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PubMed2002

Macrophages and HIV infection: therapeutical approaches toward this strategic virus reservoir.

Cells of macrophage lineage represent a key target of human immunodeficiency virus (HIV) in addition to CD4-lymphocytes. The absolute number of infected macrophages in the body is relatively low compared to CD4-lymphocytes. Nevertheless, the peculiar dynamics of HIV replication in macrophages, their long-term survival after HIV infection, and their ability to spread virus particles to bystander CD4-lymphocytes, make evident their substantial contribution to the pathogenesis of HIV infection. In addition, infected macrophages are able to recruit and activate CD4-lymphocytes through the production of both chemokines and virus proteins (such as nef). In addition, the activation of the oxidative pathway in HIV-infected macrophages may lead to apoptotic death of bystander, not-infected cells. Finally, macrophages are the most important target of HIV in the central nervous system. The alteration of neuronal metabolism induced by infected macrophages plays a crucial role in the pathogenesis of HIV-related encephalopathy. Taken together, these results strongly support the clinical relevance of therapeutic strategies able to interfere with HIV replication in macrophages. In vitro data show the potent efficacy of all nucleoside analogues inhibitors of HIV-reverse transcriptase in macrophages. Nevertheless, the limited penetration of some of these compounds in sequestered districts, coupled with the scarce phosphorylation ability of macrophages, suggests that nucleoside analogues carrying preformed phosphate groups may have a potential role against HIV replication in macrophages. This hypothesis is supported by the great anti-HIV activity of tenofovir and other acyclic nucleoside phosphonates in macrophages that may provide a rationale for the remarkable efficacy of tenofovir in HIV-infected patients. Non-nucleoside reverse transcriptase inhibitors (NNRTI) do not affect HIV-DNA chain termination, and for this reason their antiviral activity in macrophages is similar to that found in CD4-lymphocytes. Interestingly, protease inhibitors (PIs), acting at post-integrational stages of virus replication, are the only drugs able to interfere with virus production and release from macrophages with established and persistent HIV infection (chronically-infected cells). Since this effect is achieved at concentrations and doses higher than those effective in de-novo infected CD4-lymphocytes, it is possible that lack of adherence to therapy, and/or suboptimal dosage leading to insufficient concentrations of PIs may cause a resumption of virus replication from chronically-infected macrophages, ultimately resulting in therapeutic failure. For all these reasons, therapeutic strategies aimed to achieve the greatest and longest control of HIV replication should inhibit HIV not only in CD4-lymphocytes, but also in macrophages. Testing new and promising antiviral compounds in such cells may provide crucial hints about their efficacy in patients infected by HIV.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

[Kinetic analysis of interaction of human immunodeficiency virus reverse transcriptase with alkaloids].

The interactions of HIV-I reverse transcriptase with some alkaloids were studied. Among nine compounds tested three--berberine, palmatine and sanguiritrine--inhibited RT. The dependence of the inhibition on the type of template-primer was also demonstrated. The kinetic analysis as well as circular dichroism experiments suggest the complex mechanism of RT inhibition by alkaloids. This mechanism includes both enzyme-alkaloid and alkaloid-template interactions; the latter effect also results in RT inhibition.

Alkaloids↗
PubMed1999

Intramolecular chimeras of the p51 subunit between HIV-1 and FIV reverse transcriptases suggest a stabilizing function for the p66 subunit in the heterodimeric enzyme.

The human immunodeficiency virus (HIV) reverse transcriptase (RT) is a heterodimeric enzyme composed of a 66 kDa (p66) and a 51 kDa (p51) subunit. Recently we showed that p51 plays an important role in the conformation of p66 within the HIV-1 RT heterodimer and hence appears to influence its catalytic activities [Amacker, M., and H ubscher, U. (1998) J. Mol. Biol. 278, 757-765]. This was further investigated here via construction of three intramolecular chimeras of HIV-1 and FIV RTs. The first 25 and 112 amino acids of the N terminus, respectively, as well as the last 22 amino acids of the C terminus in the p51 subunit of HIV-1 RT were exchanged with the corresponding regions of the FIV RT and combined with the wild-type HIV-1 p66. Characterization of these chimeric RT heterodimers demonstrated significant biochemical differences in (i) DNA-dependent DNA synthesis, (ii) strand displacement DNA synthesis, and (iii) RNase H activity. Our results indicate that both the N and C termini of HIV-1 RT p51 appear to be important in stabilizing the RT heterodimer for enzymatic functions.

