Viral blip dynamics during highly active antiretroviral therapy.

Although intermittent episodes of low-level viremia are often observed in well-suppressed highly active antiretroviral therapy (HAART)-treated patients, the timing and amplitude of viral blips have never been examined in detail. We analyze here the dynamics of viral blips, i.e.

Human immunodeficiency virus type 1 induces persistent changes in mucosal and blood gammadelta T cells despite suppressive therapy.

Gammadelta T cells are primarily found in the gastrointestinal mucosa and play an important role in the first line of defense against viral, bacterial, and fungal pathogens. We sought to examine the impact of human immunodeficiency virus type 1 (HIV-1) infection on mucosal as well as peripheral blood gammadelta T-cell populations. Our results demonstrate that HIV-1 infection is associated with significant expansion of Vdelta1 and contraction of Vdelta2 cell populations in both the mucosa and peripheral blood.

Script memory for typical and atypical actions: controls versus patients with severe closed-head injury.

Objective: When typical and atypical information about a situation is presented, the latter is usually better recognized. This phenomenon is referred to as the 'typicality effect'. It is claimed by most theories that typical and atypical information are mediated by automatic and effortful processes, respectively.

Infectivity and replication capacity of drug-resistant human immunodeficiency virus type 1 variants isolated during primary infection.

It is believed that replication capacity is an important determinant of human immunodeficiency virus type 1 (HIV-1) pathogenicity and transmissibility. To explore this, we conducted a comprehensive analysis of the replication properties of nine drug-resistant and nine drug-susceptible viral isolates derived from patients with primary HIV-1 infection. Viral isolates were tested for single-cycle infectivity in the GHOST cell line.

Determining the antiviral activity of tenofovir disoproxil fumarate in treatment-naive chronically HIV-1-infected individuals.

Objective: To assess the efficacy of tenofovir disoproxil fumarate (TDF) monotherapy by following the initial rate of decline in plasma viral load, which is a measure of the efficacy of therapy in blocking viral replication.

Design: An open-label, single-site study of TDF monotherapy in 10 antiretroviral drug-naive chronically HIV-1-infected individuals.

Methods: Antiviral responses were assessed at baseline and during 21 days of monotherapy with TDF by measuring plasma HIV-1 RNA levels.

Discovery of a potent, non-peptide bradykinin B1 receptor antagonist.

Bradykinin (BK) plays an important role in the pathophysiological processes accompanying pain and inflammation. Selective bradykinin B1 receptor antagonists have been shown to be anti-nociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. We have explored chemical modifications in a series of dihydroquinoxalinone sulfonamides to evaluate the effects of various structural changes on biological activity.

The distribution of viral blips observed in HIV-1 infected patients treated with combination antiretroviral therapy.

Human immunodeficiency virus type 1 (HIV-1) infected patients treated with combination antiretroviral therapy frequently have the level of HIV-1 RNA detectable in plasma driven below the lower limit of detection of current assays, 50 copies ml(-1). Patients may continue to exhibit viral loads (VLs) below the assay limit for years, yet on some occasions the VL may be above the limit of detection. Whether these 'blips' in VL are simply assay errors or are indicative of intermittent episodes of increased viral replication is of great clinical concern.

A novel antiviral intervention results in more accurate assessment of human immunodeficiency virus type 1 replication dynamics and T-cell decay in vivo.

Mathematical models provide an understanding of in vivo replication kinetics of human immunodeficiency virus type 1 (HIV-1). With a novel intervention designed for increased potency, we have more accurately deduced the half-lives of virus-producing CD4(+) T cells, 0.7 day, and the generation time of HIV-1 in vivo, approximately 2 days, confirming the dynamic nature of HIV-1 replication.

Determining the relative efficacy of highly active antiretroviral therapy.

Despite the clinical benefits of combination antiviral therapy, whether maximal antiviral potency has been achieved with current drug combinations remains unclear. We studied the first phase of decay of human immunodeficiency virus type 1 (HIV-1) RNA in plasma, one early indicator of antiviral activity, after the administration of a novel combination of lopinavir/ritonavir, efavirenz, tenofovir disoproxil fumarate, and lamivudine and compared it with that observed in matched cohorts treated with alternative combination regimens. On the basis of these comparisons, we conclude that the relative potency of highly active antiretroviral therapy may be augmented by as much as 25%-30%.

Prostate cancer: advances in immunotherapy.

The absence of curative therapies for advanced or recurrent forms of prostate cancer has prompted a vigorous search for novel treatment strategies. Immunotherapy encompasses one particularly promising systemic approach to the treatment of prostate cancer. Immune-based strategies for treating prostate cancer have recently been facilitated by the identification of a number of prostate tissue/tumour antigens that can be targeted, either by antibody or T cells, to promote prostate tumour cell injury or death.

Mercury exposure in an urban pediatric population.

Objective: To determine the prevalence of elevated urinary mercury (Hg), as a marker of exposure, in a population of children drawn from an inner-city community with documented access to elemental mercury.

Methods: A prospective consecutive patient series was conducted from November 1998 to January 1999 at an inner-city clinic in New York. Anonymous urine specimens from subjects (aged 1-18 years) were collected in mercury-free containers, split, acidified with 1:100 hydrochloric acid, and frozen.

Patient satisfaction with alosetron for the treatment of women with diarrhea-predominant irritable bowel syndrome.

