Young-Keol Cho

Korean Red Ginseng Slows Depletion of CD4 T Cells in Human Immunodeficiency Virus Type 1-Infected Patients

ABSTRACT We have previously showed that long-term intake of Korean red ginseng (KRG) delayed disease progression in human immunodeficiency virus type 1 (HIV-1)-infected patients. In the present study, to investigate whether this slow progression was affected by KRG intake alone or in combination with HLA factor, we analyzed clinical data in 68 HIV-1-infected patients who lived for more than 5 years without antiretroviral therapy. The average KRG intake over 111.9 ± 31.3 months was 4,082 ± 3,928 g, and annual decrease in CD4 T cells was 35.0 ± 28.7/μl. Data analysis showed that there are significant inverse correlations between the HLA prognostic score (0.29 ± 1.19) and annual decrease in CD4 T cells (r = −0.347; P < 0.01) as well as between the amount of KRG intake and annual decrease in CD4 T cells (r = −0.379; P < 0.01). In addition, KRG intake significantly slowed the decrease in CD4 T cells even when influence of HLA class I was statistically eliminated (repeated-measure analysis of variance; P < 0.05). We also observed significant correlation between KRG intake and a decrease in serum-soluble CD8 antigen level (r = 0.62; P < 0.001). In conclusion, these data show that KRG intake independently and significantly affected the slow depletion of CD4 T cells irrespective of HLA class I.

Protective effect of ginseng polysaccharides on influenza viral infection.

Ginseng polysaccharide has been known to have multiple immunomodulatory effects. In this study, we investigated whether Panax ginseng polysaccharide (GP) would have a preventive effect on influenza infection. Administration of mice with GP prior to infection was found to confer a survival benefit against infection with H1N1 (A/PR/8/34) and H3N2 (A/Philippines/82) influenza viruses. Mice infected with the 2009 H1N1 virus suspended in GP solution showed moderately enhanced survival rates and lower levels of lung viral titers and the inflammatory cytokine (IL-6). Daily treatment of vaccinated mice with GP improved their survival against heterosubtypic lethal challenge. This study demonstrates the first evidence that GP can be used as a remedy against influenza viral infection.

Beneficial Effects of a Combination of Korean Red Ginseng and Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus Type 1-Infected Patients

ABSTRACT To determine whether Korean red ginseng (KRG) has beneficial effects on human immunodeficiency virus type 1 (HIV-1)-infected patients administered highly active antiretroviral therapy (HAART), we analyzed the CD4 T-cell count, viral load, and resistance mutations to HAART in 46 individuals. Thirteen patients harbored resistance mutations at baseline. The study population was divided into two groups: specifically, a group treated with a combination of HAART plus KRG (23 patients) and a group treated with HAART alone (23 patients). The annual increase in CD4 T-cell count in the combination group was significantly higher than that in the group treated with HAART alone (P < 0.05). Overall, 21 patients harbored resistance mutations after 3 years of therapy. Following exclusion of 13 patients displaying baseline resistance mutations, 7.1% of patients (1/14) in the combination group and 42.1% (8/19) in the HAART group were identified with resistance mutations. One patient with baseline resistance mutations in the combination group did not display resistance mutations 3 years after HAART therapy. High-level resistance mutations were significantly lower in the combination group than in the group treated with HAART alone. Five patients showed no improvement in viral copy number (26.3% [5/19]) in the combination group and 9 (45.0% [9/20]) showed no improvement in the HAART-only group. Our data support the clinical utility of KRG intake during HAART therapy.

Protective Effect of Korean Red Ginseng Extract on the Infections by H1N1 and H3N2 Influenza Viruses in Mice

Ginseng has been used in humans for thousands of years and is known to have multiple biological and immunomodulatory effects. In this study, we investigated whether Korean red ginseng extract would have preventive and antiviral effects on influenza virus infection. Oral administration to mice of red ginseng extract prior to infection significantly increased survival after infection with the 2009 pandemic H1N1 virus. Daily oral treatment of vaccinated mice with red ginseng extract provided enhanced cross-protection against antigenically distinct H1N1 and H3N2 influenza viruses. Naive mice that were infected with virus mixed with red ginseng extract showed significantly enhanced protection, lower levels of lung viral titers and interleukin-6, but higher levels of interferon-γ compared with control mice having virus infections without red ginseng extract, indicating an antiviral effect of ginseng. In addition, ginseng extract exhibited inhibitory effects on the growth of influenza virus in vitro. This study provides evidence that intake of ginseng extract will have beneficial effects on preventing lethal infection with newly emerging influenza viruses.

