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Results for “viral replication”

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PubMed2000

Analysis of the HIV-1 LTR NF-kappaB-proximal Sp site III: evidence for cell type-specific gene regulation and viral replication.

It has been widely demonstrated that the human immunodeficiency virus type 1 (HIV-1) envelope, specifically the V3 loop of the gp120 spike, evolves to facilitate adaptation to different cellular populations within an infected host. Less energy has been directed at determining whether the viral promoter, designated the long terminal repeat (LTR), also exhibits this adaptive quality. Because of the unique nature of the cell populations infected during the course of HIV-1 infection, one might expect the opportunity for such adaptation to exist. This would permit select viral species to take advantage of the different array of conditions and factors influencing transcription within a given cell type. To investigate this hypothesis, the function of natural variants of the NF-kappaB-proximal Sp element (Sp site III) was examined in human cell line models of the two major cell types infected during the natural course of HIV-1 infection, T cells and monocytes. Utilizing the HIV-1 LAI molecular clone, which naturally contains a high-affinity Sp site III, substitution of low-affinity Sp sites in place of the natural site III element markedly decreased viral replication in Jurkat T cells. However, these substitutions had relatively small effects on viral replication in U-937 monocytic cells. Transient transfections of HIV-1 LAI-based LTR-luciferase constructs into these cell lines suggest that the large reduction in viral replication in Jurkat T cells, caused by low-affinity Sp site III variants, may result from reduced basal as well as Vpr- and Tat-activated LTR activities in Jurkat T cells compared to those in U-937 monocytic cells. When the function of Sp site III was examined in the context of HIV-1 YU-2-based LTR-luciferase constructs, substitution of a high-affinity element in place of the natural low-affinity element resulted in increased basal YU-2 LTR activity in Jurkat T cells and reduced activity in U-937 monocytic cells. These observations suggest that recruitment of Sp family members to Sp site III is of greater importance to the function of the viral promoter in the Jurkat T cell line as compared to the U-937 monocytic cell line. These observations also suggest that other regions of the LTR may compensate for Sp recruitment defects in specific cell populations.

Base Sequence↗

PubMed2004

Transition from acute to persistent Theiler's virus infection requires active viral replication that drives proinflammatory cytokine expression and chronic demyelinating disease.

The dynamics of Theiler's murine encephalomyelitis virus (TMEV) RNA replication in the central nervous systems of susceptible and resistant strains of mice were examined by quantitative real-time reverse transcription-PCR and were found to correlate with host immune responses. During the acute phase of infection in both susceptible and resistant mice, levels of viral replication were high in the brain and brain stem, while levels of viral genome equivalents were 10- to 100-fold lower in the spinal cord. In the brain, viral RNA replication decreased after a peak at 5 days postinfection (p.i.), in parallel with the appearance of virus-specific antibody responses; however, by 15 days p.i., viral RNA levels began to increase in the spinal cords of susceptible mice. During the transition to and the persistent phase of infection, the numbers of viral genome equivalents in the spinal cord varied substantially for individual mice, but high levels were consistently associated with high levels of proinflammatory Th1 cytokine and chemokine mRNAs. Moreover, a large number of viral genome equivalents and high proinflammatory cytokine mRNA levels in spinal cords were only observed for susceptible SJL/J mice who developed demyelinating disease. These results suggest that TMEV persistence requires active viral replication beginning about day 11 p.i. and that active viral replication with high viral genome loads leads to increased levels of Th1 cytokines that drive disease progression in infected mice.

Animals↗

PubMed1991

The vpx gene of simian immunodeficiency virus facilitates efficient viral replication in fresh lymphocytes and macrophage.

vpx is a unique open reading frame found in simian immunodeficiency virus (SIV) and human immunodeficiency virus type 2 (HIV-2) but not in HIV-1. It encodes a 12- to 16-kDa virion-associated protein. Although vpx is dispensable for viral replication in several established human lymphocyte cell lines, there is no consensus regarding whether this gene is required for efficient viral replication in freshly isolated lymphocytes. We report here that the vpx mutant of SIVmac exhibits different degrees of impairment from wild-type SIVmac in freshly isolated lymphocytes. This defect is more pronounced in macrophages from the same donors. Our findings suggest that vpx is required for efficient viral replication in fresh lymphocytes and macrophages.

Cells, Cultured↗

PubMed1993

Human cytomegalovirus in a SCID-hu mouse: thymic epithelial cells are prominent targets of viral replication.

