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PubMed2005

The antiviral activity, mechanism of action, clinical significance and resistance of abacavir in the treatment of pediatric AIDS.

The novel carbocyclic nucleoside, abacavir, is metabolized in cells to carbovir triphosphate which is a potent inhibitor of HIV reverse transcriptase (K(i) 0.021 microM with calf thymus DNA template primer). Abacavir exhibits potent in vitro antiviral activity against wild-type HIV-1 (IC(50) 4.0 microM, MT-4 cells) but this activity is lower than the activity of AZT (IC(50) 0.040 microM, MT-4 cells). However, there is no significant difference between the levels of activity of abacavir (IC(50) 0.26 microM) and AZT (IC(50) 0.23 microM) against clinical isolates of HIV-1. The in vitro toxicity data (CC(50)) of abacavir were: 160 microM (CEM cells); 140 microM (CD4+ CEM cells) and 110 microM (normal bone progenitor cells, BFU-E). Abacavir has been approved in the United States for the treatment of pediatric and adult HIV infection and current recommendations consist of combination therapy in children with HIV infection. Resistance to abacavir develops relatively slowly, with most of the mutations conferring minimal resistance. The M184V mutation appears to be the cornerstone of higher level resistance in regimens containing abacavir, imparting a 2-4 fold reduction in the susceptibility of HIV to abacavir.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Analysis of HIV-2 RT mutants provides evidence that resistance of HIV-1 RT and HIV-2 RT to nucleoside analogs involves a repositioning of the template-primer.

Mutations that confer resistance to nucleoside analogs do not cluster around the deoxynucleotide triphosphate (dNTP) binding site. Instead, these mutations appear to lie along the groove in the enzyme where the template-primer binds. Based on such structural data and on complementary biochemical analyses, it has been suggested that resistance to nucleoside analogs involves repositioning of the template-primer. We have prepared mutations in HIV-2 RT that are the homologs of mutations that confer resistance to nucleoside analogs in HIV-1 RT. Analysis of the behavior of HIV-2 RT mutants (Leu74Val, Glu89Gly, Ser215Tyr, Leu74Val/Ser215Tyr and Glu89Gly/Ser215Tyr) in vitro confirms the results obtained with HIV-1 RT: resistance is a function of the length of the template overhang. These analyses also suggest that the homolog in HIV-2 RT of one of the mutations that confers resistance to AZT in HIV-1 RT (Thr215Tyr) confers resistance by repositioning of the template-primer.

DNA Primers↗
PubMed2002

Subtle decreases in stavudine phenotypic susceptibility predict poor virologic response to stavudine monotherapy in zidovudine-experienced patients.

To identify the level of phenotypic susceptibility for stavudine (d4T) that is associated with a diminished virologic response to d4T therapy, phenotyping was performed on archived baseline HIV isolates from 26 subjects who received d4T monotherapy in AIDS Clinical Trials Group (ACTG) 302 who had received >3 years of prior zidovudine (ZDV) monotherapy. Seven of 26 subjects achieved a virologic response of >0.3-log10 copies/mL reduction in plasma HIV RNA after 8 weeks of d4T. Responders had lower fold changes in susceptibility to d4T (1.0 vs. 1.6, p=.003), lower baseline viral loads (4.26 vs. 4.74 log10 copies/mL, p=.004), and fewer thymidine analog mutations (TAMS) (1 vs. 2, p=.059). Lower baseline d4T fold change in susceptibility predicted greater reductions in HIV RNA from baseline to week 8 after adjusting for baseline HIV RNA, ZDV fold change in susceptibility, and number of TAMS. Using the same phenotypic assay, drug susceptibility among 240 antiretroviral-naive patients found all HIV isolates to have d4T susceptibility <or=1.4-fold change. Using <or=1.4 as the d4T cutoff, the positive predictive value for a virologic response in this study was 44%, and the negative predictive value was 100%. d4T susceptibility greater than 1.4-fold change was associated with failure to achieve significant viral load reduction after 8 weeks of d4T monotherapy.

