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At least 469 records · Page 26Linked to original sources
PubMed2006

Alpha-herpesvirus infection induces the formation of nuclear actin filaments.

Herpesviruses are large double-stranded DNA viruses that replicate in the nuclei of infected cells. Spatial control of viral replication and assembly in the host nucleus is achieved by the establishment of nuclear compartments that serve to concentrate viral and host factors. How these compartments are established and maintained remains poorly understood. Pseudorabies virus (PRV) is an alpha-herpesvirus often used to study herpesvirus invasion and spread in the nervous system. Here, we report that PRV and herpes simplex virus type 1 infection of neurons results in formation of actin filaments in the nucleus. Filamentous actin is not found in the nucleus of uninfected cells. Nuclear actin filaments appear physically associated with the viral capsids, as shown by serial block-face scanning electron micropscopy and confocal microscopy. Using a green fluorescent protein-tagged viral capsid protein (VP26), we show that nuclear actin filaments form prior to capsid assembly and are required for the efficient formation of viral capsid assembly sites. We find that actin polymerization dynamics (e.g., treadmilling) are not necessary for the formation of these sites. Green fluorescent protein-VP26 foci co-localize with the actin motor myosin V, suggesting that viral capsids travel along nuclear actin filaments using myosin-based directed transport. Viral transcription, but not viral DNA replication, is required for actin filament formation. The finding that infection, by either PRV or herpes simplex virus type 1, results in formation of nuclear actin filaments in neurons, and that PRV infection of an epithelial cell line results in a similar phenotype is evidence that F-actin plays a conserved role in herpesvirus assembly. Our results suggest a mechanism by which assembly domains are organized within infected cells and provide insight into how the viral infectious cycle and host actin cytoskeleton are integrated to promote the infection process.

Actin Cytoskeleton↗
PubMed2001

Longitudinal evaluation of the structure of replicating and circulating hepatitis C virus quasispecies in nonprogressive chronic hepatitis C patients.

In previous cross-sectional studies, we demonstrated that, in most patients with chronic hepatitis C, the composition and complexity of the circulating hepatitis C virus (HCV) population do not coincide with those of the virus replicating in the liver. In the subgroup of patients with similar complexities in both compartments, the ratio of quasispecies complexity in the liver to that in serum (liver/serum complexity ratio) of paired samples correlated with disease stage. In the present study we investigated the dynamic behavior of viral population parameters in consecutive paired liver and serum samples, obtained 3 to 6 years apart, from four chronic hepatitis C patients with persistently normal transaminases and stable liver histology. We sequenced 359 clones of a genomic fragment encompassing the E2(p7)-NS2 junction, in two consecutive liver-serum sample pairs from the four patients and in four intermediate serum samples from one of the patients. The results show that the liver/serum complexity ratio is not stable but rather fluctuates widely over time. Hence, the liver/serum complexity ratio does not identify a particular group of patients but a particular state of the infecting quasispecies. Phylogenetic analysis and signature mutation patterns showed that virtually all circulating sequences originated from sequences present in the liver specimens. The overall behavior of the circulating viral quasispecies appears to originate from changes in the relative replication kinetics of the large mutant spectrum present in the infected liver.

Adult↗
PubMed1989

The influence of assay variability on pharmacokinetic parameter estimation.

The impact of assay variability on pharmacokinetic modeling was investigated. Simulated replications (150) of three "individuals" resulted in 450 data sets. A one-compartment model with first-order absorption was simulated. Random assay errors of 10, 20, or 30% were introduced and the ratio of absorption rate (Ka) to elimination rate (Ke) constants was 2, 10, or 20. The analyst was blinded as to the rate constants chosen for the simulations. Parameter estimates from the sequential method (Ke estimated with log-linear regression followed by estimation of Ka) and nonlinear regression with various weighting schemes were compared. NONMEM was run on the 9 data sets as well. Assay error caused a sizable number of curves to have apparent multicompartmental distribution or complex absorption kinetic characteristics. Routinely tabulated parameters (maximum concentration, area under the curve, and, to a lesser extent, mean residence time) were consistently overestimated as assay error increased. When Ka/Ke = 2, all methods except NONMEM underestimated Ke, overestimated Ka, and overestimated apparent volume of distribution. These significant biases increased with the magnitude of assay error. With improper weighting, nonlinear regression significantly overestimated Ke when Ka/Ke = 20. In general, however, the sequential approach was most biased and least precise. Although no interindividual variability was included in the simulations, estimation error caused large standard deviations to be associated with derived parameters, which would be interpreted as interindividual error in a nonsimulation environment. NONMEM, however, acceptably estimated all parameters and variabilities. Routinely applied pharmacokinetic estimation methods do not consistently provide unbiased answers. In the specific case of extended-release drug formulations, there is clearly a possibility that certain estimation methods yield Ka and relative bioavailability estimates that would be imprecise and biased.