Animal models of human cytomegalovirus (CMV) infections have not been available to study pathogenesis or to evaluate antiviral drugs. Severe combined immunodeficient mice implanted with human fetal tissues (SCID-hu) were found to support CMV replication and may provide a model for this species-specific virus. When conjoint implants of human fetal thymus and liver were inoculated with a low-passage-number isolate of CMV, strain Toledo, consistent high-level viral replication was detected 5, 12, 15, 28, and 35 days after inoculation and virus replication continued for up to 9 months. Other human tissue implants, including lung and colon, were also found to support viral growth but with greater variability in levels and for a shorter duration. As expected, the species specificity of human CMV was preserved in this model such that virus was detected in the human conjoint thymus/liver implant but not in surrounding mouse tissues. The majority of virus-infected cells were localized in the thymic medulla rather than cortical region of the implant and immunofluorescence analysis identified epithelial cells rather than any hematopoietic cell population as the principal hosts for viral replication. Finally, treatment of infected animals with ganciclovir reduced viral replication, thereby demonstrating the value of this system for evaluating antiviral therapies. This animal model opens the way for a range of investigations not previously possible with human CMV.

Animals↗

PubMed2000

Hepatitis C-induced hepatic allograft injury is associated with a pretransplantation elevated viral replication rate.

Hepatitis C virus (HCV) allograft infection after liver transplantation follows a variable but accelerated course compared with the nontransplantation population. Predictors of outcome and mechanisms of reinfection remain elusive. The accelerated HCV-induced allograft injury associated with a 10- to 20-fold increase in serum viral quantity posttransplantation was hypothesized to be the result of elevated intrahepatic viral replication rates. Patients (N = 23) with HCV-induced end-stage liver disease who underwent liver transplantation between October 1995 and December 1998 were prospectively studied. HCV-induced allograft injury was defined by posttransplantation persistent biochemical hepatitis or allograft fibrosis not explained by other diagnoses. Liver biopsies (N = 92) were obtained by protocol and when clinically indicated. Negative-strand HCV RNA (putative intermediate for replication) was detected by a strand-specific reverse-transcription polymerase chain reaction (RT-PCR) assay and semiquantatively compared with constitutively expressed 18S rRNA. Recipients with increased pretransplantation replication were at increased risk for the development of posttransplantation biochemical hepatitis (P =.03), an increased rate of allograft fibrosis (P =.006), and increased mortality rate (40.0% vs. 0.0%; P =.02). There was no correlation with quantities of genomic HCV RNA in the serum with relative intrahepatic viral replication either before or after liver transplantation. The relative rate of HCV replication within the allograft was not elevated in the posttransplantation period compared with that seen within the explanted liver. Accelerated allograft injury caused by HCV may be predicted by viral replication rates within the explanted liver. The stable intrahepatic replication rate after transplantation suggests that elevated serum viral loads are the result of decreased viral clearance, possibly secondary to immunosuppressive therapy.

Adolescent↗

PubMed1990

Modified oligopeptides designed to interact with the HIV-1 proteinase inhibit viral replication.

The human immunodeficiency virus 1 (HIV-1) codes for a proteinase that cuts viral proteins at specific sites. We have tested 13 modified oligopeptides related to these cleavage sites to see if they inhibit viral replication. To indicate whether a decrease in replication could be due to a general inhibition of cell metabolism, we also measured the effect of the peptides on cellular protein synthesis. Three of the peptides tested (Ac-Gln-Asn-Sta-Val-NH2, Ac-Gln-Asn-Sta-Val-Val-NH2, and Ac-Glu-Asn-Sta-Ile-NH2) inhibited HIV-1 replication at concentrations that did not inhibit protein synthesis. Ac-Gln-Asn-Sta-Val-NH2 was the most potent, causing an approximately 40% decrease in viral replication, measured as the synthesis of HIV-1 antigens and the formation of infectious particles.

Amino Acid Sequence↗

PubMed1993

Pseudorabies virus infection of the rat central nervous system: ultrastructural characterization of viral replication, transport, and pathogenesis.

