Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 90
Filter
1.
Biophys J ; 99(10): 3445-53, 2010 Nov 17.
Article in English | MEDLINE | ID: mdl-21081094

ABSTRACT

A new (to our knowledge) de novo design framework with a ranking metric based on approximate binding affinity calculations is introduced and applied to the discovery of what we believe are novel HIV-1 entry inhibitors. The framework consists of two stages: a sequence selection stage and a validation stage. The sequence selection stage produces a rank-ordered list of amino-acid sequences by solving an integer programming sequence selection model. The validation stage consists of fold specificity and approximate binding affinity calculations. The designed peptidic inhibitors are 12-amino-acids-long and target the hydrophobic core of gp41. A number of the best-predicted sequences were synthesized and their inhibition of HIV-1 was tested in cell culture. All peptides examined showed inhibitory activity when compared with no drug present, and the novel peptide sequences outperformed the native template sequence used for the design. The best sequence showed micromolar inhibition, which is a 3-15-fold improvement over the native sequence, depending on the donor. In addition, the best sequence equally inhibited wild-type and Enfuvirtide-resistant virus strains.


Subject(s)
Drug Discovery , HIV Fusion Inhibitors/pharmacology , HIV-1/drug effects , Protein Engineering/methods , Virus Internalization/drug effects , Amino Acid Sequence , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/virology , Crystallography, X-Ray , Enfuvirtide , HEK293 Cells , HIV Envelope Protein gp41/chemistry , HIV Envelope Protein gp41/pharmacology , HIV Fusion Inhibitors/chemistry , HIV-1/isolation & purification , Humans , Hydrophobic and Hydrophilic Interactions/drug effects , Inhibitory Concentration 50 , Models, Molecular , Molecular Sequence Data , Mutant Proteins/metabolism , Peptide Fragments/pharmacology , Peptides/chemistry
2.
Proc Natl Acad Sci U S A ; 106(23): 9403-8, 2009 Jun 09.
Article in English | MEDLINE | ID: mdl-19470482

ABSTRACT

In HIV-1-infected individuals on currently recommended antiretroviral therapy (ART), viremia is reduced to <50 copies of HIV-1 RNA per milliliter, but low-level residual viremia appears to persist over the lifetimes of most infected individuals. There is controversy over whether the residual viremia results from ongoing cycles of viral replication. To address this question, we conducted 2 prospective studies to assess the effect of ART intensification with an additional potent drug on residual viremia in 9 HIV-1-infected individuals on successful ART. By using an HIV-1 RNA assay with single-copy sensitivity, we found that levels of viremia were not reduced by ART intensification with any of 3 different antiretroviral drugs (efavirenz, lopinavir/ritonavir, or atazanavir/ritonavir). The lack of response was not associated with the presence of drug-resistant virus or suboptimal drug concentrations. Our results suggest that residual viremia is not the product of ongoing, complete cycles of viral replication, but rather of virus output from stable reservoirs of infection.


Subject(s)
Antiretroviral Therapy, Highly Active , HIV Infections/drug therapy , HIV-1/physiology , Viremia/drug therapy , Adult , Anti-HIV Agents , HIV Infections/virology , Humans , Prospective Studies , Virus Replication
3.
JAMA ; 286(2): 196-207, 2001 Jul 11.
Article in English | MEDLINE | ID: mdl-11448283