Adult↗
PubMed2005

ATPgammaS disrupts human immunodeficiency virus type 1 virion core integrity.

Heat shock protein 70 (Hsp70) is incorporated within the membrane of primate lentiviral virions. Here we demonstrate that Hsp70 is also incorporated into oncoretroviral virions and that it remains associated with membrane-stripped human immunodeficiency virus type 1 (HIV-1) virion cores. To determine if Hsp70 promotes virion infectivity, we attempted to generate Hsp70-deficient virions with gag deletion mutations, Hsp70 transdominant mutants, or RNA interference, but these efforts were confounded, largely because they disrupt virion assembly. Given that polypeptide substrates are bound and released by Hsp70 in an ATP-hydrolytic reaction cycle, we supposed that incubation of HIV-1 virions with ATP would perturb Hsp70 interaction with substrates in the virion and thereby decrease infectivity. Treatment with ATP or ADP had no observable effect, but ATPgammaS and GTPgammaS, nucleotide triphosphate analogues resistant to Hsp70 hydrolysis, dramatically reduced the infectivity of HIV-1 and murine leukemia virus virions. ATPgammaS-treated virions were competent for fusion with susceptible target cells, but viral cDNA synthesis was inhibited to an extent that correlated with the magnitude of decrease in infectivity. Intravirion reverse transcription by HIV-1, simian immunodeficiency virus, or murine leukemia virus was also inhibited by ATPgammaS. The effects of ATPgammaS on HIV-1 reverse transcription appeared to be indirect, resulting from disruption of virion core morphology that was evident by transmission electron microscopy. Consistent with effects on capsid conformation, ATPgammaS-treated viruslike particles failed to saturate host antiviral restriction activity. Our observations support a model in which the catalytic activity of virion-associated Hsp70 is required to maintain structural integrity of the virion core.

Adenosine Triphosphate↗
PubMed1989

Inhibition of HIV-replication by 3'-fluoro-modified nucleosides with low cytotoxicity.

From a series of newly synthesized 3'-fluoro-modified nucleosides the C-5-chloro-substituted derivative of 2',3'-dideoxy-3'-fluorouridine (FddUrd) and the 4-thio analogue of 2',3'-dideoxy-3'-fluorothymidine (FddUrd) emerged as the most efficient and selective anti-HIV agents. Their antiviral doses (ED50) proved to be 700-and 480-fold below their toxic doses (CD50) in MT-4 cells. The 50% inhibitory dose of cell proliferation of the 5-chloro-substituted FddUrd and its parent agent FddUrd was found to be in the millimolar range for various other human cell-lines and for mouse CFU-GM. The 5'-triphosphate of FddUrd as well as of its 5-Chloro derivative are demonstrated to be two of the most active and selective inhibitors of the HIV-reverse transcriptase (IC50 = 0.07 +/- 0.01 and 0.04 +/- 0.006 microM).

Animals↗
PubMed1999

Zidovudine + lamivudine: new preparation. Fewer tablets required.

(1) Combivir is a fixed-dose combination of two HIV reverse transcriptase inhibitors: zidovudine (300 mg) + lamivudine (150 mg). (2) A meta-analysis of four trials shows that this combination is more effective clinically than zidovudine monotherapy. One trial also shows that clinical efficacy is even better with the triple combination of the protease inhibitor indinavir with zidovudine + lamivudine. (3) The risk of anaemia and neutropaenia necessitates blood cell monitoring during treatment. (4) Compared with lamivudine and zidovudine taken separately, Combivir does not reduce the frequency of doses (two a day), but the daily number of tablets falls from four to two, provided that the patient does not require dose adjustment.

Anti-HIV Agents↗
PubMed1993

Inhibition of HIV-1 replication in cultured cells with phosphorylated dideoxyuridine derivatives encapsulated in immunoliposomes.