Pseudorabies virus (PRV) has been used extensively to map synaptic circuits in the CNS and PNS. A fundamental assumption of these studies is that the virus replicates within synaptically linked populations of neurons and does not spread through the extracellular space or by cell-to-cell fusion. In the present analysis we have used electron microscopy to characterize pathways of viral replication and egress that lead to transneuronal infection of neurons, and to document the non-neuronal response to neuronal infection. Three strains of PRV that differ in virulence were used to infect preganglionic motor neurons in the dorsal motor nucleus of the vagus (DMV). The data demonstrate that viral replication and transneuronal passage occur in a stepwise fashion that utilizes existing cellular processes, and that the non-neuronal response to infection serves to restrict nonspecific spread of virus by isolating severely infected neurons. Specifically, capsids containing viral DNA replicate in the cell nucleus, traverse the endoplasmic reticulum to gain access to the cytoplasm, and acquire a bilaminar membrane envelope from the trans cisternae of the Golgi. The outer leaf of this envelope fuses with the neuron membrane to release virus adjacent to axon terminals that synapse upon the infected cell. A second fusion event involving the viral envelope and the afferent terminal releases the naked capsid into the bouton. Systematic analysis of serial sections demonstrated that release of virus from infected neurons occurs preferentially at sites of afferent contact. Nonspecific diffusion of virus from even the most severely infected cells is restricted by astrocytes and other non-neuronal elements that are mobilized to the site of viral infectivity. The ability of glia and macrophages to restrict spread of virus from necrotic neurons is the product of (1) temporal differences in the mobilization of these cells to the site of infection, (2) differential susceptibility of these cells to PRV infection, and (3) abortive viral replication in cells that are permissive for infection. The findings provide further insight into the intracellular routes of viral assembly and egress and support the contention that transneuronal spread of virus in the brain results from specific passage of virions through synaptically linked neurons rather than through cell fusion or release of virus into the extracellular space.

Animals↗

PubMed2002

Restriction of viral replication by mutation of the influenza virus matrix protein.

The matrix protein (M1) of influenza virus plays an essential role in viral assembly and has a variety of functions, including association with influenza virus ribonucleoprotein (RNP). Our previous studies show that the association of M1 with viral RNA and nucleoprotein not only promotes formation of helical RNP but also is required for export of RNP from the nucleus during viral replication. The RNA-binding domains of M1 have been mapped to two independent regions: a zinc finger motif at amino acid positions 148 to 162 and a series of basic amino acids (RKLKR) at amino acid positions 101 to 105, which is also involved in RNP-binding activity. To further understand the role of the RNP-binding domain of M1 in viral assembly and replication, mutations in the coding sequences of RKLKR and the zinc finger motif of M1 were constructed using a PCR technique and introduced into wild-type influenza virus by reverse genetics. Altering the zinc finger motif of M1 only slightly affected viral growth. Substitution of Arg with Ser at position 101 or 105 of RKLKR did not have a major impact on nuclear export of RNP or viral replication. In contrast, deletion of RKLKR or substitution of Lys with Asn at position 102 or 104 of RKLKR resulted in a lethal mutation. These results indicate that the RKLKR domain of M1 protein plays an important role in viral replication.

Active Transport, Cell Nucleus↗

PubMedDate not supplied

Virus-induced increases in airway mast cells in brown Norway rats are associated with enhanced pulmonary viral replication and persisting lymphocytic infiltration.

Brown Norway (BN) rats are more susceptible than Fischer 344 (F344) rats to parainfluenza virus-induced lung injury and to bronchiolar mast cell increases that are associated with persistent airway hyperresponsiveness. In this study, pulmonary viral replication as well as immune, inflammatory, and airway mast cell responses to Sendai virus infection were compared between neonatal BN and F344 rats. BN rats supported prolonged viral replication, and viral titers in BN rats were 5-fold higher (p < .05) than in F344 rats at 7 days after inoculation. F344 rats had 18-fold higher (p < .06) numbers of lymphocytes in bronchoalveolar lavage fluid at 7 days after inoculation than did BN rats. Persisting bronchiolar aggregates of lymphocytes, plasma cells, and macrophages were more common, and increases in bronchiolar mast cells were greater in BN rats than in F344 rats. No strain differences were detected in bronchiolar intramural infiltrates of CD4 + or CD8 + cells. The greater susceptibility of BN rats to virus-induced increases in bronchiolar mast cells and airway responsiveness may be the result of their less efficient viral clearance mechanisms and more persistent bronchiole-centered inflammatory response.

Animals↗

PubMed2002

Evolution of phenotypic drug susceptibility and viral replication capacity during long-term virologic failure of protease inhibitor therapy in human immunodeficiency virus-infected adults.