Korean Red Ginseng Significantly Slows CD4 T Cell Depletion over 10 Years in HIV-1 Infected Patients: Association with HLA

We have shown that long-term intake of Korean red ginseng (KRG) delays disease progression in HIV-1 infected patients. In the present study to investigate whether this slow progression was associated with protective human leukocyte antigen (HLA) alleles as well as with KRG-intake, we have performed clinical analysis of 31 HIV-1 infected patients who have been living for more than 10 years without any antiretroviral therapy. Average amount of KRG-intake over 130±16 months was 4,797±4,921 g and the annual decrease in CD4 T cell (AD) was 30±29/㎕. We observed significant correlations among amount of KRG-intake, AD (r = -0.53, P < 0.01), and plasma HIV-1 RNA copy (r = -0.35, P < 0.05), along with a significant correlation between KRG-intake and HLA score (r = 0.49, P < 0.01), whereas there was no significant correlation between HLA score and AD or viral load. When the 31 patients were divided into 2 groups based on the amount of KRG-intake, the AD (14/㎕) in the 16 patients who had taken higher amounts ofKRG was significantly less than that (49/㎕) in the 15 patients with a little or no KRG-intake (P < 0.01). These data indicate that KRG-intake significantly slows CD4 T cell depletion in HIV-1 infected patients.

Molecular evidence of HIV‐1 transmission in 20 Korean individuals with haemophilia: phylogenetic analysis of the vif gene

Summary.  To assess whether a genetic relationship exists between the viruses infecting HIV‐positive patients with haemophilia and those infecting plasma donors, we determined the vif sequences in 169 individuals, including 20 haemophilia patients, 3 plasma donors, and 146 local controls. Twenty haemophilia patients were diagnosed with HIV‐1 at 1–2 years after exposure to factor IX (FIX) manufactured in Korea, beginning in 1989–1990. Plasma samples from donors O and P were used to manufacture clotting factors including FIX used to treat the 20 haemophiliacs. The vif gene from frozen stored serum samples obtained 1–3 years after diagnosis was amplified by RT‐PCR, and subjected to direct sequencing. Phylogenetic analysis revealed that vif sequences from 128 of the samples (including haemophilia patients and donors) belonged to the Korean subclade of HIV‐1 subtype B (KSB). Sequences from 41 other participants were identified as subtype B, but outside the Korean subclade. Sequences of the vif gene from donors O and P plus the 20 individuals with haemophilia comprised two subclusters within KSB. In addition, signature pattern analysis disclosed the presence of conserved nucleotides at two positions in donors and haemophiliacs only. Together with information on KSB, dates of plasma donations and seroconversion of haemophilia patients, our results suggest that the haemophiliacs examined here became infected by viruses in the domestic clotting factor used for treatment.

Phylogenetic Analysis of the Earliest nef Gene from Hemophiliacs and Local Controls in Korea

Abstract Twenty hemophiliacs (HPs) were found to have human immunodeficiency virus type-1 (HIV-1) 1–2 years after exposure to Factor IX manufactured in Korea in late 1989. Plasma samples collected from donors O and P during their pre-seroconversion acute infection stage were used to manufacture clotting factors, including Factor IX, to treat these patients. To assess whether a genetic relationship exists between the viruses infecting HIV-1-positive HPs and those infecting plasma donors, we evaluated the nef sequences in 216 individuals. Frozen-stored serum samples obtained 1–3 years after the diagnosis of HIV-1 in the 20 HPs were used for amplification of the nef gene by reverse transcriptase–polymerase chain reaction, and amplicons were subjected to direct sequencing. Phylogenetic analysis revealed that the nef sequences from 143 of the samples belonged to the Korean subclade of HIV-1 subtype B (KSB). Sequences of the nef gene from donors O and P and the 20 HPs comprised two subclusters within KSB together with several local control (LC) sequences. In addition, signature pattern analysis revealed the presence of conserved nucleotides at eight positions in donors O and P compared with LCs (p<0.01). These nationwide and comprehensive nef data support the previous conclusion that HPs were infected with HIV-1 from the clotting factor, although the stringency of nef is weaker than for the pol and vif genes.