ABSTRACT

CONTEXT: The continued release of human immunodeficiency virus type 1 (HIV-1) into plasma at very low levels during highly active antiretroviral therapy (HAART) can be detected using specialized techniques, but the nature and significance of this low-level viremia, especially as related to acquisition of drug resistance mutations, are unclear. OBJECTIVE: To determine genetic resistance profiles of low-level plasma HIV-1 in patients with prolonged viral suppression (<50 copies/mL of plasma HIV-1 RNA) while receiving HAART. DESIGN AND SETTING: Cross-sectional study conducted at a US academic hospital from November 1999 to February 2001 using a novel method for amplification of low levels of viral genomes in plasma. PATIENTS: Eighteen HIV-1-infected patients (7 children and 11 adults), enrolled in a longitudinal study of HIV-1 reservoirs, who had suppression of viral replication while receiving protease inhibitor-containing combination therapy. Two patients (1 adult and 1 child) with less optimal suppression of viral replication were included to assess virus predominating when plasma HIV-1 RNA levels are low but detectable (<1000 copies/mL). Follow-up analyses were conducted in 3 patients. MAIN OUTCOME MEASURE: Detection of drug resistance mutations in clones amplified from low-level plasma virus. RESULTS: Viral sequences were amplified from 8 of the 18 patients with simultaneous plasma HIV-1 measurements of less than 50 copies/mL and from 2 patients with 231 and 50 copies/mL. Clones from 3 treatment-naive patients with less than 50 copies/mL of plasma HIV-1 RNA showed continued release, for as long as 42 months, of wild-type drug-sensitive virus. The 7 patients with prior nonsuppressive therapy, with viral loads below 50 copies/mL and during "blips" to 231 and 64 copies/mL, had only resistance mutations consistent with pre-HAART therapy (although reverse transcriptase inhibitor mutations may have continued to occur). New HAART-related mutations were seen in a control patient with prior viral load levels of about 400 to 1000 copies/mL. For phylogenetic analysis, sequences were available for both resting CD4(+) T cells and plasma HIV for 7 of 10 patients and showed patient-specific clustering of sequences and a close relationship between virus in the plasma and the latent reservoir. CONCLUSIONS: Based on the samples that could be amplified, low-level viremia in children and adults receiving HAART with prolonged suppression of viremia to less than 50 copies/mL of HIV-1 RNA may result primarily from archival, pre-HAART virus, reflecting earlier treatment conditions, and does not appear to require development of new, HAART-selected mutations reflecting partial resistance to therapy. Low-level viremia below 50 copies/mL may represent less of a concern regarding impending drug failure of current HAART regimens. However, the archival drug-resistant virus may be relevant regarding future treatment strategies.


Subject(s)
Anti-HIV Agents/pharmacology , Drug Resistance, Microbial/genetics , HIV Infections/drug therapy , HIV-1/drug effects , HIV-1/genetics , Viremia/physiopathology , Adult , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Child , Child, Preschool , Cross-Sectional Studies , Female , Gene Products, pol/genetics , HIV Infections/physiopathology , HIV Infections/virology , HIV Protease/genetics , HIV Reverse Transcriptase/genetics , Humans , Male , Middle Aged , Molecular Sequence Data , Mutation , RNA, Viral/blood , Viral Load , Viremia/diagnosis
5.
J Infect Dis ; 183(4): 657-61, 2001 Feb 15.
Article in English | MEDLINE | ID: mdl-11170994

ABSTRACT

Cell-mediated immunity is affected early in human immunodeficiency virus type 1 (HIV-1) infection. HIV-1-specific CD4+ T cell proliferative responses are not measurable in most patients but have been reported in long-term nonprogressors and in patients treated with highly active antiretroviral therapy (HAART) during primary infection. However, treatment with HAART generally does not restore HIV-1-specific CD4+ T cell responses in chronically infected patients. In this study, HIV-1-specific CD4+ T cell responses in 10 HIV-1-infected patients who began HAART with low CD4 cell count nadirs and experienced significant immune reconstitution were studied. Surprisingly, 5 of these patients had proliferative responses to > or =1 HIV-1 gene product, compared with 0 of 8 chronically infected patients who started HAART when their CD4 cell counts were still relatively high. These results suggest that, in some patients with advanced HIV-1 infection, treatment with HAART can lead not only to significant increases in CD4 cell counts but also to the restoration of HIV-1-specific responses.


Subject(s)
HIV Antigens/immunology , HIV Infections/immunology , HIV Infections/virology , HIV-1/immunology , Lymphocyte Activation/immunology , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , Candida albicans/immunology , HIV Infections/drug therapy , HIV Long-Term Survivors , Humans , Tetanus Toxoid/immunology
6.
J Virol ; 75(1): 181-91, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11119587

ABSTRACT

Several retroviruses have recently been shown to promote translation of their gag gene products by internal ribosome entry. In this report, we show that mRNAs containing the human immunodeficiency virus type 1 (HIV-1) gag open reading frame (ORF) exhibit internal ribosome entry site (IRES) activity that can promote translational initiation of Pr55(gag). Remarkably, this IRES activity is driven by sequences within the gag ORF itself and is not dependent on the native gag 5'-untranslated region (UTR). This cap-independent mechanism for Pr55(gag) translation may help explain the high levels of translation of this protein in the face of major RNA structural barriers to scanning ribosomes found in the gag 5' UTR. The gag IRES activity described here also drives translation of a novel 40-kDa Gag isoform through translational initiation at an internal AUG codon found near the amino terminus of the Pr55(gag) capsid domain. Our findings suggest that this low-abundance Gag isoform may be important for wild-type replication of HIV-1 in cultured cells. The activities of the HIV-1 gag IRES may be an important feature of the HIV-1 life cycle and could serve as a novel target for antiretroviral therapeutic strategies.