Continued use of antiretroviral therapy despite the emergence of drug-resistant human immunodeficiency virus (HIV) has been associated with the durable maintenance of plasma HIV RNA levels below pretherapy levels. The factors that may account for this partial control of viral replication were assessed in a longitudinal observational study of 20 HIV-infected adults who remained on a stable protease inhibitor-based regimen despite ongoing viral replication (plasma HIV RNA levels consistently >500 copies/ml). Longitudinal plasma samples (n = 248) were assayed for drug susceptibility and viral replication capacity (measured by using a single-cycle recombinant-virus assay). The initial treatment-mediated decrease in plasma viremia was directly proportional to the reduction in replicative capacity (P = 0.01). Early virologic rebound was associated the emergence of a virus population exhibiting increased protease inhibitor phenotypic resistance, while replicative capacity remained low. During long-term virologic failure, plasma HIV RNA levels often remained stable or increased slowly, while phenotypic resistance continued to increase and replicative capacity decreased slowly. The emergence of primary genotypic mutations within protease (particularly V82A, I84V, and L90M) was temporally associated with increasing phenotypic resistance and decreasing replicative capacity, while the emergence of secondary mutations within protease was associated with more-gradual changes in both phenotypic resistance and replicative capacity. We conclude that HIV may be constrained in its ability to become both highly resistant and highly fit and that this may contribute to the continued partial suppression of plasma HIV RNA levels that is observed in some patients with drug-resistant viremia.

Adult↗

PubMed1998

Exercise effects on IFN-beta expression and viral replication in lung macrophages after HSV-1 infection.

Mice exercised to fatigue and exposed to herpes simplex virus type 1 (HSV-1) exhibit greater mortality than control mice. In this study, we examined lung macrophage resistance to HSV-1 after exercise in terms of both viral replication and interferon (IFN)-beta production. We utilized the reverse transcriptase-rapid polymerase chain reaction to measure the IFN-beta mRNA content in alveolar macrophages. IFN release was measured with a bioassay, and viral replication within the macrophage was assessed by plaque titration. Exercised (Ex) mice ran on a treadmill until fatigue while control (Con) mice remained in lanes above the treadmill. After exercise, alveolar macrophages were removed and incubated with HSV-1. Alveolar macrophage IFN-beta mRNA was greater in Ex than in Con mice. Culture supernatant from infected macrophages showed a higher degree of IFN release and a higher number of infectious viral particles in Ex vs. Con mice. It is likely that the increase in IFN-beta mRNA occurs in response to a higher degree of viral replication. These results suggest that macrophages from Ex mice are less resistant to infection with HSV-1.

Animals↗

PubMed1997

The HIV-1 associated dementia complex: a metabolic encephalopathy fueled by viral replication in mononuclear phagocytes.

HIV enters the brain soon after virus exposure but elicits profound neurological deficits in infected humans years later usually during progressive immunosuppression and the development of the acquired immune deficiency syndrome. The neurological disease complex associated with virus infection occurs in a large proportion of infected patients and is commonly referred to as HIV-1 associated dementia complex. The neuropathogenesis of central nervous system/viral infection revolves around mononuclear phagocytes (brain macrophage/microglial) infection and immune activation in brain. Macrophages secrete neurotoxic factors that elicit neuronal injury and inevitably death leading to the constellation of cognitive and motor impairments common during progressive disease. Neurotoxic factor production requires virus entry and replication, the evolution/selection of neurovirulent HIV-1 strains and the production of viral and cellular immune factors injurious to human neurons. Interestingly, neurological deficits, the HIV-1 associated neuropathology and viral replication disease are not always associated. This has led to the notion that viral replication induces the autocrine/paracrine production of cellular/viral factors leading to a metabolic encephalopathy. Anti-retroviral and anti-inflammatory therapies should prove increasingly beneficial for treatment and, ultimately, reversal of HIV-1 associated dementia complex in the affected human host.

AIDS Dementia Complex↗

PubMed1990

Innate resistance to herpes simplex virus infection. Human lymphocyte and monocyte inhibition of viral replication.