Objective: The efficacy and tolerability of alosetron in women with diarrhea-predominant irritable bowel syndrome (IBS) have been established in double-blind, placebo-controlled trials. However, the degree to which alosetron fulfills the needs of those suffering from IBS has not been thoroughly examined from the patient's perspective. This randomized, double-blind, placebo-controlled study conducted in women with diarrhea-predominant IBS evaluated patients' overall satisfaction with treatment as well as their satisfaction with respect to several specific medication attributes.

Discontinuation of antiretroviral therapy commenced early during the course of human immunodeficiency virus type 1 infection, with or without adjunctive vaccination.

Sixteen subjects were treated with highly active antiretroviral therapy within 120 days of the onset of symptoms of newly acquired human immunodeficiency virus type 1 (HIV-1) infection. Eleven of the 16 participated in an adjunctive therapeutic vaccine trial. After a mean of 3.

Compartmentalization of surface envelope glycoprotein of human immunodeficiency virus type 1 during acute and chronic infection.

Human immunodeficiency virus type 1 is characterized by extensive genetic heterogeneity. Having previously demonstrated that, in the peripheral blood, the initial viral population is more homogeneous than at subsequent stages of infection, we have extended our studies to tissue samples, allowing comparisons between viral populations in peripheral blood and tissues during both the acute and chronic stages of infection. We found that homogeneity in gp120 sequences during the acute infection phase is not just restricted to the peripheral blood but also extends to other tissue compartments.

Antiretroviral-drug resistance among patients recently infected with HIV.

Background: Among persons in North America who are newly infected with the human immunodeficiency virus (HIV), the prevalence of transmitted resistance to antiretroviral drugs has been estimated at 1 to 11 percent.

Methods: We performed a retrospective analysis of susceptibility to antiretroviral drugs before treatment and drug-resistance mutations in HIV in plasma samples from 377 subjects with primary HIV infection who had not yet received treatment and who were identified between May 1995 and June 2000 in 10 North American cities. Responses to treatment could be evaluated in 202 subjects.

Evolving patterns of HIV-1 resistance to antiretroviral agents in newly infected individuals.

Objective: To assess temporal changes in prevalence of transmitted HIV-1 drug resistance in a homogeneous cohort of newly infected individuals.

Methods: Pretreatment genotypic and phenotypic drug resistance was tested in 154 subjects with primary HIV-1 infection identified between 1995 and 2001 (group A; n = 76) and 1999 and 2001 (group B; n = 78). Sequence analysis was assessed by population-based sequencing.

Goals and milestones during treatment of HIV-1 infection with antiretroviral therapy: a pathogenesis-based perspective.

Highly active antiretroviral therapy (HAART) has reduced the morbidity and mortality related to infection with the human immunodeficiency virus-1 (HIV-1) through its ability to suppress viral replication and preserve and reconstitute specific immune responses in many infected individuals. However, the complete eradication of HIV-1 with current HAART regimens is not considered possible by most experts. Moreover, many current antivirals have metabolic complications and limiting side effects.

Porous polysilsesquioxanes for the adsorption of phenols.

Arylene- and ethylene-bridged polysilsesquioxane materials have been synthesized by the hydrolysis and condensation of alkoxysilyl precursors under basic conditions. Cetyltrimethylammonium chloride was used to increase the porosity and surface areas of these materials via the surfactanttemplate approach. Structural characterization of these materials was carried out by nitrogen gas sorption and X-ray diffraction.

Origin of human immunodeficiency virus type 1 quasispecies emerging after antiretroviral treatment interruption in patients with therapeutic failure.

The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure.

Safety and immunogenicity of ALVAC vCP1452 and recombinant gp160 in newly human immunodeficiency virus type 1-infected patients treated with prolonged highly active antiretroviral therapy.

In order to boost immune responses in persons in whom highly active antiretroviral therapy (HAART) was initiated within 120 days of the onset of symptoms of newly acquired human immunodeficiency virus type 1 (HIV-1) infection, we administered vaccines containing a canarypox virus vector, vCP1452, with HIV-1 genes encoding multiple HIV-1 proteins, and recombinant gp160. Fifteen HIV-1-infected subjects who achieved sustained suppression of plasma viremia for at least 2 years were enrolled. While continuing antiretroviral therapy, each subject received at least four intramuscular injections of the vaccines on days 0, 30, 90, and 180.

Residual viral replication during antiretroviral therapy boosts human immunodeficiency virus type 1-specific CD8+ T-cell responses in subjects treated early after infection.

Human immunodeficiency virus type 1 (HIV-1)-infected subjects treated early after infection have preserved HIV-1-specific CD4+ T-cell function. We studied the effect of highly active antiretroviral therapy (HAART) on the frequency of HIV-1-specific CD8+ T cells in patients treated during early (n = 31) or chronic (n = 23) infection. The degree of viral suppression and time of initiation of treatment influenced the magnitude of the CD8+ T-cell response.

Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy.

The mechanism of CD4(+) T cell depletion in human immunodeficiency virus (HIV)-1 infection remains controversial. Using deuterated glucose to label the DNA of proliferating cells in vivo, we studied T cell dynamics in four normal subjects and seven HIV-1-infected patients naive to antiretroviral drugs. The results were analyzed using a newly developed mathematical model to determine fractional rates of lymphocyte proliferation and death.

New antiretroviral may help failing PI regimens.

Researchers at the first International AIDS Society Conference presented findings that demonstrated the potency of a new type of antiretroviral medication: the non-peptidic protease inhibitor (NPPI). We present a Q&A with Martin Markowitz, MD, an investigator with the Aaron Diamond AIDS Research Center in New York City, about this new class of drug and about research he and others have been conducting on the first NPPI drug to have Phase II data.