A randomized trial of treatment interruption before optimized antiretroviral therapy for persons with drug-resistant HIV: 48-week virologic results of ACTG A5086.

Background: The role of structured treatment interruption (STI) before optimized antiretroviral therapy (ART) in patients with drug-resistant human immunodeficiency virus type 1 (HIV-1) is uncertain.

Methods: AIDS Clinical Trial Group protocol A5086 was a prospective trial of 41 patients with multiple drug class-resistant HIV who were randomized to undergo a 16-week STI followed by optimized ART (STI) or immediate optimized ART (no STI). The primary end point was the proportion of subjects with HIV-1 RNA loads <400 copies/mL 48 weeks after randomization.

Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection.

Context: Plasma human immunodeficiency virus (HIV) RNA level predicts HIV disease progression, but the extent to which it explains the variability in rate of CD4 cell depletion is poorly characterized.

Objective: To estimate the proportion of variability in rate of CD4 cell loss predicted by presenting plasma HIV RNA levels in untreated HIV-infected persons.

Design: Repeated-measures analyses of 2 multicenter cohorts, comprising observations beginning on May 12, 1984, and ending on August 26, 2004.

Pharmacogenetics of nevirapine-associated hepatotoxicity: an Adult AIDS Clinical Trials Group collaboration.

Associations have been reported between an MDR1 variant and responses to nonnucleoside reverse-transcriptase inhibitors. We explored associations between MDR1, CYP2B6, and CYP3A polymorphisms and nevirapine hepatotoxicity. Among participants in a randomized study in South Africa (FTC-302), MDR1 3435C-->T was significantly associated with decreased risk of hepatotoxicity (risk ratio, 0.

Biology of CCR5 and its role in HIV infection and treatment.

Chemokine receptors are found on cell surfaces and promote cellular migration by chemotaxis. The CC chemokine receptor 5 (CCR5) is used by the human immunodeficiency virus (HIV) to infect cells. Strategies that target human CCR5 are therefore being developed to prevent and treat HIV infection.

HIV coinfection impairs CD28-mediated costimulation of hepatitis C virus-specific CD8 cells.

Background: During human immunodeficiency virus (HIV) infection, reduced proportions of CD8 cells express CD28, the key costimulatory molecule for lymphocyte activation. However, it is unclear whether reduced CD28 expression affects immune responses to non-HIV antigens, potentially contributing to susceptibility to opportunistic infection.

Methods: We measured CD4- and CD8-specific interferon- gamma responses to hepatitis C virus (HCV) peptide pools in subjects with chronic HCV monoinfection (n=14), in subjects with chronic HCV/HIV coinfection (n=15), and in healthy control subjects (n=10) by enzyme-linked immunospot assay in the presence and absence of CD28 costimulation.

Cutting edge: human beta defensin 3--a novel antagonist of the HIV-1 coreceptor CXCR4.

Previously, we showed that human epithelial cell-derived beta-defensins (hBD)-2 and -3 block HIV-1 replication via a direct interaction with virions and through modulation of the CXCR4 coreceptor on immunocompetent cells. In the present study, we show that hBD-3 promotes directly the internalization of CXCR4 yet does not induce calcium flux, ERK (ERK-1/2) phosphorylation, or chemotaxis. hBD-3 competes with stromal-derived factor 1 (SDF-1), the natural ligand for CXCR4, for cellular binding and blocks SDF-1-induced calcium flux, ERK-1/2 phosphorylation, and chemotaxis, without effects on other G protein-coupled receptors.

Interferon-alpha differentially rescues CD4 and CD8 T cells from apoptosis in HIV infection.

Objective: To examine the effects of interferon-alpha (IFN-alpha) on T cell survival and activation in HIV infection.

Design: The effects of IFN-alpha on spontaneous apoptosis and CD38 expression among T cell subsets were determined in vitro and studied in relation to CD4 cell counts, plasma HIV RNA levels and the age of the subjects.

Methods: Peripheral blood mononuclear cells from 48 HIV-infected persons and 17 healthy donors were incubated in vitro overnight with or without the addition of IFN-alpha.

Microbicides and other topical strategies to prevent vaginal transmission of HIV.

The HIV epidemic is, by many criteria, the worst outbreak of infectious disease in history. The rate of new infections is now approximately 5 million per year, mainly in the developing world, and is increasing. Women are now substantially more at risk of infection with HIV than men.

HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells.