Among the 2',3'-dideoxynucleoside 5'-triphosphates containing a physiological base, 2',3'-dideoxyuridine 5'-triphosphate (ddUTP) has been reported to be among the most powerful inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT) in cell-free systems. However, in contrast to other dideoxynucleosides, 2',3'-dideoxyuridine (ddU) is inactive in treatment of HIV-infected cells in culture, since it is a poor substrate for cellular nucleoside kinases. This problem cannot be overcome by the use of phosphorylated ddU because such compounds are unable to cross cell membranes. To promote entry and thus bypass the limiting steps of intracellular phosphorylation, we have encapsulated mono- and tri-phosphorylated ddU in liposomes coupled to monoclonal antibodies (immunoliposomes). We investigated antiviral effects in two human T cell lines (MT-4, CEM). We observed that ddU nucleotides remain phosphorylated for several weeks after encapsulation in immunoliposomes, and potent antiviral activity is obtained when these drugs are delivered into infected cells by cell-specific antibodies (ED50 < or = 1 microM on CEM). In contrast, no inhibition was observed with non-targeted liposomes containing phosphorylated ddU, or with empty liposomes, whether targeted or not.

Antiviral Agents↗
PubMed1993

Two highly antigenic sites in the human immunodeficiency virus type 1 reverse transcriptase.

Antibodies to human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are found in the serum of the majority of infected individuals, and inhibition of RT polymerase activity by HIV-1-positive sera can be demonstrated in vitro. The binding sites of human antibodies on the protein have not yet been identified. We synthesized overlapping peptides covering the entire RT protein of HIV-1 and used them in an enzyme-linked immunosorbent assay system to map the reactivities of HIV-1 and HIV-2 antibody-positive sera. Two highly antigenic regions were identified by both HIV serotypes. One region was found in the central part of the RT protein (amino acids 261 to 280) and another was found at the carboxy terminus in the RNase H portion of RT (amino acids 517 to 536). Comparison of the serological results with the crystal structure of the RT revealed that the antigenic region in the RNase H portion is located at the surface of the protein. The other antibody-binding site (amino acids 261 to 280) was located in the "thumb" region of the polymerase domain of RT. Polyclonal antibodies to either of the antibody-binding sites do not affect the polymerase activity of the RT protein.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Phylogenetic analysis of reverse transcriptase in antiretroviral drug-naive Korean HIV type 1 patients.

To study whether genotypic antiretroviral resistance testing (GART) is needed to guide initial antiretroviral therapy in Korea, we determined partial pol sequences in peripheral blood mononuclear cells (PBMCs) obtained from 29 antiretroviral drug-naive HIV-1 patients. Phylogenetic analysis revealed four subtypes: B (23 patients), D (1 patient), recombinant strain (2 patients), and "untyped" (3 patients). Eighteen (78.3%) of the 23 subtype B isolates formed a distinct monophyletic cluster. The average genetic distances of 23 subtype B compared with reference strain HXB2 were 2.7% (range, 1.5-4.6%). Only one patient harbored variant virus containing a V179D mutation causing resistance to efavirenz. These data derived from therapy-naive patients suggest that potential use of primary resistance testing to guide initial antiretroviral therapy should be considered in Korea. This is the first report on the molecular nature of HIV-1 RT in Korea.

Adolescent↗
PubMed2001

Characterization of intracellular reverse transcription complexes of human immunodeficiency virus type 1.

