Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A multicenter, double-blind, placebo-controlled trial randomized 28 patients with primary (acute) human immunodeficiency virus (HIV)-1 infection (PHI) to receive zidovudine, 1000 mg daily, or placebo for 24 weeks. At week 48, compared with placebo patients, zidovudine-treated patients had significantly higher CD4 cell counts (zidovudine, 666 cells/mm3; placebo, 362; P = .004) and lower peripheral blood mononuclear cell (PBMC) culture titers (zidovudine, 0.58 log infectious units per million cells; placebo, 1.68; P = .02) but no difference in plasma RNA (zidovudine, 3.93 log copies/mL; placebo, 4.00; P = .83). Serious adverse events and minor clinical events were infrequent and comparable in both arms. There were two deaths: 1 patient died of sepsis and renal disease (zidovudine arm), and 1 patient died of sepsis and tension pneumothorax (placebo arm). Six months of high-dose zidovudine initiated during PHI results in higher CD4 cell counts and lower PBMC culture titers but no difference in plasma HIV-1 RNA. Further studies with more potent antiretroviral combination therapies are warranted.
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PMID:Zidovudine treatment in patients with primary (acute) human immunodeficiency virus type 1 infection: a randomized, double-blind, placebo-controlled trial. DATRI 002 Study Group. Division of AIDS Treatment Research Initiative. 965 26

Antiretroviral therapy commenced during primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) may limit the extent of viral replication and prevent early loss of HIV-specific CD4 lymphocyte function. We studied the effect of current standard therapy (2 nucleoside analogues and a protease inhibitor) in 16 patients with symptomatic PHI. In the 13 patients who completed 1 year of treatment, plasma HIV RNA was <50 copies/mL and median CD4 cell counts were comparable to HIV-uninfected controls, with naive (CD45RA+CD62L+), primed (CD45RO+), and T cell receptor Vbeta subsets all within normal ranges. However, HIV-1 DNA levels in treated and untreated PHI patients were similar. Furthermore, CD8 cell counts remained elevated, including activated (CD38+HLA-DR+), replicating (Ki-67+), and cytotoxic (perforin+CD28-) lymphocytes. In conclusion, early antiretroviral therapy resulted in clearance of viremia and prevented loss of crucial CD4 subsets. The persistence of HIV-1 DNA together with increased CD8 T lymphocyte turnover and activation indicate continued expression of viral antigens.
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PMID:Potent antiretroviral therapy of primary human immunodeficiency virus type 1 (HIV-1) infection: partial normalization of T lymphocyte subsets and limited reduction of HIV-1 DNA despite clearance of plasma viremia. 1076 89

We measured apoptosis of subsets of T lymphocytes by single-cell analysis of caspase activation, to confirm high turnover of chemokine receptor CCR5(+) T cells in subjects with acute, primary human immunodeficiency virus type 1 (HIV-1) infection (PHI). High levels of spontaneous apoptosis, consisting mainly of CD8(+) T lymphocytes, were closely associated with increases in the activation markers Ki-67, CD38, and the HIV coreceptor CCR5 and with decreases in Bcl-2 and the interleukin (IL)-7 receptor at the single-cell level. Increased expression of Ki-67 and CCR5 ex vivo, as well as increased apoptosis, was seen in all T cell receptor beta-chain variable region (TCRBV) subfamilies studied. The addition of IL-2 or IL-15, but not IL-7, significantly inhibited caspase activation, increased Bcl-2 expression, and rapidly initiated proliferation in vitro of CD8(+) T cells expressing CCR5 and multiple TCRBV subfamilies. Furthermore, IL-15 receptor alpha-chain messenger RNA levels were increased in peripheral blood mononuclear cells during PHI. These results suggest that CCR5(+)Ki-67(+)Bcl-2(dim) activated T cells generated during PHI traffic via blood to tissue sites, where the cells may survive and/or further proliferate under the local influence of IL-2 or IL-15. Understanding cytokine effects on CCR5(+) T cells will be important in understanding chronic HIV-1 replication and pathogenesis.
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PMID:Polyclonal proliferation and apoptosis of CCR5+ T lymphocytes during primary human immunodeficiency virus type 1 infection: regulation by interleukin (IL)-2, IL-15, and Bcl-2. 1275 Oct 31