Peripheral blood monocytes and lymphocytes isolated from most humans are resistant to HSV infection in vitro. Viral replication is inhibited very early in the cycle, prior to the onset of alpha-protein synthesis; no viral protein or DNA synthesis is detectable even up to 1 week later. The enhanced expression of two 62-kDa and 57-kDa cellular proteins, however, is induced in the lymphocyte population within 3 to 5 h after infection. A 30-kDa protein is induced in the monocyte population immediately after infection. The induced expression of 62-kDa and 57-kDa lymphocyte proteins appears to be virus-mediated because: a) HSV and pseudorabies virus (although not vaccinia virus) induce the expression of 62-kDa and 57-kDa proteins, b) heat shock or exposure of lymphocytes to uninfected cell extracts does not induce expression of either protein, c) 62-kDa protein is not induced in lymphocytes stimulated with a mitogenic concentration of PHA. UV-inactivated HSV induces expression of 62-kDa and 57-kDa proteins in a manner similar to that observed with untreated virus. In contrast, expression of 30-kDa monocyte protein is induced nonspecifically by either uninfected cell extracts or cell extracts containing virus. Sixty-two-kilodalton and 57-kDa protein induction appears to be a marker for human lymphocytes that express profound intracellular resistance to infection with HSV. Induced expression of these proteins occurs only in lymphocytes that inhibit viral replication very early in the growth cycle, prior to the onset of alpha-protein synthesis. Expression of 62-kDa and 57-kDa proteins is not induced in lymphocytes that are permissive or partially permissive to infection with HSV.

Cells, Cultured↗

PubMed1987

Association of polioviral proteins of the P2 genomic region with the viral replication complex and virus-induced membrane synthesis as visualized by electron microscopic immunocytochemistry and autoradiography.

Using high resolution electron microscopic autoradiography and immunocytochemistry with monoclonal antibodies against poliovirus proteins of the P2 genomic region, the location of these proteins in respect to the virus-induced vesicle formation and the viral RNA synthesis was followed during the viral replication cycle. It was found that P2 proteins become rER associated soon after their synthesis. At the site of protein and rER interaction, electron-dense patches appear. Simultaneously, membrane protrusions grow and form vesicles which finally budd off, carrying the patches on their outer surface. As shown by autoradiography, these patches are the site of viral RNA replication and, therefore, they represent the poliovirus replication complex. The vesicles with the replication complex, including replicating and replicated viral RNA, move away from the rER to form a continuously growing vesiculated area in the center of the infected cell, where virus maturation takes place. A likely function of the 2C protein is to attach the replication complex, or some of its components, to the vesicular membranes.

Antibodies, Monoclonal↗

PubMed1999

A novel tetracycline-inducible viral replication switch.

With the cloning of DNA encoding the trans-dominant negative mutant form of the HSV-1 origin-binding protein UL9, UL9-C535C, under the control of the tet operator-bearing hCMV major immediate-early promoter (pcmvtetO), this article demonstrates that the tetR-mediated mammalian transcription repression switch (Yao et al., Hum. Gene Ther. 9:1939-1950, 1998) can be converted to a novel HSV-1-specific viral replication switch. Using this viral replication switch, the plaque-forming efficiency of infectious HSV-1 DNA can be reversibly regulated by tetR over 100-fold in transient viral infection assays. Moreover, while less than 0 PFU/ml of HSV-1 was detected from tetR-expressing cells transfected with infectious HSV-1 DNA and plasmid pcmvtetOUL9-C535C in the presence of tetracycline, close to 1000 PFU/ml of HSV-1 was produced when similar experiments were carried out in the absence of tetracycline. The tetracycline treatment led no reduction in HSV-1 synthesis in cells transfected with infectious HSV-1 DNA alone. Taken together, given that the UL9-C535C-associated antiviral activity can be silenced in the context of this HSV-1 replication switch, the establishment of this reversible switch would allow construction of a new generation of HSV-1 recombinants able to inhibit its own replication as well as replication of wild-type virus.

Animals↗

PubMed1996

Dynamics of viral replication in infants with vertically acquired human immunodeficiency virus type 1 infection.

About one-third of vertically HIV-1 infected infants develop AIDS within the first months of life; the remainder show slower disease progression. We investigated the relationship between the pattern of HIV-1 replication early in life and disease outcome in eleven infected infants sequentially studied from birth. Viral load in cells and plasma was measured by highly sensitive competitive PCR-based methods. Although all infants showed an increase in the indices of viral replication within their first weeks of life, three distinct patterns emerged: (a) a rapid increase in plasma viral RNA and cell-associated proviral DNA during the first 4-6 wk, reaching high steady state levels (> 1,000 HIV-1 copies/10(5) PBMC and > 1,000,000 RNA copies/ml plasma) within 2-3 mo of age; (b) a similar initial rapid increase in viral load, followed by a 2.5-50-fold decline in viral levels; (c) a significantly lower (> 10-fold) viral increase during the first 4-6 wk of age. All infants displaying the first pattern developed early AIDS, while infants with slower clinical progression exhibited the second or third pattern. These findings demonstrate that the pattern of viral replication and clearance in the first 2-3 mo of life is strictly correlated with, and predictive of disease evolution in vertically infected infants.