Amino Acid Sequence↗
PubMed2004

Distinct patterns of natural selection in the reverse transcriptase gene of HIV-1 in the presence and absence of antiretroviral therapy.

The emergence of human immunodeficiency virus (HIV) drug-resistant mutations during antiretroviral therapy is explained by either the preexistence of low-frequency-resistant strains before the start of therapy or by the selection of unsuppressed resistant strains during therapy. We used pairwise and maximum likelihood analyses of the ratio of nonsynonymous to synonymous substitutions per site (d(N)/d(S)) to study the extent of positive selection in the reverse transcriptase (RT) gene of HIV-1 from multiple data sets of drug-treated (117 sequences) and drug-naive patients (270 sequences). In the pairwise analysis, evidence for positive selection (d(N)/d(S) > 1) was only found in drug-treated individuals and in codons conferring drug resistance. By the maximum likelihood method, a positive selection at codons conferring drug resistance was only observed in patients receiving therapy, and although positive selection was detected in drug-naive patients, this was always at codons unrelated to drug resistance. We therefore document a striking difference in the process of allele fixation in drug resistance codons (RC) between populations of HIV-1-infected individuals naive to treatment and those receiving therapy. Furthermore, although mutations associated with drug resistance are sometimes found in drug-naive patients, we suggest that these are fixed because of linkage to sites experiencing immune escape. Finally, we show that compensatory changes are likely to be important in the development of HIV drug resistance by counter-acting the deleterious effects normally associated with drug resistance mutations.

Amino Acid Sequence↗
PubMed2006

A concise and selective synthesis of novel 5-aryloxyimidazole NNRTIs.

[reaction: see text] A concise and efficient route to the construction of a 5-aryloxyimidazole has been developed. The key step was the selective O-arylation of a 2,4-dimethoxybenzyl-protected imidazolone. The final compound is a potent inhibitor of HIV reverse transcriptase.

Anti-HIV Agents↗
PubMed2004

V118I substitution in the reverse transcriptase gene of HIV type 1 CRF02_AG strains infecting drug-naive individuals in Cameroon.

We describe the resistance-associated substitutions that are present in the reverse transcriptase (RT) genes of HIV-1 CRF02_AG strains infecting drug-naive villagers of Cameroon. The 11 sequences analyzed were previously subtyped as CRF02_AG in the gag, pro, and env genes, and this work revealed that most (10/11) had a concordant subtype (CRF02_AG) in the pol gene, while one sequence had discordant subtype (A1) in the pol gene. Classification of the CRF02_AG sequences was further confirmed by recombination breakpoint analysis, which revealed a mosaic composition similar to the reference strain IbNG. Analysis of the RT genes for resistance-associated substitutions revealed two sequences containing a V118I substitution. Even though no other resistance-associated substitutions were found, the presence of V118I, which is implicated in resistance to reverse transcriptase inhibitors, in CRF02_AG strains infecting drug-naive individuals should be considered when introducing these antiretrovirals in areas where CRF02_AG is the predominant subtype, such as Cameroon.

Amino Acid Substitution↗
PubMed1992

A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. The NIAID AIDS Clinical Trials Group.

