infections in patients with chronic adult T-cell leukemia/lymphoma: case report and review.
Adult T-cell leukemia/lymphoma (ATLL) is caused by the human T-cell lymphotropic virus type I (HTLV-I). ATLL is classified into the smoldering, chronic, lymphoma, and acute subtypes. We describe a North American woman with chronic ATLL who presented with pneumonia caused by Pneumocystis carinii, Cryptococcus neoformans, Mycoplasma pneumoniae, and Mycobacterium avium complex. Although opportunistic infections have been documented in patients with ATLL, there are few case reports detailing infectious complications in patients with chronic ATLL.
Aged↗
Unsuspected primary human immunodeficiency virus type 1 infection in seronegative emergency department patients.
To estimate the number of recently infected patients in the window period before human immunodeficiency virus type 1 (HIV-1) seroconversion among patients seeking medical care, randomly selected adults presenting to an inner city emergency department were tested for HIV-1 antibody and p24 antigen. Of 2300 patients enrolled, 180 (7.8%; 95% confidence interval [CI]: 6.7%-8.9%) were Western blot (WB)-positive for HIV-1 antibodies. Of 2120 antibody-negative or WB-indeterminate patients, none of whom were identified on clinical grounds as having primary HIV-1 infection, 6 (0.28%; CI, 0.07%-0.51%) were p24 antigen-positive with serologies consistent with primary HIV-1 infection. Of these 6, 3 were seronegative even with third-generation antibody ELISA. HIV-1 infection in these 6 patients was further confirmed by polymerase chain reaction amplification of virion-associated RNA in serum demonstrating 10(4)-10(5) virions/mL. With 40,000 new HIV-1 infections in the United States annually, approximately 750 persons with undiagnosed primary HIV-1 infections may seek primary health care in any given week in the United States. Testing for viral antibodies alone will fail to detect a large proportion of these persons. Thus, early identification by p24 antigen testing may be important to diagnose and treat symptomatic illness, implement public health and counseling measures, and arrange appropriate medical follow-up.
Adult↗
Clinical experience with atovaquone: a new drug for treating Pneumocystis carinii pneumonia.
Atovaquone is a new hydroxynapthoquinone antiprotozoal agent active against Pneumocystis carinii in vitro and in animal models. The authors report an experience using atovaquone to treat 25 patients with mild to moderate P. carinii pneumonia. Eligible patients were treated for 21 days with 750 mg of atovaquone orally three times daily. Prednisone was added when the P(A-a)O2 gradient was between 35-45 mm Hg. Patients were treated under three treatment protocols. Patients in Group 1 participated in one of two randomized comparative drug trials, designed for patients with and without sulfonamide intolerance. Six of seven patients successfully completed treatment, and one patient discontinued treatment because of an adverse reaction (> 5 times baseline increase in transaminase level). Patients in Group 2 were treated with atovaquone for mild to moderate P. carinii pneumonia under a treatment Investigational New Drug protocol because of prior sulfonamide reactions. Fifteen of these 18 patients successfully completed treatment; one died from other complications during treatment and two discontinued treatment for adverse reactions (> 5 times baseline increase in transaminase levels, and a diffuse rash). Serum transaminase levels returned to normal at the end of treatment in all patients with elevated levels. All patients demonstrated clinical resolution of their pneumonia and improvement of pretreatment hypoxemia (Group 1: pretreatment PaO2 = 82 +/- 14 mm Hg, posttreatment PaO2 = 92 +/- 9 mm Hg). Overall, 21 (84%) of 25 patients successfully finished therapy without significant adverse reactions. Atovaquone appears to be an effective and well-tolerated oral treatment for mild to moderate P. carinii pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)
AIDS-Related Opportunistic Infections↗
Idiopathic CD4+ T-lymphocytopenia--immunodeficiency without evidence of HIV infection.
BACKGROUND: The human immunodeficiency virus (HIV), the etiologic agent of the acquired immunodeficiency syndrome (AIDS), infects and depletes CD4+ T lymphocytes. Recently, patients have been described with profound CD4+ T-lymphocytopenia but without evident HIV infection, a condition now termed idiopathic CD4+ T-lymphocytopenia, and a national surveillance network has been set up to investigate such cases. METHODS: We studied 12 patients with CD4+ T-lymphocytopenia who were referred to us from three U.S. cities. Blood samples were tested for HIV with specific antibody assays, viral cultures, and polymerase-chain-reaction (PCR) techniques. RESULTS: The patients (10 men and 2 women) ranged in age from 30 to 69 years. Eight had risk factors for HIV infection. The clinical manifestations were heterogeneous: five patients had opportunistic infections, five had syndromes of unknown cause, and two had no symptoms. Two patients died from acute complications of their immunodeficiency. The patients' lowest CD4+ lymphocyte counts ranged from 3 to 308 per cubic millimeter (mean, 149). Three patients had complete or partial spontaneous reversal of the CD4+ T-lymphocytopenia. Concomitant CD8+ T-lymphocytopenia was noted in three patients, and abnormal immunoglobulin levels were found in five. Multiple virologic studies by serologic testing, culture, and PCR were completely negative for HIV in all patients. CONCLUSIONS: Our 12 patients with idiopathic CD4+ T-lymphocytopenia appear to be epidemiologically, clinically, and immunologically heterogeneous. It is unclear whether this syndrome is new, transmissible, or acquired. Many of the clinical and immunologic features are distinct from those found in AIDS, and our extensive virologic studies found no evidence of HIV infection. The cause of this condition remains unknown.
Adult↗
Infectious decay of human immunodeficiency virus type 1 in plasma.
AIDS is caused by the human immunodeficiency virus type 1 (HIV-1). Recent methods have been developed to estimate infectious titer in various bodily fluids, including blood. However, lack of information about HIV-1 stability in blood has restricted the use of these techniques to fresh samples in immediately accessible virology laboratories. In studies of infectious virus decay, it was found that at room temperature, complete decay of infectious HIV-1 in plasma can require > 7 days. Furthermore, the stability of HIV-1 was enhanced by storage at 4 degrees C, suggesting that fresh plasma could be sent on ice to core laboratories for viral quantitation. These studies also emphasize the need for thorough decontamination of all potentially infectious material.
Blood↗
Medical management of AIDS patients. Bacterial and fungal infections.
The rapid and thus far generally inexorable rise in HIV infections has led to a series of opportunistic infection that includes those caused by bacteria, yeasts, and members of the Eumycetes. The infections range in prevalence from occasional to highly prevalent, in severity from trivial to fatal, and in anatomic areas involved from local to disseminated. They occur as isolated, concurrent, or sequential infections with regard to other opportunistic diseases. Some vary in their geographic distribution. They may be newly acquired or reactivated and occur early or late in the course of HIV infection. Bacterial infections are usually easily treated, although they frequently disseminate and often recur after seemingly appropriate treatment. In contrast, all but the mildest fungal infections are difficult to treat and even more difficult or impossible to eradicate. The diagnosis of bacterial and fungal infections begins with clinical suspicion and involves relatively standard methodology. Treatment of the systemic mycoses and some bacterial infections in HIV infected patients is punctuated by exaggerated side effects of therapy, frequent relapses, and the need for maintenance suppressive therapy.
Acquired Immunodeficiency Syndrome↗