Gene/Protein Disease Symptom Drug Enzyme Compound
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The synthesis, chemistry, biochemistry, and anti-HIV activity of a series of 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)pyrimidines have been studied in an attempt to find useful anti-AIDS drugs. Synthesis is carried out via a 2,3-dideoxyribose intermediate which facilitates the preparation of analogues by removing the sugar 3'-hydroxyl group prior to, rather than after, condensation with a uracil or cytosine aglycon. The 2'-F-dd-uridine analogues 7a-d (with H, F, Cl, and CH3 substitution in the 5-position) as well as the 4-deoxy compound (12b) are nonprotective to ATH8 or CEM cells infected with HIV-1. In the corresponding cytidine series, the 5-chloro analogue (11) is inactive. However, 2'-fluoro-2',3'-dideoxyarabinosylcytosine, 10a, and its 5-fluoro analogue, 10b, are both active. While neither compounds is a potent as ddC or 5-F-ddC (2b), 10b gives complete protection against the cytopathic effects of HIV in both host cell lines. 2'-Fluoro substitution confers increased chemical and enzymatic stability on dideoxynucleosides. Even though dideoxy pyrimidine nucleosides are inherently more stable than the corresponding purine analogues toward acid-catalyzed cleavage of the glycosidic bond, 2'-fluoro substitution (10a) still increases stabilization relative to ddC (2b). No detectable deamination by partially purified cytidine deaminase is observed with the 2'-fluoro compounds 10a, 10b, or 11 under conditions which rapidly deaminate cytidine. A small amount of 2'-F-dd-ara-U (7a) is formed from 10a in monkey plasma after greater than 24 h of exposure. The octanol-water partition coefficients for the dideoxynucleosides in this study indicate their hydrophilic character, with log P values varying from -0.28 to -1.18.
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PMID:Chemistry and anti-HIV properties of 2'-fluoro-2',3'-dideoxyarabinofuranosylpyrimidines. 135 45

The effect of thymidine and deoxyadenosine on the antiviral and antibacterial effect of zidovudine was studied in human immunodeficiency virus type 1 (HIV-1) Escherichia coli and Salmonella typhimurium. In quantitative assays, 10 micrograms mL-1 thymidine was shown to increase the 50% inhibitory concentration (IC50) of zidovudine for HIV-1 by approximately 100-fold and to reduce zidovudine (1 microM)-induced protection of C8166 cells from 2.04 to 0.18 log syncytial-forming units. Thymidine also antagonized the antibacterial effect of zidovudine for two E. coli and three S. typhimurium species in a dose-dependent manner; 10 micrograms mL-1 of thymidine increased the minimum inhibitory concentration of zidovudine for E. coli strains by 10-40-fold and for S. typhimurium strains by three-fold. Deoxyadenosine reduced the minimum inhibitory concentration of zidovudine against all five bacterial strains but had no effect on the IC50 of zidovudine for HIV-1, nor did it significantly reverse the antagonism of the antibacterial and antiviral activity of thymidine. The induction of the SOS response in E. coli was reversed in a dose-dependent manner by thymidine while the presence of deoxyadenosine increased induction of the SOS response by zidovudine at suboptimal concentrations.
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PMID:The effect of thymidine on the antibacterial and antiviral activity of zidovudine. 135 4

The primary immune response to a viral antigen (tick-borne encephalitis, TBE) has been determined in haemophiliacs. Twelve HIV-negative and four clinically asymptomatic, HIV-positive haemophiliacs as well as 16 age-matched healthy controls were included in the study. Antibody responses after TBE vaccination were comparable in HIV-negative haemophiliacs and controls; however, antibody titres in HIV-infected haemophiliacs were significantly lower after completion of the three-dose vaccination schedule (geometric mean reciprocal antibody titres (SEM): controls, 193 (1.37), HIV-positive haemophiliacs, 13 (2.18), P < 0.005). TBE vaccination failed to induce a T cell proliferative response in the HIV-positive haemophiliacs. While in HIV-negative patients the antigen-specific lymphoproliferative responses after primary and one booster vaccination were comparable to those of the controls, cellular responses were decreased in HIV-negative haemophiliacs following a second booster immunization 19 months after primary immunization (3H-thymidine incorporation, delta dpm, mean +/- SEM: controls, 34662 +/- 7129, HIV-negative haemophiliacs, 14339 +/- 7420, P < 0.005). As the protective mechanisms for TBE infection are not yet completely understood, further work will be necessary to determine whether the decreased capacity to mount a sufficient long-term cellular memory response in HIV-negative haemophiliacs might be important for the protective effect of TBE vaccination in this population.
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PMID:Cellular and humoral immune responses in haemophiliacs after vaccination against tick-borne encephalitis. 141 20