To examine the early events of the life cycle of human immunodeficiency virus type 1 (HIV-1), we analyzed the intracellular complexes mediating reverse transcription isolated from acutely infected cells. Partial purification of the reverse transcription complexes (RTCs) by equilibrium density fractionation and velocity sedimentation indicated that two species of RTCs are formed but only one species is able to synthesize DNA. Most of the capsid, matrix, and reverse transcriptase (RT) proteins dissociate from the complex soon after cell infection, but Vpr remains associated with the RTC. The RTCs isolated 1, 4, and 7 h after infection are competent for reverse transcription in vitro, indicating that a small proportion of RT remains associated with them. HIV RTCs isolated early after infection have a sedimentation velocity of approximately 560S. Later, different species with a sedimentation velocity ranging from 350S to 100S appear. Nuclear-associated RTCs have a sedimentation velocity of 80S. Shortly after initiation of reverse transcription, the viral strong-stop DNA within the RTC is sensitive to nuclease digestion and becomes protected when reverse transcription is almost completed.

Blotting, Western↗
PubMed2005

Solution structure and thermodynamic investigation of the HIV-1 frameshift inducing element.

Expression of the HIV reverse transcriptase and other essential viral enzymes requires a -1 translational frameshift. The frameshift event is induced by two highly conserved RNA elements within the HIV-1 mRNA: a UUUUUUA heptamer known as the slippery sequence, and a downstream RNA structure. Here, we report structural and thermodynamic evidence that the HIV-1 frameshift site RNA forms a stem-loop and lower helix separated by a three-purine bulge. We have determined the structure of the 45 nucleotide frameshift site RNA using multidimensional heteronuclear nuclear magnetic resonance (NMR) methods. The upper helix is highly thermostable (T(m)>90 degrees C), forming 11 Watson-Crick base-pairs capped by a stable ACAA tetraloop. The eight base-pair lower helix was found to be only moderately stable (T(m)=47 degrees C). A three-purine bulge separates the highly stable upper helix from the lower helix. Base stacking in the bulge forms a wedge, introducing a 60 degrees bend between the helices. Interestingly, this bend is similar to those seen in a number of frameshift inducing pseudoknots for which structures have been solved. The lower helix must denature to allow the ribosome access to the slippery site, but likely functions as a positioning element that enhances frameshift efficiency.

Frameshifting, Ribosomal↗
PubMed2003

How does expert advice impact genotypic resistance testing in clinical practice?

The Havana trial, a randomized, prospective study, demonstrated that expert interpretation of genotypic resistance test (GRT) results improved virological outcomes in human immunodeficiency virus type 1 (HIV-1)-infected patients for whom highly active antiretroviral therapy (HAART) was failing. The impact of expert advice in routine clinical practice is unknown. We retrospectively evaluated the virological outcomes of 74 patients for whom HAART was failing and whose clinical providers accepted or rejected HAART regimens recommended by an expert panel who routinely reviewed GRT results. Fifty (68%) of 74 patients received regimens recommended by the expert panel ("advice accepted" [AA]), and 24 patients (32%) received regimens per the clinician's preference ("advice rejected" [AR]). After 24 weeks, AA and AR groups had median decreases in the plasma HIV-1 RNA viral load of 2.6 and 1.3 log(10) copies/mL, respectively (P=.0001). Twenty-six (52%) of 50 patients in the AA group and 5 (21%) of 24 patients in the AR group had a plasma HIV-1 RNA viral load of <50 copies/mL (P=.01). Consideration should be given to enlisting expert assistance in the interpretation of GRT results in routine clinical practice.

Adult↗
PubMed1997

1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity.

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Rational approaches to resistance: using saquinavir.