PHI-443 (N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea) is a rationally designed novel thiophene thiourea nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent anti-HIV activity against the wild-type and drug-resistant primary clinical human immunodeficiency virus (HIV-1) isolates. This study examined the potential utility of PHI-443 as a nonspermicidal microbicide for prevention of sexual transmission of HIV. Our goal in this study was to test the effects of PHI-443 on in vivo sperm functions under conditions shown to inactivate viruses in human cells. PHI-443 completely prevented the vaginal transmission of a genotypically and phenotypically drug-resistant HIV-1 isolate in the humanized severe combined immunodeficient (Hu-SCID) mouse model of sexually transmitted AIDS. Exposure of human sperm to PHI-443 at doses 30 000 times higher than those that yield effective concentrations against the AIDS virus had no adverse effect on sperm motility, kinematics, cervical mucus penetrability, or the viability of vaginal and cervical epithelial cells. Exposure of rabbit semen to PHI-443 either ex vivo or in vivo had no adverse impact on in vivo fertilizing ability in the rabbit model. Reproductive indices (i.e., pregnancy rate, embryo implantation, and preimplantation losses) were not affected by pretreatment of rabbit semen with PHI-443. Likewise, intravaginal application of 2% PHI-443 via a self-emulsifying gel at the time of artificial insemination resulted in healthy offspring with no apparent peri- or postnatal repercussions. Repeated intravaginal administration of 0.5%- 2% PHI-443 gel was found to be safe in rabbits and lacked systemic absorption. PHI-443 has clinical potential as a prophylactic broad-spectrum anti-HIV microbicide without contraceptive activity.
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PMID:PHI-443: a novel noncontraceptive broad-spectrum anti-human immunodeficiency virus microbicide. 1530 58

The meaning of viral blips in human immunodeficiency virus type 1 (HIV-1)-infected patients treated with seemingly effective highly active antiretroviral therapy (HAART) is still controversial and under investigation. Blips might represent low-level ongoing viral replication in the presence of drug or simply release of virions from the latent reservoir. Patients treated early during HIV-1 infection are more likely to have a lower total body viral burden, a homogenous viral population, and preserved HIV-1-specific immune responses. Consequently, viral blips may be less frequent in them than in patients treated during chronic infection. To test this hypothesis, we compared the occurrence of viral blips in 76 acutely infected patients (primary HIV infection [PHI] group) who started therapy within 6 months of the onset of symptoms with that in 47 patients who started HAART therapy during chronic infection (chronic HIV infection [CHI] group). Viral blip frequency was approximately twofold higher in CHI patients (0.122 +/- 0.12/viral load [VL] sample, mean +/- standard deviation) than in PHI patients (0.066 +/- 0.09/VL sample). However, in both groups, viral blip frequency did not increase with longer periods of observation. Also, no difference in viral blip frequency was observed between treatment subgroups, and the occurrence of a blip was not associated with a recent change in CD4(+) T-cell count. Finally, in PHI patients the VL set point was a significant predictor of blip frequency during treatment.
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PMID:Dynamics of intermittent viremia during highly active antiretroviral therapy in patients who initiate therapy during chronic versus acute and early human immunodeficiency virus type 1 infection. 1536 23

Treatment of primary human immunodeficiency virus (HIV) infection (PHI) may provide an opportunity to achieve a long lasting suppression of viral replication. Although there is growing evidence of the benefit of treating PHI, clinical data are still very limited. Special therapeutic considerations in this clinical setting include the prevalence of resistant viruses in the community, complexity of regimens and their long-term toxicity. In addition, adjunctive therapies aimed at exploring the role of immune modulation and intensification of antiretroviral therapy are becoming areas of great interest. In this regard, the role of hydroxyurea, a cytostatic agent that potentiates the antiviral effect of didanosine, and possibly of stavudine is being investigated. A pilot study to assess the antiviral effect of a combination of didanosine plus stavudine plus nevirapine with or without hydroxyurea in the treatment of PHI is currently under way. Preliminary results on 22 patients who completed at least 36 weeks of therapy suggest that the combination is safe, well tolerated and effective for the treatment of PHI.
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PMID:Treatment of primary HIV infection: a pilot study of stavudine and didanosine plus nevirapine with or without hydroxyurea. 1602 80

The increased risk of heterosexual transmission of human immunodeficiency virus-1 (HIV-1) has prompted the search for safe and effective female-controlled vaginal microbicides. Because endogenous reverse transcription is implicated in augmenting the sexual transmission of HIV-1, potential microbicides should have the inherent ability to optimally inhibit both wild-type and drug-resistant mutant strains of HIV-1. N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (PHI-236) is a rationally designed non-nucleoside inhibitor of HIV-1 reverse transcriptase (NNRTI) that was deduced from changes in binding pocket size, shape and residue character that result from clinically observed NNRTI resistance mutations. PHI-236 displayed high-binding affinity (Ludi K(i) = 0.07 microM) for HIV-1 RT and robust anti-HIV activity against the wild type (IC50 = <0.001 microM) as well as primary clinical isolates (IC50 = 0.009-0.04 microM) carrying multiple RT gene mutations associated with NRTI and NNRTI resistance. PHI-236 displayed high-selectivity index against human vaginal and cervical epithelial cells and did not affect human sperm functions. In the humanized severe combined immunodeficient mouse model for HIV/acquired immune deficiency syndrome (AIDS), pretreatment of HIV-1 (BaL)-infected human monocytes and semen with PHI-236 prevented the systemic infection via the vaginal route. PHI-236 has particular clinical utility as a non-spermicidal microbicide as well as a prophylactic antiviral agent to inactivate cell-free and cell-associated HIV-1 in semen before assisted reproductive technology procedures.
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PMID:Discovery of 2,5-dimethoxy-substituted 5-bromopyridyl thiourea (PHI-236) as a potent broad-spectrum anti-human immunodeficiency virus microbicide. 1625 3