Biometry↗
PubMed2004

Recruitment of a cytoplasmic response regulator to the cell pole is linked to its cell cycle-regulated proteolysis.

The response regulator CtrA, which silences the Caulobacter origin of replication and controls multiple cell cycle events, is specifically proteolyzed in cells preparing to initiate DNA replication. At the swarmer-to-stalked cell transition and in the stalked compartment of the predivisional cell, CtrA is localized to the cell pole just before its degradation. Analysis of the requirements for CtrA polar localization and CtrA proteolysis revealed that both processes require a motif within amino acids 1-56 of the CtrA receiver domain, and neither process requires CtrA phosphorylation. These results strongly suggest that CtrA polar localization is coupled to its cell cycle-regulated proteolysis. The polarly localized DivK response regulator promotes CtrA localization and proteolysis, but it does not directly recruit CtrA to the cell pole. Mutations in the divJ and pleC histidine kinases perturb the characteristic asymmetry of CtrA localization and proteolysis in the predivisional cell. We propose that polar recruitment of CtrA evolved to ensure that CtrA is degraded only in the stalked half of the predivisional cell, perhaps by localizing a proteolytic adaptor protein to the stalked pole. This is an example of controlled proteolysis of a cytoplasmic protein that is associated with its active recruitment to a specific subcellular address.

Bacterial Proteins↗
PubMed2006

Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR.

The promyelocytic leukemia (PML) nuclear body (NB) is a dynamic subnuclear compartment that is implicated in tumor suppression, as well as in the transcription, replication, and repair of DNA. PML NB number can change during the cell cycle, increasing in S phase and in response to cellular stress, including DNA damage. Although topological changes in chromatin after DNA damage may affect the integrity of PML NBs, the molecular or structural basis for an increase in PML NB number has not been elucidated. We demonstrate that after DNA double-strand break induction, the increase in PML NB number is based on a biophysical process, as well as ongoing cell cycle progression and DNA repair. PML NBs increase in number by a supramolecular fission mechanism similar to that observed in S-phase cells, and which is delayed or inhibited by the loss of function of NBS1, ATM, Chk2, and ATR kinase. Therefore, an increase in PML NB number is an intrinsic element of the cellular response to DNA damage.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1996

Anti-idiotypic antibody to the V3 domain of gp120 binds to vimentin: a possible role of intermediate filaments in the early steps of HIV-1 infection cycle.

Although the CD4 molecule is the major cellular receptor for human immunodeficiency virus (HIV), several lines of evidence suggest participation of additional molecules that are engaged after the binding of HIV to the CD4 receptor and that may facilitate viral entry into the target cell. Some of the post-CD4 binding, perfusion events involve the third hypervariable region (V3 loop) of the viral envelope protein gp120. To identify cellular proteins that interact with the V3 loop, we chose as a probe an antiidiotypic monoclonal antibody (MAb), anti-id2, which was prepared against the neutralizing MAb 110.4 that binds the V3 domain in the envelope glycoprotein gp120 of the LAI isolate of HIV-1. Anti-id2 reacted specifically with a 55- to 60-kDa protein in human T cell and monocytoid cell lines, and in a mouse melanoma cell line. This protein was identified immunologically and by protein sequence analysis as vimentin, an intermediate filament protein of lymphoid and other cells of mesodermal origin. Antiserum raised against vimentin inhibited nuclear translocation of HIV-1 DNA following infection of monocytes and CD4+ T cells with live virus, and reduced the amount of HIV-1 gag-specific RNA in the nuclei of monocytes following inoculation with HIV-1 pseudovirions. These data suggest that vimentin may participate in the early steps of HIV-1 replication, perhaps during the uptake of HIV-1 preintegration complexes into the nuclear compartment.

Animals↗
PubMed2006

Systemic vaccination prevents the total destruction of mucosal CD4 T cells during acute SIV challenge.