AIM: To review drug-resistance patterns of HIV protease inhibitors, with particular reference to saquinavir, and how resistance and cross-resistance patterns may influence disease management. RESISTANCE TO SAQUINAVIR: Resistance to saquinavir in vitro and in vivo is associated with mutations L90M and G48V in HIV protease. L90M is the predominant mutation in vivo. Clinically, G48V is uncommon and the double mutation rare. This pattern of mutation differs from those seen with other protease inhibitors. CROSS-RESISTANCE: Long-term treatment with saquinavir in most cases does not induce a significant decrease in sensitivity to saquinavir itself or other protease inhibitors. Where significant resistance to saquinavir does develop (i.e. fourfold increase in the median inhibitory concentration), there are observed instances of cross-resistance. Preliminary phenotypic studies of patients on combination therapy with saquinavir (plus zalcitabine and/or zidovudine) for 1 year indicate that > 80% should subsequently respond to indinavir, ritonavir or VX-478. CONCLUSIONS: Resistance to saquinavir develops slowly and in a minority of patients on long-term therapy. Reduced susceptibility to saquinavir is associated with mutations different from those associated with other HIV protease inhibitors. Saquinavir appears to be a good first-choice protease inhibitor for combination therapy with HIV reverse transcriptase inhibitors as it should provide prolonged antiretroviral activity without limiting subsequent therapeutic options.

Anti-HIV Agents↗
PubMed1999

Role of post-transcriptional modifications of primer tRNALys,3 in the fidelity and efficacy of plus strand DNA transfer during HIV-1 reverse transcription.

During HIV reverse transcription, (+) strand DNA synthesis is primed by an RNase H-resistant sequence, the polypurine tract, and continues as far as a 18-nt double-stranded RNA region corresponding to the 3' end of tRNALys,3 hybridized to the viral primer binding site (PBS). Before (+) strand DNA transfer, reverse transcriptase (RT) needs to unwind the double-stranded tRNA-PBS RNA in order to reverse-transcribe the 3' end of primer tRNALys,3. Since the detailed mechanism of (+) strand DNA transfer remains incompletely understood, we developed an in vitro system to closely examine this mechanism, composed of HIV 5' RNA, natural modified tRNALys,3, synthetic unmodified tRNALys,3 or oligonucleotides (RNA or DNA) complementary to the PBS, as well as the viral proteins RT and nucleocapsid protein (NCp7). Prior to (+) strand DNA transfer, RT stalls at the double-stranded tRNA-PBS RNA complex and is able to reverse-transcribe modified nucleosides of natural tRNALys,3. Modified nucleoside m1A-58 of natural tRNALys,3 is only partially effective as a stop signal, as RT can transcribe as far as the hyper-modified adenosine (ms2t6A-37) in the anticodon loop. m1A-58 is almost always transcribed into A, whereas other modified nucleosides are transcribed correctly, except for m7G-46, which is sometimes transcribed into T. In contrast, synthetic tRNALys,3, an RNA PBS primer, and a DNA PBS primer are completely reverse-transcribed. In the presence of an acceptor template, (+) strand DNA transfer is efficient only with templates containing natural tRNALys,3 or the RNA PBS primer. Sequence analysis of transfer products revealed frequent errors at the transfer site with synthetic tRNALys,3, not observed with natural tRNALys,3. Thus, modified nucleoside m1A-58, present in all retroviral tRNA primers, appears to be important for both efficacy and fidelity of (+) strand DNA transfer. We show that other factors such as the nature of the (-) PBS of the acceptor template and the RNase H activity of RT also influence the efficacy of (+) strand DNA transfer.

Base Sequence↗
PubMed2002

Inhibitory effects of antifungal proteins on human immunodeficiency virus type 1 reverse transcriptase, protease and integrase.

A variety of antifungal proteins were isolated from seeds of leguminous plants including French bean, cowpea, field bean, mung bean, peanut and red kidney bean. They were assayed for ability to inhibit human immunodeficiency virus type I (HIV-1) reverse transcriptase, protease and integrase, enzymes essential to the life cycle of HIV-1 . It was found that the cowpea beta-antifungal protein had a high potency in inhibiting HIV-1 protease and HIV-1 integrase. Cowpea alpha-antifungal protein was potent in inhibiting HIV-1 reverse transcriptase and HIV-1 integrase. Peanut antifungal protein was characterized by a high inhibitory activity against HIV-1 integrase and an intermediate potency in inhibiting HIV- I reverse transcriptase and HIV- I protease. French bean thaumatin-like protein expressed low HIV- I protease inhibitory activity and red kidney bean lectin inhibited HIV- I integrase by only a very small extent. Antifungal proteins from the field bean and mung bean had an intermediate potency in inhibitory HIV-1 protease and integrase. However, mung bean antifungal protein was not capable of inhibiting HIV-1 reverse transcriptase. The results indicate that nearly all leguminous antifungal proteins examined were able to inhibit HIV-1 reverse transcriptase, protease and integrase to some extent.

