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J C Kappes

Publications and source records attributed to J C Kappes.

At least 37 records · Page 2Linked to original sources
PubMed1995

Targeting foreign proteins to human immunodeficiency virus particles via fusion with Vpr and Vpx.

The human immunodeficiency virus type 1 (HIV-1) and HIV-2 Vpr and Vpx proteins are packaged into virions through virus type-specific interactions with the Gag polyprotein precursor. To examine whether HIV-1 Vpr (Vpr1) and HIV-2 Vpx (Vpx2) could be used to target foreign proteins to the HIV particle, their open reading frames were fused in frame with genes encoding the bacterial staphylococcal nuclease (SN), an enzymatically inactive mutant of SN (SN*), and chloramphenicol acetyltransferase (CAT). Transient expression in a T7-based vaccinia virus system demonstrated the synthesis of appropriately sized Vpr1-SN/SN* and Vpx2-SN/SN* fusion proteins which, when coexpressed with their cognate p55Gag protein, were efficiently incorporated into virus-like particles. Packaging of the fusion proteins was dependent on virus type-specific determinants, as previously seen with wild-type Vpr and Vpx proteins. Particle-associated Vpr1-SN and Vpx2-SN fusion proteins were enzymatically active, as determined by in vitro digestion of lambda phage DNA. To determine whether functional Vpr1 and Vpx2 fusion proteins could be targeted to HIV particles, the gene fusions were cloned into an HIV-2 long terminal repeat/Rev response element-regulated expression vector and cotransfected with wild-type HIV-1 and HIV-2 proviruses. Western blot (immunoblot) analysis of sucrose gradient-purified virions revealed that both Vpr1 and Vpx2 fusion proteins were efficiently packaged regardless of whether SN, SN*, or CAT was used as the C-terminal fusion partner. Moreover, the fusion proteins remained enzymatically active and were packaged in the presence of wild-type Vpr and Vpx proteins. Interestingly, virions also contained smaller proteins that reacted with antibodies specific for the accessory proteins as well as SN and CAT fusion partners. Since similar proteins were absent from Gag-derived virus-like particles and from virions propagated in the presence of an HIV protease inhibitor, they must represent cleavage products produced by the viral protease. Taken together, these results demonstrate that Vpr and Vpx can be used to target functional proteins, including potentially deleterious enzymes, to the human or simian immunodeficiency virus particle. These properties may be exploitable for studies of HIV particle assembly and maturation and for the development of novel antiviral strategies.

Amino Acid Sequence↗
PubMed1994

Optimization of quantitative culture assay for human immunodeficiency virus from plasma. Plasma Viremia Group Laboratories of the AIDS Clinical Trials Group (National Institute of Allergy and Infectious Diseases).

Experimental conditions essential to a simple, reproducible, quantitative human immunodeficiency virus plasma assay were determined. Five parameters were evaluated: length of culture, reproducibility, assay dilution schema, washing procedures, and anticoagulant usage. The recommended quantitative plasma assay utilizes undiluted citrated plasma cultured with peripheral blood mononuclear cells for 14 days with fivefold dilutions and a medium change on day 1 with no washing.

Blood↗
PubMed1994

Localization of the Vpx packaging signal within the C terminus of the human immunodeficiency virus type 2 Gag precursor protein.