BACKGROUND: Although zidovudine is effective in patients with human immunodeficiency virus (HIV) infection, its efficacy may decline with prolonged use. Didanosine is another inhibitor of HIV reverse transcriptase. We evaluated the effectiveness of changing anti-HIV treatment from zidovudine to didanosine. METHODS: This multicenter, double-blind study involved 913 patients who had tolerated zidovudine for at least 16 weeks. The patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex with less than or equal to 300 CD4 cells per cubic milliliter, or asymptomatic HIV infection with less than or equal to 200 CD4 cells per cubic milliliter. They were randomly assigned to receive 600 mg per day of zidovudine, 750 mg per day of didanosine, or 500 mg per day of didanosine. RESULTS: There were significantly fewer new AIDS-defining events and deaths among the 298 subjects assigned to 500 mg per day of didanosine than among the subjects who continued to receive zidovudine (relative risk, 1.39; 95 percent confidence interval, 1.06 to 1.82; P = 0.015). With 750 mg of didanosine, there was no clear benefit over zidovudine (relative risk, 1.10; 95 percent confidence interval, 0.86 to 1.42). The efficacy of didanosine was unrelated to the duration of previous zidovudine treatment. In the two didanosine groups, there were improvements in the number of CD4 cells (P less than 0.001 for both groups) and in p24 antigen levels (P = 0.03 in the 500-mg group; P = 0.005 in the 750-mg group), as compared with the zidovudine group. CONCLUSIONS: Changing treatment from zidovudine to 500 mg per day of didanosine appears to slow the progression of HIV disease.

AIDS-Related Complex↗
PubMed2006

Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy: impact on bone mineral density in HIV-infected children.

OBJECTIVE: Tenofovir disoproxil fumarate, a nucleotide analog HIV reverse transcriptase inhibitor with demonstrated activity against nucleoside-resistant HIV, is approved for use in adults but not children. Metabolic bone abnormalities have been seen in young animals given high-dose tenofovir and HIV-infected adults that were treated with oral tenofovir disoproxil fumarate. However, tenofovir disoproxil fumarate is being used in children despite a lack of bone safety data. We hypothesized that, given the higher rate of bone turnover that is associated with normal skeletal growth, the potential for TDF-related bone toxicity may be greater in children than in adults. METHODS: Fifteen highly antiretroviral-experienced HIV-infected children who were 8 to 16 years of age (mean +/- SD: 12 +/- 2) and required a change in therapy received tenofovir disoproxil fumarate 175 to 300 mg/m2 per day (adult dose equivalent) as part of highly active antiretroviral therapy for up to 96 weeks. Bone mineral density of the lumbar spine, femoral neck, and total hip by dual-energy x-ray absorptiometry and blood and urine markers of bone metabolism were measured at 0, 24, 48, 72, and 96 weeks. RESULTS: Median z score (SD score compared with age, gender, and ethnicity-matched control subjects) of the lumbar spine, femoral neck, and total hip were decreased from baseline at 24 weeks and 48 weeks and then stabilized. Lumbar spine bone mineral apparent density (which estimates volumetric bone mineral density independent of bone size) z scores also decreased at 24 weeks. Absolute decreases in bone mineral density were observed in 6 children; the mean age of these children was significantly younger than the bone mineral density stable group (10.2 +/- 1.1 vs 13.2 +/- 1.8 years). The change in lumbar spine bone mineral density correlated with decreases in HIV plasma RNA during treatment. Metabolic markers of bone formation and resorption were variable. Two children in whom tenofovir disoproxil fumarate was discontinued because of bone loss that exceeded protocol allowances demonstrated partial or complete recovery of bone mineral density by 96 weeks. CONCLUSIONS: Tenofovir disoproxil fumarate use in children seems to be associated with decreases in bone mineral density that, in some children, stabilize after 24 weeks. Increases in bone markers and calcium excretion suggest that tenofovir disoproxil fumarate may stimulate bone resorption. Bone turnover is higher in children than in older adolescents and adults because of skeletal growth, potentially explaining the greater effect seen in young children. Decreases in bone mineral density correlate with decreases in viral load and young age, suggesting that young responders may be at greater risk for bone toxicity.

Adenine↗
PubMed1994

Therapy other than reverse transcriptase inhibitors for HIV infection.

Antiretroviral drugs against HIV infection have been developed that inhibit various stages of the HIV replication cycle. Agents other than reverse transcriptase inhibitors are reviewed with particular attention to those under study in clinical trials, including inhibitors of the virus-encoded protease enzyme. In addition, innovative strategies using gene therapy are described. It is concluded that combinations of agents may be the best approach for minimizing toxicity and reducing or delaying the emergence of drug-resistant virus during therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Protease and reverse transcriptase mutation patterns in HIV type 1 isolates from heavily treated persons: comparison of isolates from Northern California with isolates from other regions.