Subject(s)
Genes, gag , HIV-1/genetics , Ribosomes/physiology , 5' Untranslated Regions , Animals , Blotting, Northern , COS Cells , Open Reading Frames , Protein Biosynthesis , Virus Replication
8.
Virology ; 278(1): 227-33, 2000 Dec 05.
Article in English | MEDLINE | ID: mdl-11112497

ABSTRACT

The introduction of highly active antiretroviral therapy (HAART) for the treatment of HIV-1 infection has allowed dramatic reductions in plasma virus levels to below the limit of detection in many patients. However, latently infected CD4(+) memory T lymphocytes persist as an important reservoir for the virus in the presence of this aggressive therapy and represent a major barrier to HIV-1 eradication with HAART. The mechanism through which the latent compartment is formed has not yet been established. It may involve actively proliferating CD4(+) T-cell intermediates that are infected with HIV-1 and revert back to a resting state, carrying integrated provirus at some low frequency. The HIV-1 accessory protein Vpr, which mediates G(2) cell cycle arrest in host cells, may interfere with the formation of the latently infected T cells by preventing them from exiting the cell cycle to return to a resting state. To investigate the role of the Vpr in the formation of latently infected memory T cells, we cloned and characterized vpr genes from viruses in the latent reservoir. Both sequence analysis and functional assays demonstrated that the vpr gene products of the viruses isolated from the latent pool did not differ significantly from those of a functional Vpr (NL4-3). These results indicate that the generation of resting G(0) memory T lymphocytes that carry latent HIV-1 provirus occurs despite the G(2) arrest function of the vpr gene product.


Subject(s)
CD4-Positive T-Lymphocytes/virology , Gene Products, vpr/physiology , HIV-1/physiology , Virus Latency , Amino Acid Sequence , CD4-Positive T-Lymphocytes/cytology , Cell Cycle , Cell Line , Cloning, Molecular , Gene Products, vpr/genetics , Genes, Viral , HIV-1/chemistry , HIV-1/genetics , Humans , Molecular Sequence Data , Sequence Alignment , Virus Replication , vpr Gene Products, Human Immunodeficiency Virus
9.
J Infect Dis ; 182(6): 1636-42, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11069234

ABSTRACT

Latent infection of resting CD4(+) T cells represents a major barrier to eradication of human immunodeficiency virus type 1 (HIV-1). The establishment and rate of decay of latent HIV-1 in resting CD(+) T cells from 9 acute seroconverters, 7 of whom began to receive highly active antiretroviral therapy (HAART) shortly after presentation, were studied. Before the initiation of therapy, these patients had very high frequencies of latently infected CD4(+) T cells, with a median frequency of 205 infectious units per million resting CD4(+) T cells. These values are > or =1 log higher than those seen in chronically infected patients who are not undergoing HAART. The number of latently infected cells declined dramatically after initiation of HAART but then tended to level off at a low but stable level. The biphasic decay of latent HIV in resting CD4(+) T cells in acute seroconverters supports current models of pre- and postintegration latency.


Subject(s)
CD4-Positive T-Lymphocytes/virology , HIV Infections/immunology , HIV-1 , Acute Disease , Adult , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , CD4-Positive T-Lymphocytes/immunology , Cells, Cultured , HIV Infections/drug therapy , HIV Seropositivity/immunology , HIV-1/physiology , Humans , Lymphocyte Count , Male , Middle Aged , Time Factors , Virus Latency
10.
J Virol ; 74(24): 11811-24, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11090181

ABSTRACT

Active nuclear import of the human immunodeficiency virus type 1 (HIV-1) preintegration complex (PIC) is essential for the productive infection of nondividing cells. Nuclear import of the PIC is mediated by the HIV-1 matrix protein, which also plays several critical roles during viral entry and possibly during virion production facilitating the export of Pr55(Gag) and genomic RNA. Using a yeast two-hybrid screen, we identified a novel human virion-associated matrix-interacting protein (VAN) that is highly conserved in vertebrates and expressed in most human tissues. Its expression is upregulated upon activation of CD4(+) T cells. VAN is efficiently incorporated into HIV-1 virions and, like matrix, shuttles between the nucleus and cytoplasm. Furthermore, overexpression of VAN significantly inhibits HIV-1 replication in tissue culture. We propose that VAN regulates matrix nuclear localization and, by extension, both nuclear import of the PIC and export of Pr55(Gag) and viral genomic RNA during virion production. Our data suggest that this regulatory mechanism reflects a more global process for regulation of nucleocytoplasmic transport.