Dehydroepiandrosterone (DHEA) and its interconvertible sulfate derivative (DHEA-S) are human androgenic steroids that have been reported to inhibit viral expression and have been associated with a decreased risk of cancer. The relationship between serum DHEA and DHEA-S levels and subsequent progression to AIDS was investigated in a sample of human immunodeficiency virus (HIV)-infected men from the San Francisco Men's Health Study followed prospectively since 1984. Among 108 men seropositive for HIV at study entry and with CD4 lymphocyte counts of 200-499 microliters 24 months later, serum DHEA levels below the lower limit of normal (less than 180 ng/dl) at this later date were predictive of subsequent progression to AIDS (relative hazard = 2.34; 95% confidence interval = 1.18-4.63; P = .01) after controlling for hematocrit, age, and log absolute CD4 cell number in a Cox proportional hazards model. This is the first large prospective cohort in which an endocrinologic variable has been observed to independently predict progression to AIDS. These observations, in addition to recent in vitro data, suggest that DHEA might have a protective effect in HIV infection.
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PMID:Decreased serum dehydroepiandrosterone is associated with an increased progression of human immunodeficiency virus infection in men with CD4 cell counts of 200-499. 168 93

The pharmacokinetics of zidovudine were evaluated in 41 patients with Centers for Disease Control HIV class IVA infection. The patients were assigned escalating doses of zidovudine (300, 600, or 1,500 mg daily) and were randomized to receive either zidovudine alone or zidovudine with a high dose of acyclovir (4,800 mg per day). Single and multiple intravenous- and oral-dose pharmacokinetic studies were performed on days 1 and 7 and weeks 6 and 12 of therapy. Zidovudine concentrations were analyzed by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by noncompartmental methods. Zidovudine concentrations in serum declined in a biphasic manner, with half-lives ranging from 1 to 2 h, and were independent of acyclovir administration or length of zidovudine therapy. The median time of peak concentrations in serum following oral doses was 0.75 h (range, 0.25 to 3 h). Accumulation of zidovudine in serum was not observed, but the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve increased proportionally with increased zidovudine doses. Mean day 7 oral Cmax values were 0.20 +/- 0.12, 0.55 +/- 0.33, and 1.0 +/- 0.5 micrograms/ml for 17 patients receiving total daily doses of, respectively, 300, 600, and 1,500 mg of zidovudine alone, whereas Cmax values were, respectively, 0.27 +/- 0.18, 0.43 +/- 0.33, and 1.2 +/- 0.80 micrograms/ml for 15 comparably treated recipients of zidovudine plus acyclovir (P was not significant). The median bioavailability of oral zidovudine was 67% (42 to 120%) and did not vary with dosage. Absolute and apparent total body clearances were similar among the patients given the various zidovudine doses regardless of whether there was concomitant acyclovir therapy. Drug-related toxicities were observed more frequently in the subjects who received high doses of zidovudine than they were in those who received median and low doses of zidovudine (P=0.03). Overall, acyclovir did not influence the disposition of zidovudine over a wide range of zidovudine doses. No unusual toxicities could be attributed to the zidovudine and high-dose acyclovir combination during the 12-week observation period.
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PMID:Pharmacokinetic evaluations of low- and high-dose zidovudine plus high-dose acyclovir in patients with symptomatic human immunodeficiency virus infection. 180 95

As part of a prospective cohort study initiated in 1983, the human immunodeficiency virus type 1 (HIV-1) status has been periodically determined for patients with clotting disorders (hemophilia A or B, von Willebrand's disease, miscellaneous). The University of North Carolina Hospitals has conducted comprehensive surveillance for nosocomial infections (NI) using modified Centers for Disease Control criteria since 1980 and entered this information in a computerized data base. Cross-matching of our NI data base and hemophiliac/HIV-1 study data base for the time period 1980-1989 revealed that 13 NI occurred in 11 patients during 659 hospitalizations (5,723 hospital days). NI rates per 100 admissions (per 1,000 hospital days) by HIV-1 status were as follows: HIV-1 negative = 0.91 (1.18), HIV-1 positive pre-AIDS = 1.65 (1.84), and AIDS = 6.67 (6.48). NI occurred with a similar frequency in HIV-1 positive pre-AIDS hemophiliacs and HIV-1 negative hemophiliacs (Fisher's exact test, p greater than 0.10). However, NI occurred more frequently in hemophiliacs with AIDS versus HIV-1 positive or negative hemophiliacs (Fisher's exact test, p less than 0.05). We conclude that HIV-1 infection does not appreciably alter the risk of developing a NI, but that patients who have progressed to AIDS are at significantly increased risk of developing a NI per hospital day or per hospitalization.
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PMID:Nosocomial infection rate as a function of human immunodeficiency virus type 1 status in hemophiliacs. 192 66