Amino Acid Sequence↗
PubMed2003

l-2',3'-Didehydro-2',3'-dideoxy-3'-fluoronucleosides: synthesis, anti-HIV activity, chemical and enzymatic stability, and mechanism of resistance.

As antiviral nucleosides containing a 2',3'-unsaturated sugar moiety with 2'-fluoro substitution are endowed with increased stabilization of the glycosyl bond, it was of interest to investigate the influence of the fluorine atom at the 3'-position. Various pyrimidine and purine L-3'-fluoro-2',3'-unsaturated nucleosides were synthesized from their precursors, L-3',3'-difluoro-2',3'-dideoxy nucleosides, by elimination of hydrogen fluoride. In the L-3',3'-difluoro-2',3'-dideoxy nucleoside series, cytidine 16 and 5-fluorocytidine 18 analogues showed modest antiviral activity (EC(50) 11.5 and 8.8 microM, respectively) when evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. In the 2',3'-unsaturated series, L-3'-fluoro-2',3'-didehydro-2',3'-dideoxycytidine 24 and 5-fluorocytidine 26 showed highly potent antiviral activity (EC(50) 0.089 and 0.018 microM, respectively) without significant cytotoxicity. The guanosine analogue 48 showed only marginal anti-HIV activity with some cytotoxicity (EC(50) 38.5 microM, and IC(50) 17.4, 58.4, 36.5 microM in PBM, CEM, and Vero cells, respectively). The cytidine 24 and 5-fluorocytidine 26 analogues, however, showed significantly decreased antiviral activity against the clinically important lamivudine-resistant variants (HIV-1(M184V)). Molecular modeling studies demonstrated that the 3'-fluoro atom of the L-3'-fluoro-2',3'-unsaturated nucleoside is within the hydrogen bonding distance with the amide backbone of Asp185, which favors the binding of the nucleoside triphosphate to the wild-type RT. This favorable binding mode, however, cannot be maintained when the triphosphate of 3'-fluoro 2',3'-unsaturated nucleoside binds to the active site of M184V RT because the bulky side chain of Val184 occupies the space needed for the nucleotide. The biological results suggest that, in addition to the sugar conformation, the base moiety may also play a role in their interaction with the M184V RT.

Anti-HIV Agents↗
PubMed2004

Increased replication of HIV-1 minor variants during hematopoietic stem-cell mobilization with filgrastim.

The hypothesis that filgrastim (r-met-huG-CSF) activates replication of minor variants of human inmmunodeficiency virus type 1 (HIV-1) was tested by analysis of plasma quasi-species composition in 7 subjects in whom plasma HIV-1 RNA had increased during filgrastim treatment. Inferred phylogenetic trees of env sequences from 3 subjects during filgrastim treatment contained unique intrasubject subclusters that shared a most recent common ancestor with the baseline HIV-1 quasi species. Genotypes in the unique subclusters were not detected before filgrastim treatment, yet they composed 40%-70% of the plasma quasi species during treatment. The minority variants that appeared in 1 subject were more distantly related to plasma quasi species present 5 years before filgrastim treatment than were the majority of the pretreatment plasma quasi species. These findings provide evidence that increased HIV-1 replication during filgrastim treatment was associated with activation of HIV-1 variants that, before filgrastim treatment, were minor components of the plasma quasi species.

Amino Acid Sequence↗