Subject(s)
Acquired Immunodeficiency Syndrome/virology , Gene Products, gag/physiology , HIV Antigens/physiology , HIV-1/physiology , Nuclear Proteins/physiology , Viral Proteins , Virion/physiology , Virus Replication , Amino Acid Sequence , Biological Transport , Humans , Molecular Sequence Data , Sequence Alignment , gag Gene Products, Human Immunodeficiency Virus
12.
Proc Natl Acad Sci U S A ; 97(20): 10948-53, 2000 Sep 26.
Article in English | MEDLINE | ID: mdl-11005867

ABSTRACT

HIV type 1 (HIV-1) drug resistance mutations were selected during antiretroviral therapy successfully suppressing plasma HIV-1 RNA to <50 copies/ml. New resistant mutant subpopulations were identified by clonal sequencing analyses of viruses cultured from blood cells. Drug susceptibility tests showed that biological clones of virus with the mutations acquired during successful therapy had increased resistance. Each of the five subjects with new resistant mutants had evidence of some residual virus replication during highly active antiretroviral therapy (HAART), based on transient episodes of plasma HIV-1 RNA > 50 copies/ml and virus env gene sequence changes. Each had received a suboptimal regimen before starting HAART. Antiretroviral-resistant HIV-1 can be selected from residual virus replication during HAART in the absence of sustained rebound of plasma HIV-1 RNA.


Subject(s)
Anti-HIV Agents/pharmacology , Drug Resistance, Microbial/genetics , HIV Infections/drug therapy , HIV Infections/virology , HIV-1/genetics , Mutation , Anti-HIV Agents/therapeutic use , HIV-1/drug effects , Humans , Molecular Sequence Data
13.
J Virol ; 74(17): 7824-33, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10933689

ABSTRACT

Latently infected resting CD4(+) T cells provide a long-term reservoir for human immunodeficiency virus type 1 (HIV-1) and are likely to represent the major barrier to virus eradication in patients on combination antiretroviral therapy. The mechanisms by which viruses enter the latent reservoir and the nature of the chemokine receptors involved have not been determined. To evaluate the phenotype of the virus in this compartment with respect to chemokine receptor utilization, full-length HIV-1 env genes were cloned from latently infected cells and assayed functionally. We demonstrate that the majority of the viruses in the latent reservoir utilize CCR5 during entry, although utilization of several other receptors, including CXCR4, was observed. No alternative coreceptors were shown to be involved in a systematic fashion. Although R5 viruses are present in the latent reservoir, CCR5 was not expressed at high levels on resting CD4(+) T cells. To understand the mechanism by which R5 viruses enter latent reservoir, the ability of an R5 virus, HIV-1 Ba-L, to infect highly purified resting CD4(+) T lymphocytes from uninfected donors was evaluated. Entry of Ba-L could be observed when virus was applied at a multiplicity approaching 1. However, infection was limited to a subset of cells expressing low levels of CCR5 and markers of immunologic memory. Naive cells could not be infected by an R5 virus even when challenged with a large inoculum. Direct cell fractionation studies showed that latent virus is present predominantly in resting memory cells but also at lower levels in resting naive cells. Taken together, these findings provide support for the hypothesis that the direct infection of naive T cells is not the major mechanism by which the latent infection of resting T cells is established.