The selenium concentration in the serum of 67 patients with HIV infection was measured to determine whether selenium deficiency occurred in the different stages of the disease. In the first stage of the study, patients were divided into four groups: symptom-free subjects, PGL (persistent generalized lymphadenopathy), ARC (AIDS related complex), and AIDS (acquired immunodeficiency syndrome). Selenium concentrations were normal in HIV antibody positive symptom-free subjects (1.18 +/- 0.27 mumol/L) and lower than normal in the other three groups (p less than 0.001). There was a significant correlation (p less than 0.001) between selenium levels and values of hemoglobin and erythrocyte sedimentation rate. Selenium deficiency was in no case associated with a lack of zinc in serum (also determined in all patients). In the second stage of the study, 12 patients were treated for a period of two months with low doses of selenium to assess whether such supplementation was able to restore their impaired immunological and hematological functions. The therapy increased serum selenium concentrations (from 0.77 +/- 0.23 to 1.44 +/- 0.41 mumol/L) and symptomatic improvements were noted. However, no changes were observed in the immunological and hematological parameters.
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PMID:Serum selenium concentration and disease progress in patients with HIV infection. 204 94

Three hundred and fifty-five prostitutes working in The Gambia were enrolled in a study of retroviral infections. Eight-seven (24.6%) were infected with HIV-2 only, two (0.6%) with HIV-1 only, four (1.1%) had sera showing double HIV-1/HIV-2 reactivity, and 37 (10.4%) were seropositive for HTLV-I. After allowing for socioeconomic and serological variables in a multivariate analysis, HIV-2 infection was associated with serological evidence of a previous episode of syphilis [a rapid plasma reagin (RPR) positive/Treponema pallidum haemagglutination assay (TPHA) positive; odds ratio (OR) = 2.18, 95% confidence interval (CI) = 1.19-3.98], with having antibodies against Haemophilus ducreyi (OR = 2.05, 95% CI = 0.89-4.70) or against HTLV-I (OR = 2.17, 95% CI = 0.91-5.19). HIV-2-seropositive prostitutes were three times more likely [17 out of 78 (22%) versus 15 out of 219 (7%), P less than 0.001] to have generalized lymphadenopathy than those who were seronegative. These data suggest that genital ulcer diseases may facilitate the transmission of HIV-2, and that HIV-2 rapidly induces the appearance of generalized lymphadenopathy in a substantial proportion of infected individuals.
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PMID:HIV-2 infection among prostitutes working in The Gambia: association with serological evidence of genital ulcer diseases and with generalized lymphadenopathy. 205 63

Monkey kidney cells CV-1 were infected with recombinant vaccinia virus carrying HIV-1 gag gene with a deletion of 230 nucleotide pairs from the 3'-terminus. The main gene product detected in the lysates of infected cells was the gag precursor rp50. The protein was accumulated on the cell membranes suggesting that it had a myristylated N-terminus, and was cleaved by a recombinant virus specific protease with the formation of two proteins, p17 and p24 corresponding in molecular masses to mature gag proteins. Virus-like particles similar to immature HIV virions were budding from the surface of infected cells. They look like the ring of optically dense material covered with a lipid bilayer, of the same size (100-120 nm) and of the same density in a sucrose gradient (1.16-1.18 g/ml) as HIV-1 virions. The particles contained rp50 and cellular heterogeneous RNA. Thus, the unprocessed gag precursor with deleted 77 amino acid residues from the C-terminus is able to form virus-like particles in the absence of env proteins and virus-specific RNA, and these particles are budding from the cell surface. The question about the use of extracellular Gag-particles for AIDS diagnostic work and construction of vaccines is discussed.
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PMID:[Formation of virus-like particles by HIV-1 Gag proteins, expressed by a recombinant vaccinia virus]. 209 14

A cohort of 418 lower socioeconomic strata prostitutes were enrolled in a study of the epidemiology of sexually transmitted diseases (STDs) between January and April 1985. Sixty-two per cent of the women were seropositive for HIV infection at enrollment. Significant associations were found between HIV seropositivity and Tanzanian origin (OR = 2.12, CI 95% = 1.18-3.81, P less than 0.03), younger age, a shorter duration of prostitution, reduced fecundity, use of oral contraceptives (OR = 1.8, CI 95% = 1.1-2.9, P less than 0.05) and genital ulcer disease (OR = 3.32, P less than 0.00001). No associations were noted with other STD. Stepwise logistic regression analysis confirmed independent associations between HIV infection and Tanzanian origin (OR = 2.27, CI 95% = 1.25-4.14, P less than 0.007), reduced fecundity (OR = 0.83, CI 95% = 0.74-0.94, P less than 0.003), oral contraceptive use (OR = 2.02, CI 95% = 1.22-3.35, P less than 0.006) and duration of prostitution (OR = 0.39, CI 95% = 0.23-0.65, P less than 0.004). Oral contraceptives may increase susceptibility to HIV or may be a marker for other factors which increase risk of acquisition. Further studies are necessary to confirm this association.
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PMID:HIV infection among lower socioeconomic strata prostitutes in Nairobi. 232 96


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