Viral protein X (Vpx) is a human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus accessory protein that is packaged into virions in molar amounts equivalent to Gag proteins. To delineate the processes of virus assembly that mediate Vpx packaging, we used a recombinant vaccinia virus-T7 RNA polymerase system to facilitate Gag protein expression, particle assembly, and extracellular release. HIV genes were placed under control of the bacteriophage T7 promoter and transfected into HeLa cells expressing T7 RNA polymerase. Western immunoblot analysis detected p55gag and its cleavage products p39 and p27 in purified particles derived by expression of gag and gag-pol, respectively. In trans expression of vpx with either HIV-2 gag or gag-pol gave rise to virus-like particles that contained Vpx in amounts similar to that detected in HIV-2 virus produced from productively infected T cells. Using C-terminal deletion and truncation mutants of HIV-2 Gag, we mapped the p15 coding sequence for determinants of Vpx packaging. This analysis revealed a region (residues 439 to 497) downstream of the nucleocapsid protein (NC) required for incorporation of Vpx into virions. HIV-1/HIV-2 gag chimeras were constructed to further characterize the requirements for incorporation of Vpx into virions. Chimeric HIV-1/HIV-2 Gag particles consisting of HIV-1 p17 and p24 fused in frame at the C terminus with HIV-2 p15 effectively incorporate Vpx, while chimeric HIV-2/HIV-1 Gag particles consisting of HIV-2 p17 and p27 fused in frame at the C terminus with HIV-1 p15 do not. Expression of a 68-amino-acid sequence of HIV-2 containing residues 439 to 497 fused to the coding regions of HIV-1 p17 and p24 also produced virus-like particles capable of packaging Vpx in amounts similar to that of full-length HIV-2 Gag. Sucrose gradient analysis confirmed particle association of Vpx and Gag proteins. These results demonstrate that the HIV-2 Gag precursor (p55) regulates incorporation of Vpx into virions and indicates that the packaging signal is located within residues 439 to 497.

Amino Acid Sequence↗
PubMed1993

A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. L-697,661 Working Group.

BACKGROUND: The non-nucleoside reverse transcriptase inhibitors are novel antiretroviral agents with selective activity in vitro against human immunodeficiency virus type 1 (HIV-1). They act through direct inhibition of reverse transcriptase and are not incorporated into DNA. METHODS: We evaluated a pyridinone non-nucleoside reverse transcriptase inhibitor, L-697,661, in separate six-week double-blind trials in patients with HIV-1 infection whose CD4 counts ranged from 200 to 500 cells per cubic millimeter (68 patients) or less than 200 cells per cubic millimeter (67 patients). Eligible patients were randomly assigned to receive L-697,661 orally in one of three doses (25 mg twice a day, 100 mg three times a day, or 500 mg twice a day) or zidovudine (100 mg five times a day). Clinical and laboratory assessments were performed weekly. Viral isolates were obtained from a subgroup of patients before and after treatment and were evaluated for in vitro sensitivity to L-697,661. RESULTS: Both L-697,661 and zidovudine were well tolerated. Transient increases in CD4 counts were noted in the patients with fewer than 200 CD4 cells per cubic millimeter who received the two higher doses of L-697,661, but not in those who received the lowest dose or zidovudine. Patients who received L-697,661 had rapid, dose-related decreases in plasma p24 antigen levels. However, this response virtually disappeared after six weeks in some patients receiving L-697,661, coincidently with the emergence of resistant viruses. This change in susceptibility was more frequent among patients receiving the higher doses of L-697,661 and was associated with amino acid substitutions at positions 103 and 181 in the HIV-1 reverse transcriptase gene. CONCLUSIONS: L-697,661 is safe and well tolerated and has significant dose-related activity against HIV-1. However, resistant strains of the virus emerge rapidly and may limit the effectiveness of non-nucleoside reverse transcriptase inhibitors as monotherapy for HIV-1 infection.

Adult↗
PubMed1993

High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR.

Quantitative competitive polymerase chain reaction (QC-PCR) methods were used to quantify virion-associated human immunodeficiency virus type-1 (HIV-1) RNA in plasma from 66 patients with Centers for Disease Control stage I to IVC1 infection. HIV-1 RNA, ranging from 100 to nearly 22,000,000 copies per milliliter of plasma (corresponding to 50 to 11,000,000 virions per milliliter), was readily quantified in all subjects, was significantly associated with disease stage and CD4+ T cell counts, and decreased by as much as 235-fold with resolution of primary infection or institution of antiretroviral therapy. Plasma virus levels determined by QC-PCR correlated with, but exceeded by an average of 60,000-fold, virus titers measured by endpoint dilution culture. Quantitation of HIV-1 in plasma by QC-PCR may be useful in assessing the efficacy of antiretroviral agents, especially in early stage disease when conventional viral markers are often negative.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Intracellular transport and virion incorporation of vpx requires interaction with other virus type-specific components.