Establishing a CD8(+) T cell-mediated immune correlate of protection in HIV disease is crucial to the development of vaccines designed to generate cell-mediated immunity. Historically, neither the quantity nor breadth of the HIV-specific CD8(+) T-cell response has correlated conclusively with protection. Here, we assess the quality of the HIV-specific CD8(+) T-cell response by measuring 5 CD8(+) T-cell functions (degranulation, IFN-gamma, MIP-1beta, TNF-alpha, and IL-2) simultaneously in chronically HIV-infected individuals and elite nonprogressors.

Differential effect of interleukin-2 treatment on primary and secondary immunizations in HIV infected individuals.

Objectives: As interleukin (IL)-2 therapy increases CD4 cell counts in HIV infected subjects, it emerged as a candidate for the partial restoration of immune competence in this disease.

Methods: We studied the frequencies of antigen-specific T cells using single cell resolution cytokine ELISPOT assays and titers of specific antibodies before and after immunization of HIV infected subjects who were treated with HAART or HAART plus IL-2.

Results: Subjects seronegative to hepatitis A were vaccinated with hepatitis A antigen.

Distinct mechanisms of T cell reconstitution can be identified by estimating thymic volume in adult HIV-1 disease.

Background: We have attempted to identify factors associated with T cell reconstitution in response to highly active antiretroviral therapy.

Methods: In a prospective, multicenter cohort study, we compared clinical, immune, and viral responses to an initial antiretroviral regimen in older (>or=45 years old) versus younger (18-30 years old) human immunodeficiency virus type 1-infected subjects. Multivariable linear-regression models identified independent factors associated with changes in T cell counts.

Peripheral S-phase T cells in HIV disease have a central memory phenotype and rarely have evidence of recent T cell receptor engagement.

Heightened proliferation and death of T lymphocytes may play a key role in human immunodeficiency virus (HIV) pathogenesis; however, the mechanism that mediates this effect and the phenotype of the proliferating T cells have not been clearly determined. We assessed S-phase cell frequencies and phenotype by ex vivo bromodeoxyuridine incorporation and flow-cytometric analysis in a group of 35 HIV-infected individuals. Frequencies of S-phase T cells were increased in HIV disease and were related to plasma HIV RNA levels but not to CD4 cell, total T cell, or total lymphocyte counts.

Capacity building for the clinical investigation of AIDS malignancy in East Africa.

Purpose: To build capacity in the resource-poor setting to support the clinical investigation and treatment of AIDS-related malignancies in a region of the world hardest hit by the AIDS pandemic.

Methods: An initial MEDLINE database search for international collaborative partnerships dedicated to AIDS malignancies in developing countries failed to identify any leads. This search prompted us to report progress on our collaboration in this aspect of the epidemic.

Monitoring processed, mature Human Immunodeficiency Virus type 1 particles immediately following treatment with a protease inhibitor-containing treatment regimen.

Protease inhibitors (PIs) block HIV-1 maturation into an infectious virus particle by inhibiting the protease processing of gag and gag-pol precursor proteins. We have used a simple anti-HIV-1 p24 Western blot to monitor the processing of p55gag precursor into the mature p24 capsid immediately following the first dosage of a PI-containing treatment regimen. Evidence of PI activity was observed in plasma virus as early as 72 hours post treatment-initiation and was predictive of plasma viral RNA decrease at 4 weeks.

Impaired monocyte maturation in response to CpG oligodeoxynucleotide is related to viral RNA levels in human immunodeficiency virus disease and is at least partially mediated by deficiencies in alpha/beta interferon responsiveness and production.

The biological activity of CpG oligodeoxynucleotide 2216 (ODN2216), a Toll-like receptor 9 agonist, was investigated with monocytes from human immunodeficiency virus (HIV)-negative and HIV-positive (HIV+) donors. Exposure of peripheral blood mononuclear cells to CpG ODN2216 led to decreased expression of the monocyte marker CD14 and increased expression of the dendritic cell marker CD83, as well as increased expression of HLA-DR, CD40, CD80, and CD86 among the monocytes. Several features of the CpG ODN-induced maturation were diminished in monocytes from HIV+ donors, and these deficiencies were related to increased viremia but not to CD4 cell counts.

Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects.

Human immunodeficiency virus (HIV)-infected South African patients (n=468) received blinded lamivudine or emtricitabine, stavudine, and either nevirapine or efavirenz (based on screening viral load). Baseline characteristics were analyzed in univariate and multivariate regression, to identify risk factors for hepatotoxicity (grade 3 or greater increase in serum aminotransferase levels). The occurrence of early hepatotoxicity was 17% in the nevirapine group and 0% in the efavirenz group and was balanced between the lamivudine and emtricitabine arms.

Association of DC-SIGN promoter polymorphism with increased risk for parenteral, but not mucosal, acquisition of human immunodeficiency virus type 1 infection.