We compared HIV-1 subtype B reverse transcriptase (RT) and protease mutation patterns in isolates from heavily treated persons in Northern California with those from persons described in the published literature predominantly from other parts of the United States and Europe. There were few differences in the prevalence of single, double, and triple mutations between the two sets of sequences. More complex patterns of mutations could be characterized by clustering the sequences into eight groups of RT sequences and nine groups of protease sequences according to the presence of known drug-resistance mutations. This clustering accounted for 63% of the variation at RT inhibitor-resistance positions and 68% of the variation at protease inhibitor-resistance positions. The majority of clusters contained Northern California and literature sequences in similar proportions.

California↗
PubMed2004

Positive selection detection in 40,000 human immunodeficiency virus (HIV) type 1 sequences automatically identifies drug resistance and positive fitness mutations in HIV protease and reverse transcriptase.

Drug resistance is a major problem in the treatment of AIDS, due to the very high mutation rate of human immunodeficiency virus (HIV) and subsequent rapid development of resistance to new drugs. Identification of mutations associated with drug resistance is critical for both individualized treatment selection and new drug design. We have performed an automated mutation analysis of HIV Type 1 (HIV-1) protease and reverse transcriptase (RT) from approximately 40,000 AIDS patient plasma samples sequenced by Specialty Laboratories Inc. from 1999 to mid-2002. This data set provides a nearly complete mutagenesis of HIV protease and enables the calculation of statistically significant K(a)/K(s) values for each individual amino acid mutation in protease and RT. Positive selection (i.e., a K(a)/K(s) ratio of >1, indicating increased reproductive fitness) detected 19 of 23 known drug-resistant mutation positions in protease and 20 of 34 such positions in RT. We also discovered 163 new amino acid mutations in HIV protease and RT that are strong candidates for drug resistance or fitness. Our results match available independent data on protease mutations associated with specific drug treatments and mutations with positive reproductive fitness, with high statistical significance (the P values for the observed matches to occur by random chance are 10(-5.2) and 10(-16.6), respectively). Our mutation analysis provides a valuable resource for AIDS research and will be available to academic researchers upon publication at http://www.bioinformatics.ucla.edu/HIV. Our data indicate that positive selection mapping is an analysis that can yield powerful insights from high-throughput sequencing of rapidly mutating pathogens.

Amino Acid Sequence↗
PubMed2002

HIV-1 subtype C reverse transcriptase sequences from drug-naive pregnant women in South Africa.

The HIV-1 reverse transcriptase genes from 37 HIV-1-positive pregnant women attending an antenatal clinical in Soweto, South Africa were sequenced and analyzed for the presence of drug resistance mutations. All women were antiretroviral drug naive, but were being screened as potential participants in clinical trials of antiretroviral drugs aimed at preventing mother-to-child transmission. Sequence analysis revealed that all belonged to HIV-1 subtype C, the predominant subtype among heterosexual populations in South Africa. Twenty-three amino acid loci associated with resistance to zidovudine, lamivudine, didanosine, stavudine, and nevirapine were examined and found not to encode mutations that would confer resistance to these drugs. Polymorphisms at these loci occurred infrequently, with three patients harboring the A98S and V179I polymorphisms. An additional three patients harbored V118I, which can function as an accessory resistance mutation, but in this context is also likely to be a polymorphism. These data show that pregnant women who are candidates for receiving antiretroviral drug therapies do not contain naturally occurring or preexisting drug resistance mutations and that such drug therapies are likely to be highly effective in this setting.

Amino Acid Sequence↗
PubMed2000

Impact of highly active anti-retroviral therapy (HAART) on cytokine production and monocyte subsets in HIV-infected patients.