Subject(s)
HIV Infections/virology , HIV-1/pathogenicity , Receptors, CCR5/physiology , Receptors, CXCR4/physiology , Virus Latency , CD4-Positive T-Lymphocytes/virology , Gene Products, env/genetics , Gene Products, env/metabolism , HIV-1/physiology , Humans , RNA, Viral/analysis , Receptors, CCR5/metabolism , Receptors, CXCR4/metabolism
16.
Annu Rev Immunol ; 18: 665-708, 2000.
Article in English | MEDLINE | ID: mdl-10837072

ABSTRACT

The success of combination antiretroviral therapy for HIV-1 infection has generated interest in mechanisms by which the virus can persist in the body despite the presence of drugs that effectively inhibit key steps in the virus life cycle. It is becoming clear that viral reservoirs established early in the infection not only prevent sterilizing immunity but also represent a major obstacle to curing the infection with the potent antiretroviral drugs currently in use. Mechanisms of viral persistence are best considered in the context of the dynamics of viral replication in vivo. Virus production in infected individuals is largely the result of a dynamic process involving continuous rounds of de novo infection of and replication in activated CD4(+) T cells with rapid turnover of both free virus and virus-producing cells. This process is largely, but not completely, interrupted by effective antiretroviral therapy. After a few months of therapy, plasma virus levels become undetectable in many patients. Analysis of viral decay rates initially suggested that eradication of the infection might be possible. However, there are several potential cellular and anatomical reservoirs for HIV-1 that may contribute to long-term persistence of HIV-1. These include infected cell in the central nervous system and the male urogenital tract. However, the most worrisome reservoir consists of latently infected resting memory CD4(+) T cells carrying integrated HIV-1 DNA. Definitive demonstration of the presence of this form of latency required development of methods for isolating extremely pure populations of resting CD4(+) T cells and for demonstrating that a small fraction of these cells contain integrated HIV-1 DNA that is competent for replication if the cells undergo antigen-driven activation. Most of the latent virus in resting CD4(+) T cells is found in cells of the memory phenotype. The half-life of this latent reservoir is extremely long (44 months). At this rate, eradication of this reservoir would require over 60 years of treatment. Thus, latently infected resting CD4(+) T cells provide a mechanism for life-long persistence of replication-competent forms of HIV-1, rendering unrealistic hopes of virus eradication with current antiretroviral regimens. The extraordinary stability of the reservoir may reflect gradual reseeding by a very low level of ongoing viral replication and/or mechanisms that contribute to the intrinsic stability of the memory T cell compartment. Given the substantial long-term toxicities of current combination therapy regimens, novel approaches to eradicating this latent reservoir are urgently needed.


Subject(s)
HIV Infections/drug therapy , HIV Infections/virology , HIV-1/physiology , Virus Latency , Animals , Anti-HIV Agents/therapeutic use , Antiviral Agents/therapeutic use , CD4-Positive T-Lymphocytes/immunology , Central Nervous System/virology , Drug Therapy, Combination , HIV Infections/immunology , HIV-1/immunology , Humans , Male , Virus Replication
17.
AIDS Read ; 10(4): 224-9, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10808605

ABSTRACT

A pool of latently infected CD4+ T cells is established within the first few weeks of HIV infection. Because these memory T cells are inactive, the viral DNA integrated into their chromosomes remains invisible to immune surveillance and to antiretrovirals. Research shows that this reservoir of infected memory T cells does not decay in a clinically meaningful time frame--that is, within 60 years--in patients being treated with potent combination antiretrovirals. Even a hypothetical regimen that prevents any new infection of cells would not hasten the decay of this latent reservoir. Treatments that activate this reservoir have been studied in patients with suppressed viremia, but such interventions are highly toxic and have not succeeded so far. Studying rare individuals who manage to control activation of these latent cells may provide important clues to long-term control of HIV infection.


Subject(s)
Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , HIV-1/physiology , Drug Therapy, Combination , HIV Infections/immunology , HIV Infections/virology , Humans , Virus Latency
18.
J Clin Invest ; 105(7): 995-1003, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10749578

ABSTRACT

HIV-1 persists in a latent state in resting CD4(+) T lymphocytes of infected adults despite prolonged highly active antiretroviral therapy (HAART). To determine whether a latent reservoir for HIV-1 exists in infected children, we performed a quantitative viral culture assay on highly purified resting CD4(+) T cells from 21 children with perinatally acquired infection. Replication-competent HIV-1 was recovered from all 18 children from whom sufficient cells were obtained. The frequency of latently infected resting CD4(+) T cells directly correlated with plasma virus levels, suggesting that in children with ongoing viral replication, most latently infected cells are in the labile preintegration state of latency. However, in each of 7 children who had suppression of viral replication to undetectable levels for 1-3 years on HAART, latent replication-competent HIV-1 persisted with little decay, owing to a stable reservoir of infected cells in the postintegration stage of latency. Drug-resistance mutations generated by previous nonsuppressive regimens persisted in this compartment despite more than 1 year of fully suppressive HAART, rendering untenable the idea of recycling drugs that were part of failed regimens. Thus the latent reservoir for HIV-1 in resting CD4(+) T cells will be a major obstacle to HIV-1 eradication in children.