BACKGROUND: Acute human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infections are accompanied by a systemic loss of memory CD4 T cells, with mucosal sites serving as a major site for viral replication, dissemination and CD4 T cell depletion. Protecting the mucosal CD4 T cell compartment thus is critical to contain HIV, and preserve the integrity of the mucosal immune system. The primary objective of this study was to determine if systemic vaccination with DNA/rAd-5 encoding SIV-mac239-env, gag and pol could prevent the destruction of CD4 T cells in mucosal tissues. METHODS: Rhesus macaques were immunized with DNA/r-Ad-5 encoding SIV genes and compared with those immunized with sham vectors following high dose intravenous challenge with SIVmac251. SIV specific CD4 and CD8 T cell responses, cell associated viral loads and mucosal CD4 T cell dynamics were evaluated. RESULTS: Strong SIV specific immune responses were induced in mucosal tissues of vaccinated animals as compared with sham controls. These responses expanded rapidly following challenge suggesting a strong anamnestic response. Immune responses were associated with a decrease in cell associated viral loads, and a loss of fewer mucosal CD4 T cells. Approximately 25% of mucosal CD4 T cells were preserved in vaccinated animals as compared with <5% in sham controls. These results demonstrate that systemic immunization strategies can induce immune responses in mucosal tissues that can protect mucosal CD4 T cells from complete destruction following challenge. CONCLUSIONS: Preservation of mucosal CD4 T cells can contribute to maintaining immune competence in mucosal tissues and provide a substantial immune benefit to the vaccinees.

Animals↗
PubMed2006

Creation and reduction of a morphologically detailed model of a leech heart interneuron.

Conductance-based neuron models aid in understanding the role intrinsic and synaptic currents play in producing neuronal activity. Incorporating morphological detail into a model allows for additional analysis of nonhomogeneous distributions of active and synaptic conductances, as well as spatial segregation of electrical events. We developed a morphologically detailed "Full Model" of a leech heart interneuron that replicates reasonably well intracellular recordings from these interneurons. However, it constitutes hundreds of compartments, each increasing parameter space and simulation time. To reduce the number of compartments of the Full Model, while preserving conductance densities and distributions, its compartments were grouped into functional groups that each share identical conductance densities. Each functional group was sequentially reduced to one or two compartments, preserving surface area, conductance densities, and its contribution to input resistance. As a result, the input resistance and membrane time constant were preserved. The axial resistances of several compartments were rescaled to match the amplitude of synaptic currents and low-threshold calcium currents and the shape of action potentials to those in the Full Model. This reduced model, with intrinsic conductances, matched the activity of the Full Model for a variety of simulated current-clamp and voltage-clamp data. Because surface area and conductance distribution of the functional groups of the Full Model were maintained, parameter changes introduced into the reduced model can be directly translated to the Full Model. Thus our computationally efficient reduced morphology model can be used as a tool for exploring the parameter space of the Full Model and in network simulations.

Action Potentials↗
PubMed1991

[Miracidial attraction by Biomphalaria straminea, Lymnaea columella and Physa sp on miracidia of Schistosoma mansoni BH strain].

The attraction exercised over Schistosoma mansoni miracidia by Biomphalaria straminea, Lymnaea columella and Physa sp using a specially designed apparatus consisting of two circular glass chambers joined by an open channel were studied. The molluscs or their snail-conditioned water (SCW) was placed in one of the chambers (randomly chosen). In the channel ten miracidia was deposited and the count of miracidia in each of the three compartments (the two chambers and the channel) was recorded during fifteen minutes. Ten replications of each experiment with different specimens of molluscs and miracidia were made. Statistical and ad-hoc exploratory data analysis showed that: a) the three species of molluscs and their SCW attract the miracidia; b) Physa sp attract more miracidia then L. columella. There was an isolated single B. straminea specimen that had a repulsive effect to the miracidia.

Animals↗
PubMed1997

High-resolution analysis of DNA replication domain organization across an R/G-band boundary.

Establishing how mammalian chromosome replication is regulated and how groups of replication origins are organized into replication bands will significantly increase our understanding of chromosome organization. Replication time bands in mammalian chromosomes show overall congruency with structural R- and G-banding patterns as revealed by different chromosome banding techniques. Thus, chromosome bands reflect variations in the longitudinal structure and function of the chromosome, but little is known about the structural basis of the metaphase chromosome banding pattern. At the microscopic level, both structural R and G bands and replication bands occupy discrete domains along chromosomes, suggesting separation by distinct boundaries. The purpose of this study was to determine replication timing differences encompassing a boundary between differentially replicating chromosomal bands. Using competitive PCR on replicated DNA from flow-sorted cell cycle fractions, we have analyzed the replication timing of markers spanning roughly 5 Mb of human chromosome 13q14.3/q21.1. This is only the second report of high-resolution analysis of replication timing differences across an R/G-band boundary. In contrast to previous work, however, we find that band boundaries are defined by a gradient in replication timing rather than by a sharp boundary separating R and G bands into functionally distinct chromatin compartments. These findings indicate that topographical band boundaries are not defined by specific sequences or structures.