HIV infection is associated with cytokine production by monocytes and expansion of a monocyte subset that expresses high levels of CD16. Our study was designed to investigate the effects of anti-retroviral therapies on these immune parameters. Four groups of HIV+ patients were included in the study. The first group comprised drug-naive patients (n = 20); the second included patients who received two inhibitors of HIV reverse transcriptase (n = 45); the third group received a therapy combining these two inhibitors and one inhibitor of HIV protease (HAART) (n = 35); the fourth consisted of patients who had stopped their treatment (n = 20). The release of inflammatory cytokines (tumour necrosis factor, IL-1beta, IL-6) and immunoregulatory cytokines such as IL-10 by monocytes was determined by ELISA. The monocyte subsets expressing low or high levels of CD16 were studied by flow cytometry. Monocytes from patients naive of treatment released higher amounts of inflammatory cytokines and IL-10 than HIV- individuals. Each anti-retroviral therapy restored a normal pattern of cytokine secretion. Nevertheless, the release of cytokines increased again after the arrest of the treatment. The expansion of the monocyte subset that expresses high levels of CD16 was significantly decreased by HAART but not by the treatment including two inhibitors of reverse transcriptase. These results suggest that only HAART controls monocyte activation in the treatment of HIV infection.

Adult↗
PubMed1999

Synthesis and anti-HIV activity of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs): a new family of HIV-1 specific non-nucleoside reverse transcriptase inhibitors.

The anti-HIV activity of a novel series of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs) has been described. The compounds were synthesized via Curtius rearrangement of appropriate sulfamoylcarboxy azides which, in turn, were prepared from known starting materials. Several 4-substituted-2-benzyl-derivatives were found to selectively inhibit human immunodeficiency virus type 1 [HIV-1 (IIIB)] replication in MT-4 and CEM cells. These TTDs were also effective against other strains of HIV-1 (RF, HE, MN, NDK), including those that are resistant to AZT, but not against HIV-2 (ROD) or simian immunodeficiency virus [SIV(MAC251)] at subtoxic concentrations. Some of the test compounds exhibited antiviral activity against L100I RT mutant virus, but significantly lost antiviral activity against K103N, V106A, E138K, Y181C and Y188H RT mutant viruses. Compounds 6d, 6f and 6g were inhibitory to HIV-1 RT at concentrations that rank between 16.4 and 59.8 microM (nevirapine: IC50 = 4.5 microM against HIV-1 RT). Inhibition of HIV-1 RT by compound 6g was purely non-competitive with respect to the natural substrate (dGTP), which is in agreement with the nature of inhibition shown by other NNRTIs such as nevirapine and delarvidine. A structure-activity relationship was established for the anti-HIV activity of these heterocyclic compounds. TTDs represent a new chemical class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs).

Anti-HIV Agents↗
PubMed1995

Cytotoxic ent-kaurene diterpenoids from three Isodon species.

From Isodon loxothyrsa, one new diterpenoid, loxothyrin A, together with one known diterpenoid, adenolin B, from I.pleiophyllus, three known diterpenoids, coetsoidins A, B and G, and from I. adenoloma, one known diterpenoid, longikaurin F, were isolated. The structure determination of loxothyrin A, and the unambiguous NMR spectral assignments of the known compounds were made by a combination of 1D and 2D NMR techniques and computer modelling calculations. The isolates showed potent cytotoxic activities.

Antimalarials↗
PubMed1994

1,2,3-Triazole-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D- ribofuranosyl]-3'-spiro-5"-(4"-amino-1",2"-oxathiole 2",2"-dioxide) (TSAO) analogues: synthesis and anti-HIV-1 activity.

Several 4- or 5-monosubsituted and 4,5-disubstituted 1,2,3-triazole analogues of the anti-HIV-1 lead compound [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D- ribofuranosyl]thymine]-3'-spiro-5"-(4"-amino-1",2"-oxathiole 2",2"-dioxide) (TSAO-T) have been prepared and evaluated as inhibitors of HIV-1-induced cytopathicity. These analogues have been prepared by 1,3-diplar cycloaddition of [2,5-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]- 3-spiro-5'-(4'-amino- and 4'-(N-acetylamino)-1',2'-oxathiole 2',2'-dioxide) (TSAO) azides to various substituted acetylenes. Several 4- and 5-substituted 1,2,3-triazole-TSAO analogues proved superior to the unsubstituted derivative by 1-2 orders of magnitude. In particular the 5-substituted amido-, (methylamido)-, and (dimethylamido)-1,2,3-triazole derivatives of TSAO were endowed with potent anti-HIV-1 activity (50% effective concentration: 0.056-0.52 microM). They show a similar resistance spectrum as previously noted for TSAO-T and related derivatives.

Antiviral Agents↗