Viral protein X (vpx) is a virion-associated HIV-2/SIV accessory protein that enhances viral infectivity and replication in natural target cells. To investigate whether other viral components affect its biosynthesis, subcellular localization, and virion incorporation, we expressed HIV-2 vpx in a mammalian cell system and examined its transport and packaging requirements using an in trans complementation assay. The complete vpx coding region of HIV-2ST was placed under the control of a high-efficiency promoter system (SR alpha) which contained both an SV40 promoter/enhancer region and R/U5 elements of the HTLV-1 LTR. Following transfection of Cos-1 cells, this construct (pSR alpha-vpx) facilitated high level expression of vpx, as demonstrated by Western blot analysis of transfected cell lysates. Moreover, indirect immunofluorescence analysis revealed an intense vpx staining pattern distributed evenly throughout the cytoplasm of transfected cells. This distribution differed markedly from cells expressing wild-type HIV-2 in which vpx localized to the inner surface of the plasma membrane. To determine whether other HIV components were required for this surface localization, we expressed vpx in the context of replication competent HIV-1 and HIV-2 proviruses. Following cotransfection with a vpx-deficient HIV-2 provirus (pXM7), eukaryotically expressed vpx targeted to the plasma membrane and colocalized with HIV-2 p27 gag in a pattern indistinguishable from wild-type HIV-2. Moreover, progeny virions from cotransfected Cos-1 cells contained wild-type amounts of vpx protein, demonstrating that vpx could be efficiently packaged in trans. Under the same experimental conditions, cotransfection of vpx with wild-type HIV-1 (pHXB2) and with vpr-deficient HIV-1 (pR2) failed to result in detectable cell surface targeting or virion incorporation of vpx despite its high level cellular expression. These results demonstrate that efficient intracellular transport and packaging of vpx require interaction with other type-specific virus components.

Amino Acid Sequence↗
PubMed1993

Determination of plasma viral load in HIV-1 infection by quantitative competitive polymerase chain reaction.

OBJECTIVES: To better characterize viral load profiles through the course of HIV-1 disease and in response to treatment, and to further evaluate quantitative competitive polymerase chain reaction for measurement of viral load, we extended our comparative evaluation of this and other viral load measurements to a total of 118 patients, representing all stages of HIV-1 disease. DESIGN: For cross-sectional analysis across the spectrum of HIV-1 disease, plasma viral load was evaluated in 112 HIV-1-infected patients by quantitative competitive polymerase chain reaction analysis, plasma p24 antigen assay, plasma immune complex-dissociated p24 antigen assay and an endpoint dilution viral culture. Longitudinal specimens from six additional patients were analyzed, extending from the time of presentation with symptomatic acute HIV-1 infection through up to more than 2 years of follow-up. Longitudinal specimens were also studied for three patients over the period of initiation of zidovudine treatment, for 6 weeks of treatment and following temporary withdrawal of the treatment. METHODS: All measurement techniques were assessed in replicate aliquots of plasma. RESULTS: Quantitative competitive polymerase chain reaction was the most sensitive measure of viral load, and was best correlated with CD4+ T-cell counts. In longitudinally studied patients, this technique also allowed measurement of plasma virus levels throughout the period of follow-up, even when culture and p24 assays became negative following resolution of acute HIV-1 infection. The quantitative competitive polymerase chain reaction was also able to detect rapid and substantial changes in viral load associated with initiation and temporary withdrawal of antiviral treatment. CONCLUSIONS: The quantitative competitive polymerase chain reaction is promising as a sensitive and accurate method for measuring plasma viral load in HIV-1-infected patients, and is useful for following changes in viral load over the natural history of infection and following treatment intervention. The technique is particularly useful for patients with > 200 x 10(6) CD4+ T cells/l, in whom other viral markers are typically negative.

Biomarkers↗
PubMed1991

High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection.