Cell Cycle↗
PubMed2002

Telomeres and telomerase in human health and disease.

Epigenetics refers to the durable changes affecting the genome of an individual during development and aging, but which are not necessarily passed on to subsequent generations. Among the best studied of these epigenetic changes is the shortening of chromosome ends or telomeres. Telomeres are specialized structures, consisting of characteristic DNA repeat sequences and the complex of associated proteins, which cap and protect chromosome ends and serve to preserve genome integrity. In most somatic cells, progressive rounds of cell division are associated with telomere shortening. Such progressive attrition of telomere length eventuates in loss of replicative capacity (cellular senescence). In order to protect the germline and the subpopulation of stem cells from senescence, mechanisms have evolved to prevent telomere attrition in these cellular compartments. The most common and best studied mechanism involves the activation of a ribonucleoprotein enzyme complex, known as telomerase. Activity of telomerase circumvents loss of replicative capacity, by preserving telomere length and chromosome integrity. Hence the detailed mechanisms governing the expression and activity of telomerase have been intensively studied in development and differentiation. Early embryonic development and cellular differentiation are associated with a progressive diminution in telomerase activity. This decrease in activity is principally mediated at the level of the promoter for the gene encoding the catalytic unit of the telomerase complex. Unraveling the detailed mechanisms involved in the regulation of telomere length and telomerase activity will have important and far-reaching implications in understanding many aspects of human health and disease, ranging from accelerated aging syndromes to cancer pathogenesis, among others. Furthermore, insights gleaned from continuing research in this area will likely be applicable to the development of strategies to circumvent cellular senescence in regenerative medicine and stem cell therapeutics in the years to come.

Animals↗
PubMed1993

Assembly of vaccinia virus: role of the intermediate compartment between the endoplasmic reticulum and the Golgi stacks.

Vaccinia virus, the prototype of the Poxviridae, is a large DNA virus which replicates in the cytoplasm of the host cell. The assembly pathway of vaccinia virus displays several unique features, such as the production of two structurally distinct, infectious forms. One of these, termed intracellular naked virus (INV), remains cells associated while the other, termed extracellular enveloped virus (EEV), is released from the cell. In addition, it has long been believed that INVs acquire their lipid envelopes by a unique example of de novo membrane biogenesis. To examine the structure and assembly of vaccinia virus we have used immunoelectron microscopy using antibodies to proteins of different subcellular compartments as well as a phospholipid analysis of purified INV and EEV. Our data are not consistent with the de novo model of viral membrane synthesis but rather argue that the vaccinia virus DNA becomes enwrapped by a membrane cisterna derived from the intermediate compartment between the ER and the Golgi stacks, thus acquiring two membranes in one step. Phospholipid analysis of purified INV supports its derivation from an early biosynthetic compartment. This unique assembly process is repeated once more when the INV becomes enwrapped by an additional membrane cisterna, in agreement with earlier reports. The available data suggest that after fusion between the outer envelope and the plasma membrane, mature EEV is released from the cell.

Endoplasmic Reticulum↗
PubMed2003

HIV-1 in genital tract and plasma of women: compartmentalization of viral sequences, coreceptor usage, and glycosylation.

Worldwide, 90% of HIV-1 infections are transmitted heterosexually. Because the genital mucosa are the sites of initial contact with HIV-1 for most exposed individuals, study of the virus from the genital tract is critical for the development of vaccines and therapeutics. Previous analyses of HIV-1 in various tissues have documented compartmentalization of viral genomes. Whether compartmentalization was associated with viral phenotypic differences or immune status, however, was not well understood. We compared HIV-1 gp120 env sequences from the genital tract and plasma of 12 women. Eight women displayed compartmentalized HIV-1 RNA genomes, with viral sequences from each site that were clearly discrete, yet phylogenetically related. The remaining four exhibited env sequences that were intermingled between the two sites. Women with compartmentalized HIV-1 genomes had higher CD4+ cell counts than those displaying intermingled strains (P = 0.02). Intrapatient HIV-1 recombinants comprising sequences that were characteristic of both sites were identified. We next compared viral phenotypes in each compartment. HIV-1 coreceptor usage was often compartmentalized (P 0.01). The number of N-linked glycosylation sites, associated with neutralization resistance, also differed between compartments (P < 0.01). Furthermore, disparities between the density of gp120 glycosylations in each compartment correlated with higher CD4+ counts (P = 0.03). These data demonstrate that the genital tract and plasma can harbor populations of replicating HIV-1 with different phenotypes. The association of higher CD4+ cell counts with compartmentalization of viral genomes and density of gp120 glycosylations suggests that the immune response influences the development of viral genotypes in each compartment. These findings are relevant to the prevention and control of HIV-1 infection.