DNA, Viral↗

PubMed2005

Effects of valproic acid derivatives on inositol trisphosphate depletion, teratogenicity, glycogen synthase kinase-3beta inhibition, and viral replication: a screening approach for new bipolar disorder drugs derived from the valproic acid core structure.

Inositol-1,4,5-trisphosphate (InsP3) depletion has been implicated in the therapeutic action of bipolar disorder drugs, including valproic acid (VPA). It is not currently known whether the effect of VPA on InsP3 depletion is related to the deleterious effects of teratogenicity or elevated viral replication, or if it occurs via putative inhibitory effects on glycogen synthase kinase-3beta (GSK-3beta). In addition, the structural requirements of VPA-related compounds to cause InsP3 depletion are unknown. In the current study, we selected a set of 10 VPA congeners to examine their effects on InsP3 depletion, in vivo teratogenic potency, HIV replication, and GSK-3beta activity in vitro. We found four compounds that function to deplete InsP3 in the model eukaryote Dictyostelium discoideum, and these drugs all cause growth-cone enlargement in mammalian primary neurons, consistent with the effect of InsP3 depletion. No relationship was found between InsP3 depletion and teratogenic or elevated viral replication effects, and none of the VPA congeners were found to affect GSK-3beta activity. Structural requirements of VPA congers to maintain InsP3 depletion efficacy greater than that of lithium are a carboxylic-acid function without dependence on side-chain length, branching, or saturation. Noteworthy is the enantiomeric differentiation if a chiral center exists, suggesting that InsP3 depletion is mediated by a stereoselective mode of action. Thus, the effect of InsP3 depletion can be separated from that of teratogenic potency and elevated viral replication effect. We have used this to identify two VPA derivatives that share the common InsP3-depleting action of VPA, lithium and carbamazepine, but do not show the side effects of VPA, thus providing promising novel candidates for bipolar disorder treatment.

Animals↗

PubMed2003

Multispecific vaccine-induced mucosal cytotoxic T lymphocytes reduce acute-phase viral replication but fail in long-term control of simian immunodeficiency virus SIVmac239.

Given the current difficulties generating vaccine-induced neutralizing antibodies to human immunodeficiency virus (HIV), the focus of the vaccine community has shifted toward creating cytotoxic-T-lymphocyte (CTL)-based vaccines. Recent reports of CTL-based vaccine trials in macaques challenged with simian/human immunodeficiency virus SHIV-89.6P have supported the notion that such vaccines can ameliorate the course of disease. However, almost all of these studies included Env as an immunogen and since SHIV-89.6P is sensitive to neutralizing antibodies it is difficult to determine the mechanism(s) of protection. Consequently, SHIV-89.6P challenge of macaques may be a poor model for determining vaccine efficacy in humans. To ascertain the effect of vaccine-induced multispecific mucosal CTL, in the absence of Env-specific antibody, on the control of an immunodeficiency virus challenge, we vaccinated Mamu-A*01(+) macaques with constructs encoding a combination of CTL epitopes and full-length proteins (Tat, Rev, and Nef) by using a DNA prime/recombinant modified vaccinia virus Ankara (rMVA) boost regimen. The vaccination induced virus-specific CTL and CD4(+) helper T lymphocytes with CTL frequencies as high as 20,000/million peripheral blood mononuclear cells. The final rMVA vaccination, delivered intravenously, engendered long-lived mucosal CTL. At 16 weeks after the final rMVA vaccination, the vaccinees and naive, Mamu-A*01(+) controls were challenged intrarectally with SIVmac239. Massive early anamnestic cellular immune responses controlled acute-phase viral replication; however, the three vaccinees were unable to control virus replication in the chronic phase. The present study suggests that multispecific mucosal CTL, in the absence of neutralizing antibodies, can achieve a modicum of control over early viral replication but are unable to control chronic-phase viral replication after a high-dose mucosal challenge with a pathogenic simian immunodeficiency virus.

Acute Disease↗