There is considerable debate about the fundamental mechanisms that underlie and restrict acquisition of human immunodeficiency virus type 1 (HIV-1) infection. In light of recent studies demonstrating the ability of C type lectins to facilitate infection with HIV-1, we explored the potential relationship between polymorphisms in the DC-SIGN promoter and risk for acquisition of HIV-1 according to route of infection. Using samples obtained from 1,611 European-American participants at risk for parenteral (n = 713) or mucosal (n = 898) infection, we identified single-nucleotide polymorphisms in the DC-SIGN promoter using single-strand conformation polymorphism.

Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5.

Topical agents, such as microbicides, that can protect against human immunodeficiency virus (HIV) transmission are urgently needed. Using a chimeric simian/human immunodeficiency virus (SHIV SF162), which is tropic for the chemokine receptor CCR5, we report that topical application of high doses of PSC-RANTES, an amino terminus-modified analog of the chemokine RANTES, provided potent protection against vaginal challenge in rhesus macaques. These experimental findings have potentially important implications for understanding vaginal transmission of HIV and the design of strategies for its prevention.

Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection.

AMD3100 is a CXCR4 receptor inhibitor with anti-HIV-1 activity in vitro. We tested the safety, pharmacokinetics, and antiviral effect of AMD3100 administered for 10 days by continuous intravenous infusion in an open-label dose escalation study from 2.5 to 160 microg/kg/h.

Long-term changes in circulating CD4 T lymphocytes in virologically suppressed patients after 6 years of highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) initiated in advanced HIV disease is associated with CD4 lymphocyte increases (200-300 cells/mm3 after 2-4 years), although longer-term cellular dynamics have not been studied. We observed a significant median CD4 lymphocyte increase of 126 cells/mm3 and 54 naive CD4 lymphocytes from year 3 to 6 of HAART among 20 individuals with pre-HAART CD4 cell counts of 100-300 cells/mm3. This cohort represents the longest prospective immunological follow-up of virologically suppressed patients on HAART.

Increased expression of the natural killer cell inhibitory receptor CD85j/ILT2 on antigen-specific effector CD8 T cells and its impact on CD8 T-cell function.

We investigated whether inhibitory natural killer cell receptor (iNKR) expression contributes to impaired antigen-specific cytotoxicity and interferon-gamma (IFN-gamma) production by CD8 T cells during chronic infection. iNKR immunoglobulin-like transcript-2 (ILT2/CD85j) is expressed on 40-55% of cytomegalovirus (CMV)-, Epstein-Barr virus (EBV)- and human immunodeficiency virus (HIV)-specific CD8 T cells in both healthy and HIV-infected donors. Other iNKRs (CD158a, b1, e1/e2, k, CD94/NKG2A) are expressed on only a small minority of CD8 T cells and are not preferentially expressed on tetramer-staining virus-specific cells.

Daily low-dose subcutaneous interleukin-2 added to single- or dual-nucleoside therapy in HIV infection does not protect against CD4+ T-cell decline or improve other indices of immune function: results of a randomized controlled clinical trial (ACTG 248).

Context: Approaches to preserve or enhance immune function in HIV-1 infection are needed.

Objectives: To examine the ability of daily low-dose interleukin-2 (IL-2) in combination with antiretroviral therapy to preserve circulating CD4+ T-cell counts, the clinical safety and tolerability of this treatment, and safety with respect to changes in plasma HIV-1 RNA levels.

Design: Twenty-four-week, phase 2, multicenter, randomized, open-label trial conducted at 12 AIDS Clinical Trials Units between September 1995 and May 1997.

Proliferation responses to HIVp24 during antiretroviral therapy do not reflect improved immune phenotype or function.

Objective: To ascertain whether lymphoproliferation (LP) responses to HIVp24 in chronically infected patients treated with antiretroviral therapy (ART) predict an improved cytolytic T-cell phenotype or better in vivo immune function as measured by immunization responses.

Methods: HIV-infected patients who started ART during chronic infection and who achieved viral suppression (HIV-RNA < 400 copies/ml for > 12 months) were grouped by the presence of strong [stimulation index (SI) > 10; n = 21] or absent (SI < 3; n = 18) LP to HIV-core antigen. The two groups were compared for functional immune responses to vaccination with diphtheria-toxoid, tetanus-toxoid and keyhole-limpet-hemocyanin, frequency of circulating naive and memory CD4+ and CD8+ T lymphocytes, maturation phenotype and expression of cytolytic molecules on total and HIV-specific CD8+ T cells, and frequency of memory CD4+ T cells with intracellular HIV-mRNA.