Adult↗
PubMed2006

Time- and temperature-dependent activation of hepatitis C virus for low-pH-triggered entry.

Hepatitis C virus (HCV) is an important human pathogen associated with chronic liver disease. Recently, based on a genotype 2a isolate, tissue culture systems supporting complete replication and infectious virus production have been developed. In this study, we used cell culture-produced infectious HCV to analyze the viral entry pathway into Huh-7.5 cells. Bafilomycin A1 and concanamycin A, inhibitors of vacuolar ATPases, prevented HCV entry when they were present prior to infection and had minimal effect on downstream replication events. HCV entry therefore appears to be pH dependent, requiring an acidified intracellular compartment. For many other enveloped viruses, acidic pH triggers an irreversible conformational change, which promotes virion-endosomal membrane fusion. Such viruses are often inactivated by low pH. In the case of HCV, exposure of virions to acidic pH followed by return to neutral pH did not affect their infectivity. This parallels the observation made for the related pestivirus bovine viral diarrhea virus. Low pH could activate the entry of cell surface-bound HCV but only after prolonged incubation at 37 degrees C. This suggests that there are rate-limiting, postbinding events that are needed to render HCV competent for low-pH-triggered entry. Such events may involve interaction with a cellular coreceptor or other factors but do not require cathepsins B and L, late endosomal proteases that activate Ebola virus and reovirus for entry.

Cathepsin B↗
PubMed1997

Proliferation and differentiation of smooth muscle cell precursors occurs simultaneously during the development of the vessel wall.

Formation of the blood vessel wall depends on the recruitment, proliferation, and differentiation of smooth muscle cell (SMC) precursors. The temporal events associated with the onset of expression of several SMC proteins have been well characterized in mouse and avian species. However, the timing of cell proliferation during this process has not been explored. More importantly, it has not been clear whether commitment to the smooth muscle pathway precludes proliferation during development. In the present study, we have determined the kinetics of replication in developing chick aortae between days 2.5 and 19 and have correlated these data with the expression of various SMC differentiation markers. We found that proliferation of aortic SMC precursors occurs in two waves; an early phase of rapid proliferation (15-17%; between days 4 and 12), and a second phase, when replication was reduced to less than 5% (days 16 to hatching). Proliferation of SMC during the first wave occurred concomitantly with the progressive accumulation of SMC contractile proteins, such as SM alpha-actin, calponin, myosin heavy chain, and the 1E12 antigen. We also found that the relative proliferation capacity within each compartment of the vessel wall, ie., intima, media, and adventitia varies throughout development. Approximately, 55-63% of all replicating cells were found in the tunica adventitia from days 6 to 12, whereas 35% were found in the tunica media (tunica media:adventitia = 1:2). This ratio was inverted after day 12, when most of the replicating cells were located in the tunica media (tunica media:adventitia = 2:1). In addition, we observed a ventral-to-dorsal gradient in the proliferation of SMC precursors between days 2.5 and 5. The ventral-to-dorsal proliferation gradient was similar to the previously described differential expression of two early SMC markers: alpha-actin and the 1E12 antigen. These data support the concept that a polarity exists either in the pool of SMC precursors or, in expression of factors that regulate recruitment of presumptive SMC.

Animals↗
PubMedDate not supplied

Secondary heterotypic versus homotypic infection by Coxsackie B group viruses: impact on early and late histopathological lesions and virus genome prominence.