BACKGROUND: Primary infection with the human immunodeficiency virus (HIV-1) frequently causes an acute, self-limited viral syndrome. To examine the relations among viral replication, the immune response of the host, and clinical illness during this initial phase of infection, we undertook a quantitative, molecular, and biologic analysis of infectious HIV-1 in the blood and plasma of three patients with symptomatic primary infection and of a sexual partner of one of them. METHODS: During an eight-week period of primary infection, HIV-1 was cultured frequently in dilutions of plasma and peripheral-blood mononuclear cells (PBMC), and levels of HIV-1 antigen and antibody were determined sequentially by enzyme-linked immunosorbent assay and immunoblotting. Replication-competent HIV-1 proviruses were cloned and characterized biologically. RESULTS: Six to 15 days after the onset of symptoms, high titers of infectious HIV-1 (from 10 to 10(3) tissue-culture-infective doses per milliliter of plasma) and viral p24 antigen were detected in the plasma of all three patients. These titers fell precipitously by day 27, and the decline coincided with an increase in the levels of antiviral antibodies and the resolution of symptoms. Sequential isolates of virus from plasma and PBMC obtained throughout the period of primary infection, as well as virus derived from two molecular proviral clones, were highly cytopathic for normal-donor PBMC and immortalized T cells, despite the marked reduction in the titers of virus in plasma. CONCLUSIONS: Primary, symptomatic HIV-1 infection is associated with high titers of cytopathic, replication-competent viral strains, and during such infection potential infectivity is enhanced. Effective control of HIV-1 replication during primary infection implies the activation of clinically important mechanisms of immune defense that merit further examination in relation to the development of antiviral therapy and vaccines.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Human immunodeficiency virus type 2 vpx protein augments viral infectivity.

The genomes of HIV and SIV are complex and contain several accessory genes which modulate viral replication and pathogenicity. One of these genes, vpx, is unique to the HIV-2/SIV group of viruses and encodes a virion-associated protein of unknown function. To examine the function of vpx, we constructed a vpx-deficient HIV-2 proviral clone and characterized its in vitro biological properties. Following transfection into immortalized T-cell lines, vpx-mutant HIV-2 was fully replication competent and exhibited growth kinetics and cytopathic properties equivalent to wild-type HIV-2. In addition, vpx-deficient virions were indistinguishable from wild-type HIV-2 in ultrastructure, composition of major structural proteins, and reverse transcriptase activity. In PHA-stimulated normal peripheral blood mononuclear cells (PBMCs), however, vpx-deficient virus replicated at substantially lower titers and required a 100- to 1000-fold higher inoculum to establish a productive infection. This defect was localized to early events in the viral life cycle since vpx-deficient virus exhibited a 5- to 10-fold reduction in initial (single cycle) viral DNA synthesis following acute infection of primary PBMCs. Paradoxically, in long-term (9-23 months) cultures of immortalized T-cells (SupT1) continuous high level replication of vpx-deficient, but not wild-type, virus was observed, indicating less efficient viral spread and cell killing and a more attenuated phenotype of vpx-deficient HIV-2. Taken together, these results demonstrate that vpx is required for the production of fully infectious and cytopathic HIV-2 virions and that it functions early in the viral life cycle by facilitating viral entry and/or reverse transcription. The pronounced replicative defect of vpx-deficient HIV-2 in primary PBMCs but not in short-term cultures of immortalized T-cell lines emphasizes the need to characterize the properties of nonessential HIV accessory gene products in natural target cells.

Amino Acid Sequence↗
PubMed1991

Molecular characterization of human immunodeficiency virus type 1 cloned directly from uncultured human brain tissue: identification of replication-competent and -defective viral genomes.

All presently available replication-competent proviral clones of human immunodeficiency virus type 1 (HIV-1) are derived from cell culture-amplified virus. Since tissue culture is highly selective for viral strains with an in vitro growth advantage, such clones may not be representative of the biologically relevant virus present in vivo. In this study, we report the molecular cloning and genotypic characterization of 10 HIV-1 genomes directly from uncultured brain tissue of a patient with AIDS dementia complex. Targeting unintegrated circular HIV-1 molecules for recombinant lambda phage cloning, we obtained four full-length genomes with one or two long terminal repeats (LTRs), three defective genomes with internal deletions, two rearranged genomes with inverted LTR sequences, and one integrated proviral half with flanking cellular sequences. Nucleotide sequence analysis of these clones demonstrated chromosomal integration, circle formation, genomic inversion, and LTR-mediated autointegration of HIV-1 genomes in vivo. Comparison of a 510-bp hypervariable envelope region among 8 lambda phage-derived and 12 polymerase chain reaction-derived clones from the same brain specimen identified a predominant viral form as well as genetically divergent variants. Variability among 19 of 20 clones ranged between 0.2 and 1.2%. One clone exhibited 8.2% nucleotide sequence differences consisting almost exclusively of G-to-A changes. Transfection of the four full-length HIV-1 genomes identified one clone (YU-2) as replication competent and exhibiting growth characteristics similar to those of tissue culture-derived macrophage tropic strains of HIV-1. These results demonstrate, for the first time, that replication-competent HIV-1 genomes, complex mixtures of defective viral forms, and chromosomally integrated provirus persist in vivo. In addition, the brain-derived viral clones are expected to prove valuable for future studies of macrophage and neurotropism as well as for the analysis of other viral properties that are subject to in vitro selection pressures.