Frequent Genetic Defects in the HIV-1 5’ LTR/gag Gene in Hemophiliacs Treated with Korean Red Ginseng: Decreased Detection of Genetic Defects by Highly Active Antiretroviral Therapy

We investigated whether Korean red ginseng (KRG) and highly active antiretroviral therapy (HAART) affect the frequency of gross deletion in 5’LTR/gag in 20 hemophiliacs. This study is a prospective study in 20 hemophiliacs who were infected with Korean subclade B of HIV-1 from two cash-paid plasma donors in 1990. Over a 13-year period, we obtained 436 amplicons of 5’LTR/gag genes by nested polymerase chain reaction using 147 peripheral blood mononuclear cells. Of the 436 amplicons, 92 (21.1%) showed gross deletion in 5’LTR/gag. Despite of a 2.3-fold higher monthly dose of KRG intake, the frequency of gross deletion in 5’LTR/gag (16.4%) was significantly decreased during HAART compared with 28.1% prior to HAART (p<0.01). Gross deletion in 5’LTR/gag was 10% more detected on KRG-therapy than prior to KRG-therapy (p<0.05). In addition, we also obtained 28 amplicons containing premature stop codon or isoleucine at initiation codon of 254 amplicons sequenced on KRG intake (7.5%) or HAART (13.6%) compared with 0% before KRG intake. These findings indicate that high frequency of gross deletion in 5’LTR/gag and genetic defects prior to HAART are significantly associated with KRG intake and the detection of gross deletion in 5’LTR/gag is decreased by HAART.

Long-term follow up of HIV-1-infected Korean haemophiliacs, after infection from a common source of virus

In the early 1990s, 20 haemophiliacs (HPs) were infected with a common source of HIV‐1 viruses through the contaminated clotting factor IX. The aim of this study is to review 20 HPs infected with a common source of virus. The enrolled patients have been consecutively treated with Korean red ginseng (KRG), zidovudine (ZDV) or two‐drug therapy and highly active antiretroviral therapy (HAART). We determined full‐length pol gene over 20 years and human leukocyte antigen (HLA) class I with peripheral blood mononuclear cells and reviewed medical records. Eighteen HPs experienced various opportunistic infections or clinical manifestations. There were significant inverse correlations between the HLA prognostic score and the annual decrease in CD4+ T‐cell counts prior to HAART (AD) (P < 0.05) and the amount of KRG and the AD (P < 0.01). From 1998, the HPs had been treated with HAART. Each of the two patients died without and with HAART regimen respectively. At present, 16 HPs have been alive with HAART. Among the 16 HPs, 12 and 4 are on HAART‐plus‐KRG and HAART only respectively. Eleven HPs including 2 HPs with G‐to‐A hypermutations had revealed resistance mutations. Ten and two HPs have shown poor adherence and incomplete viral suppres‐sion on HAART respectively. Virological failure based on WHO guidelines was not observed on KRG‐plus‐HAART. Two HPs revealed additional resistance mutations against two classes on KRG‐plus‐HAART. As a nationwide study, we first report overall features on clinical course of Korean haemophiliacs. Further education on the importance of drug adherence is needed.

Genetic defects in the nef gene are associated with Korean Red Ginseng intake: monitoring of nef sequence polymorphisms over 20 years

Background The presence of gross deletions in the human immunodeficiency virus nef gene (gΔnef) is associated with long-term nonprogression of infected patients. Here, we investigated how quickly genetic defects in the nef gene are associated with Korean Red Ginseng (KRG) intake in 10 long-term slow progressors. Methods This study was divided into three phases over a 20-yr period; baseline, KRG intake alone, and KRG plus highly active antiretroviral therapy (ART). nef gene amplicons were obtained using reverse transcription polymerase chain reaction (PCR) and nested PCR from 10 long-term slow progressors (n = 1,396), and nested PCR from 36 control patients (n = 198), and 28 ART patients (n = 157), and these were then sequenced. The proportion of gΔnef, premature stop codons, and not in-frame insertion or deletion of a nucleotide was compared between three phases, control, and ART patients. Results The proportion of defective nef genes was significantly higher in on-KRG patients (15.6%) than in baseline (5.7%), control (5.6%), on-KRG plus ART phase (7.8%), and on-ART patients (6.6%; p < 0.01). Small in-frame deletions or insertions were significantly more frequent among patients treated with KRG alone compared with controls (p < 0.01). Significantly fewer instances of genetic defects were detected in samples taken during the KRG plus ART phase (7.8%; p < 0.01). The earliest defects detected were gΔnef and small in-frame deletions after 7 mo and 67 mo of KRG intake, respectively. Conclusion KRG treatment might induce genetic defects in the nef gene. This report provides new insight into the importance of genetic defects in the pathogenesis of AIDS.