The objective of this study was to develop a nontoxic and noncontraceptive vaginal drug delivery vehicle for lipophilic anti-human immunodeficiency virus (HIV) microbicides. Three representative poorly water-soluble novel broad-spectrum anti-HIV microbicides, PHI-113, PHI-346, and PHI-443, were evaluated in 11 different solvent systems. Based on their solubility profiles, a novel nonspermicidal self-emulsifying gel (viz Conceival) composed of pharmaceutical excipients, sorbitol, polyethylene glycol 400, polysorbate 80, microcrystalline cellulose, xanthan gum, and water was optimized. Conceival enhanced the solubility of these poorly water-soluble (<0.001 mg/mL) anti-HIV drugs by at least 150- to 270-fold. Conceival was evaluated in vivo in the New Zealand white rabbit model for the preservation of sperm function based on pregnancy outcome and the potential for vaginal irritation following single and multiple intravaginal applications, respectively. Conceival administered intravaginally immediately prior to artificial insemination with semen had no adverse effects on subsequent reproductive performance, neonatal survival, or pup development when compared with untreated control group. Histologic evaluation of vaginal tissues of rabbits exposed intravaginally to Conceival for 14 consecutive days revealed lack of epithelial, submucosal, and vascular changes at the gel application site (total irritation score <3 out of a possible 16). These findings indicate that Conceival has potential to become a clinically useful, safe noncontraceptive vaginal vehicle for lipophilic microbicides.
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PMID:Conceival, a novel noncontraceptive vaginal vehicle for lipophilic microbicides. 1635 64

Central to our understanding of human immunodeficiency virus-induced fusion is the high resolution structure of fragments of the gp41 fusion protein folded in a low energy core conformation. However, regions fundamental to fusion, like the fusion peptide (FP), have yet to be characterized in the context of the cognate protein regardless of its conformation. Based on conformation-specific monoclonal antibody recognition, we identified the polar region consecutive to the N36 fragment as a stabilizer of trimeric coiled-coil assembly, thereby enhancing inhibitory potency. This tertiary organization is retained in the context of the hydrophobic FP (N70 fragment). Our data indicate that the N70 fragment recapitulates the expected organization of this region in the viral fusion intermediate (N-terminal half of the pre-hairpin intermediate (N-PHI)), which happens to be the prime target for fusion inhibitors. Regarding the low energy conformation, we show for the first time core formation in the context of the FP (N70 core). The alpha-helical and coiled-coil stabilizing polar region confers substantial thermal stability to the core, whereas the hydrophobic FP does not add further stability. For the two key fusion conformations, N-PHI and N70 core, we find that the FP adopts a nonhelical structure and directs higher order assembly (assembly of coiled coils in N-PHI and assembly of bundles in the N70 core). This supra-molecular organization of coiled coils or folded cores is seen only in the context of the FP. This study is the first to characterize the FP region in the context of the folded core and provides a basic understanding of the role of the elusive FP for key gp41 fusion conformations.
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PMID:Characterization of the HIV N-terminal fusion peptide-containing region in context of key gp41 fusion conformations. 1675 Nov 88

Early anti-retroviral treatment (ART) in primary human immunodeficiency virus (HIV) infection (PHI) may have unique, restorative immunological and virological benefits which could enhance clinical outcomes. However, the sustainability of these HIV-specific immune responses and their impact on clinical outcome remains unclear. We present a 3-year longitudinal clinical and immunological follow-up of a single-arm, prospective study assessing the long-term impact of a short-course of ART (SCART) during PHI. Twenty-eight subjects with defined PHI received 3 months of SCART at HIV-1 seroconversion. HIV-specific interferon-gamma+ CD4+ T cell responses, CD4 cell counts and plasma viral loads were assessed prospectively. Clinical outcome was defined as the time taken from PHI to a fall in CD4 cell counts <350 cells/mul on two or more occasions. Of 28 patients, 25 (89%) had detectable HIV-specific CD4+ helper responses at baseline. Five of 11 (45%) patients had preserved HIV-specific CD4+ responses 3 years after stopping SCART. Neither the presence nor magnitude of HIV-1-specific T helper responses either at baseline or 3 years following SCART cessation predicted clinical outcome. Rebound viraemia associated with stopping SCART did not diminish HIV-1-specific CD4+ responses. Long-term (>3 years) preservation of virus-specific CD4+ cells occurred in 45% of patients receiving SCART in PHI. There was no correlation between either the presence or magnitude of these responses and clinical outcome.
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PMID:Human immunodeficiency virus (HIV)-specific T helper responses fail to predict CD4+ T cell decline following short-course treatment at primary HIV-1 infection. 1842 32


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