The impact of prior exposure to a different or identical strain of Coxsackievirus B (CVB) on murine CVB myocarditis was studied using a susceptible murine host (A/J[H-2a]) and myocarditic CVB3 or avirulent CVB2 as primary or secondary infectants. The effects of secondary heterotypic infection (CVB2 followed by CVB3) and homotypic infection (CVB3 followed by CVB3) 28 days after primary inoculation, versus CVB2 or CVB3 alone, on injury and viral genomic replication, both early (day 7) and late (days 28 and 56), were evaluated. After the primary infection by CVB2, trivial viral RNA was present in the heart and other organs, and a substantial positivity was observed with CVB3 infection. Seven days after secondary heterotypic (CVB2-CVB3) infection, the quantity of CVB genome in heart, pancreas, liver, and spleen was increased compared with the virus genome in the CVB3-CVB3 group and in the group with primary CVB3 infection alone. This phenomenon was seen in the heart and spleen up to day 28 postsecondary infection. Tissue inflammation and necrosis in heart and pancreas were prominent 7 days postsecondary infection with CVB2-CVB3 and correlated well with an increased quantity of CVB genome. Virus genome was present in heart and spleen 28 days after CVB3 infection alone. Serum CVB3 neutralization titer was increased to 1:128 in CVB2-CVB3 group at days 7 and 28 postsecondary infection, and serum completely neutralized cytopathological effects of CVB3 in the CVB3-CVB3 group at day 7 and 28 postsecondary infection. Our results indicate that secondary heterotypic infection by CVB causes increased injury, inflammation, and CVB replication in target organs such as the heart and pancreas, as well as in immune compartments like the spleen. Compared with CVB3 alone, the intense inflammatory infiltriate in the CVB2-CVB3 group is as not due solely to postviral sensitization of the immune system, but rather to the inability of the host to eradicate the virus.

Animals↗
PubMed2004

Adenoviral capsid modulates secretory compartment organization and function in acinar epithelial cells from rabbit lacrimal gland.

Although adenovirus (Ad) exhibits tropism for epithelial cells, little is known about the cellular effects of adenoviral binding and internalization on epithelial functions. Here, we examine its effects on the secretory acinar epithelial cells of the lacrimal gland, responsible for stimulated release of tear proteins into ocular fluid. Exposure of reconstituted rabbit lacrimal acini to replication-defective Ad for 16-18 h under conditions that resulted in >80% transduction efficiency did not alter cytoskeletal filament or biosynthetic/endosomal membrane compartment organization. Transduction specifically altered the organization of the stimulated secretory pathway, eliciting major dispersal of rab3D immunofluorescence from apical stores normally associated with mature secretory vesicles. Biochemical studies revealed that this dispersal was not associated with altered rab3D expression nor its release from cellular membranes. Ultraviolet (UV)-inactivated Ad elicited similar dispersal of rab3D immunofluorescence. In acini exposed to replication-defective or UV-inactivated Ad, carbachol-stimulated release of bulk protein and beta-hexosaminidase were significantly (P< or =0.05) inhibited to an extent proportional to the loss of rab3D-enriched mature secretory vesicles associated with these treatments. We propose that the altered secretory compartment organization and function caused by Ad reflects changes in the normal maturation of secretory vesicles, and that these changes are caused by exposure to the Ad capsid.

Adenoviridae↗
PubMed1997

To sequence or not to sequence?

There is now incontrovertible evidence that a combination of two nucleoside analogues is superior to AZT monotherapy for the treatment of HIV infection. There is also evidence that a range of antiretroviral combinations can produce profound drops in plasma HIV viral load, often below the detectable limits of the assay. A lower rate of viral replication is associated with delays in the selection of viral mutants resistant to drugs; the principal reason for therapeutic failure. These highly effective combinations are likely to delay clinical events and considerably improve the prognosis in HIV-infected individuals. Using mathematical modelling techniques to assess the half-life of plasma virus infectious cells and proviral DNA, one group has gone so far as to suggest it may be possible to stop therapy after several years, as the virus will have been eliminated. More sanguine investigators, however, believe that this is unlikely, as some infected cellular compartments may have long half-lives and the virus may persist, or even continue to replicate slowly, in sanctuary sites, such as the CNS and genital tract, poorly penetrated by drugs. Thus, some virologists and clinicians believe that it is crucially important to give initial therapy with the strongest possible combination of drugs to achieve an 'undetectable' plasma viral load and that, providing compliance is good, this will lead to a prolonged therapeutic effect. In these circumstances no sequencing issues arise. Others, however, continue to believe that, in due course, the virus is likely to evade drug pressure. In these circumstances, consideration of a sequence of drugs, to avoid initial and subsequent therapy from squandering future therapy options through, principally, cross-resistance, becomes an important issue. None of the issues discussed in this review has been tested by controlled clinical trials but they generate hypotheses requiring urgent evaluation.

Editorial↗