AIDS Dementia Complex↗
PubMed1990

Molecular characterization of an attenuated human immunodeficiency virus type 2 isolate.

Naturally occurring strains of human immunodeficiency virus (HIV) can vary considerably in their in vitro biological properties, and such differences may also be reflected in their in vivo pathogenesis. In an attempt to define genetic determinants of viral pathogenicity, we have molecularly cloned, sequenced, and characterized an attenuated isolate of HIV type 2 (HIV-2/ST) that differs from prototype HIV-2 strains in its inability to fuse with and kill susceptible CD4-bearing target cells. A proviral clone, termed JSP4-27, was identified to be transfection competent and to fully exhibit the noncytopathic and nonfusogenic properties of its parental isolate. Nucleotide sequence analysis of this clone revealed a genomic organization very similar to that of cytopathic HIV-2 strains and an overall nucleotide sequence homology of 88 to 90%. Amino acid sequence comparison confirmed the integrity of all major viral gene products in JSP4-27 but identified two amino acid sequence substitutions in its envelope fusion region. To investigate whether these mutations were responsible for the nonfusogenic phenotype of JSP4-27, we amplified, cloned, and sequenced the envelope fusion regions of four additional HIV-2/ST strains, two of which represented in vitro-generated, fusogenic and cytopathic variants of HIV-2/ST. The analysis showed that all HIV-2/ST strains examined, including the fusogenic variants, contained the same amino acid sequence changes. On the basis of these findings, we conclude that the attenuated phenotype of JSP4-27, and that of its parental virus, is not due to a direct alteration of the envelope fusion domain. Our results also show, for the first time, that individual replication-competent proviral clones can be representative of attenuated strains of HIV.

Amino Acid Sequence↗
PubMed1988

West African HIV-2-related human retrovirus with attenuated cytopathicity.

Clinical and seroepidemiological studies in West Africa indicate that human immunodeficiency virus type 2 (HIV-2) is widespread and associated with immunodeficiency states of variable degree. In this study, an isolate of HIV-2 from a patient in Senegal was molecularly cloned and characterized. This isolate (HIV-2ST) was shown by hybridization and restriction enzyme analysis to be more related to the prototype HIV-2ROD than to other human or primate retroviruses. Cultures of HIV-2ST showed genotypic polymorphism, and clones of the virus had transmembrane envelope glycoproteins of 30 and 42 kilodaltons. Unlike other immunodeficiency viruses, HIV-2ST did not cause cell death or induce cell fusion in peripheral blood lymphocytes or in any of four CD4+ cell lines tested. Although HIV-2ST entered cells by a CD4-dependent mechanism and replicated actively, cell-free transmission of the virus was retarded at the level of cell entry. These findings suggest that immunodeficiency viruses prevalent in West African populations are members of the HIV-2 virus group and that certain strains of this virus have attenuated virulence.

Cell Line↗
PubMed1988

Enhanced in vitro reactivation of latent herpes simplex virus from neural and peripheral tissues with hexamethylenebisacetamide.

We evaluated the effect of the demethylating agent hexamethylenebisacetamide on reactivation of latent herpes simplex virus type 2 (HSV-2) from guinea pig neural and extraneural tissues. Four explant cultures from the dorsal root ganglia of 42 latently infected guinea pigs and vaginal and cervical explant cultures from 33 animals were divided so that half received 5 mM of hexamethylenebisacetamide supplemented media and half media alone. HSV-2 was recovered earlier and from a greater percentage of treated cultures than controls. For example, seven days after explant, HSV-2 was recovered from 35 of 84 (42%) treated dorsal root ganglia cultures compared to seven of 84 control cultures (p less than 0.0001). Likewise, HSV-2 was recovered seven days after explant from 11 of 66 (17%) treated external genital skin cultures and 2 of 66 control cultures (p less than 0.009), Hexamethylenebisacetamide had no effect on productive HSV-2 infection in guinea pig dorsal root ganglia cultures. This study provides evidence for a role of demethylation in the reactivation of latent HSV from neural as well as peripheral tissues and suggests that latent virus exists at these sites in a similar state. Hexamethylenebisacetamide should be useful in studies of herpes virus latency because it decreases the time necessary to recover virus from latently infected tissues and enhances the recovery of virus.