Subject(s)
CD4-Positive T-Lymphocytes/virology , HIV Infections/immunology , HIV-1/immunology , Virus Latency , Adolescent , Anti-HIV Agents/therapeutic use , Base Sequence , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , Child , Child, Preschool , DNA, Viral , Drug Resistance, Microbial , Drug Therapy, Combination , Genes, pol , HIV Infections/drug therapy , HIV Infections/virology , HIV-1/drug effects , HIV-1/genetics , HIV-1/isolation & purification , Humans , Infant , Molecular Sequence Data , Mutagenesis , RNA, Viral/blood , Reverse Transcriptase Inhibitors/therapeutic use , Virus Replication/immunology , Zidovudine/therapeutic use
19.
Science ; 290(5491): 463-5, 2000 Oct 20.
Article in English | MEDLINE | ID: mdl-11183769

ABSTRACT

Although there has been some success in treating human immunodeficiency virus (HIV) patients with triple drug therapy (highly active antiretroviral therapy or HAART), the best hope for combating AIDS (the disease caused by HIV) could be a combination of drug therapy and vaccination, according to Shen and Siliciano in their Perspective. A new study in rhesus monkeys treated with a DNA vaccine (Barouch et al.) demonstrates that a powerful vaccine-induced CD8(+) cytolytic T cell response reduces the amount of virus in the blood to very low levels preventing the drastic decrease in CD4(+) T helper cells and subsequent immunodeficiency. As the Perspective authors explain, vaccinating HIV patients that are receiving HAART may enable HIV levels to be permanently brought under control such that the drug treatment can eventually be stopped.


Subject(s)
AIDS Vaccines/therapeutic use , Acquired Immunodeficiency Syndrome/prevention & control , HIV Infections/therapy , HIV-1 , Vaccines, DNA/therapeutic use , Animals , Antibodies, Viral/immunology , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , Disease Progression , HIV Antibodies/immunology , HIV Infections/immunology , HIV Infections/virology , HIV-1/genetics , HIV-1/immunology , HIV-1/physiology , Humans , Interleukin-2/genetics , Interleukin-2/immunology , Interleukin-2/therapeutic use , Macaca mulatta , Neutralization Tests , SAIDS Vaccines/therapeutic use , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/therapy , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/genetics , Simian Immunodeficiency Virus/immunology , Simian Immunodeficiency Virus/physiology , T-Lymphocytes, Cytotoxic/immunology , Vaccination , Viral Load , Viremia , Virus Replication
20.
J Infect Dis ; 180(6): 1827-32, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10558937

ABSTRACT

Current treatments for human immunodeficiency virus (HIV) require uninterrupted drug administration because they are unable to reconstitute the immune response and do not affect the viral reservoir. Ten patients were treated during acute HIV infection before complete Western blot (WB) seroconversion with the combination of hydroxyurea, didanosine, and indinavir. This treatment was associated with the normalization of some immune parameters and functions. No loss of naive CD4 T lymphocytes was observed, and recovery of up to 35% of naive CD8 T lymphocytes occurred in several weeks. A vigorous HIV-specific T helper response (stimulation index >8) was observed in 7 of 8 patients treated before complete WB seroconversion but in only 1 of 5 controls treated after seroconversion. In addition, a limited latent viral reservoir (<0.02-0.5 infectious units/106 cells) was documented in quiescent peripheral blood lymphocytes after treatment initiated before complete WB seroconversion.


Subject(s)
Anti-HIV Agents/therapeutic use , Didanosine/therapeutic use , HIV Antibodies/blood , HIV Infections/drug therapy , Hydroxyurea/therapeutic use , Indinavir/therapeutic use , Blotting, Western , CD4 Lymphocyte Count , CD4-CD8 Ratio , CD8-Positive T-Lymphocytes/immunology , Drug Therapy, Combination , Flow Cytometry , HIV Infections/immunology , HIV Infections/virology , HIV Protease Inhibitors/therapeutic use , Humans , Lymphocyte Activation , Viral Load
SELECTION OF CITATIONS
SEARCH DETAIL
...