Acetamides↗
PubMed1988

Antibody to herpes simplex virus (HSV) ICP-35 proteins after HSV challenge of animals immunized with HSV subunit vaccines.

The serological response to the ICP-35 group of herpes simplex virus type 2 (HSV-2) proteins was examined 30 d after vaginal challenge with HSV-2 of guinea pigs previously immunized with HSV glycoproteins. Detection of antibodies to ICP-35 proteins correlated best with the magnitude of vaginal viral replication. Animals that developed antibody to ICP-35 proteins had more-frequent recurrences (P less than .0002) that were of longer duration (P less than .005) than animals that did not. By covariate analysis the number of recurrences appeared to be related to the severity of the acute disease, inversely related to the enzyme-linked immunosorbent assay titer of antibody to HSV glycoproteins, and related to the detection of antibody to ICP-35 proteins. The duration of recurrent disease, however, could only be correlated with the presence of antibody to ICP-35 proteins. Detection of antibody to ICP-35 proteins is thus a useful prognostic indicator for identifying animals that developed more-severe recurrent disease.

Acute Disease↗
PubMed1988

Enhanced in vitro reactivation of herpes simplex virus type 2 from latently infected guinea-pig neural tissues by 5-azacytidine.

5-Azacytidine (5-AZC) reduces cytosine methylation in DNA and has been reported to activate quiescent virus genes. Treatment of explant cultures of latently herpes simplex virus type 2 (HSV-2)-infected guinea-pig dorsal root ganglia and spinal cords in vitro with 5-AZC significantly enhanced the rate of HSV recovery. Both the number of isolates from ganglia (P less than 0.001) and the rate of recovery (P less than 0.001) were significantly increased with the addition of 50 microM-5-AZC to explant cultures. Increased virus recovery appeared to be due to the induction of reactivation of latent virus, rather than an increase in replication, since 5-AZC inhibited HSV replication. These data support a role for methylation in HSV latency and reactivation.

Animals↗
PubMed1988

Identification of a novel retroviral gene unique to human immunodeficiency virus type 2 and simian immunodeficiency virus SIVMAC.

Human and simian immunodeficiency-associated retroviruses are extraordinarily complex, containing at least five genes, tat, art, sor, R, and 3' orf, in addition to the structural genes gag, pol, and env. Recently, nucleotide sequence analysis of human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus SIVMAC revealed the existence of still another open reading frame, termed X, which is highly conserved between these two viruses but absent from HIV-1. In this report, we demonstrate for the first time that the X open reading frame represents a functional retroviral gene in both HIV-2 and SIVMAC and that it encodes a virion-associated protein of 14 and 12 kilodaltons, respectively. We also describe the production of recombinant TrpE/X fusion proteins in Escherichia coli and show that sera from some HIV-2-infected individuals specifically recognize these proteins.

Amino Acid Sequence↗
PubMed1987

Antibody response to herpes simplex virus glycoprotein D: effects of acyclovir and relation to recurrence.

We developed an enzyme-linked immunosorbent assay (ELISA) for measuring the antibody response to herpes simplex virus (HSV) glycoprotein D (gD). The ELISA was specific and more sensitive than immunoblotting techniques. Antibody to HSV gD was detected in 10 of 12 sera (geometric mean titer, 36.3) obtained from HSV-2-infected guinea pigs 14 days after intravaginal inoculation, and the titer increased to greater than or equal to 5,120 on day 60. Therapy with acyclovir delayed and diminished the antibody response to gD, although by day 60 the titers of antibody to gD in acyclovir-treated animals were not significantly different from those in controls. An increased titer of antibody to gD seemed to be associated with a reduced number of recurrent episodes and to a reduced number of days with recurrent lesions.

Acyclovir↗