[Antimicrobial therapy for patients with HIV infection].
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Anti-Bacterial Agents↗
Biomedical subjects
Aikichi Iwamoto
Publications and source records attributed to Aikichi Iwamoto.
Molecular epidemiology of hepatitis A virus in metropolitan areas in Japan.
BACKGROUND: Transmission routes of hepatitis A virus (HAV) in Japan have changed. The present study investigated changes of transmission routes in relation to genetic drift. METHODS: All 60 patients who were admitted between 1993 and 2003 with a diagnosis of hepatitis A were retrospectively analyzed. Nucleotide sequences of the VP1/2A region of the HAV recovered from their sera were determined. RESULTS: The suspected transmission routes were household contact, 19 (31%); food or waterborne, 16 (27%); homosexual activity, 11 (18%); international travel, 4 (7%); and unknown 10. (17%). The 11 patients presumably infected through homosexual activity were found exclusively in 1998 and 1999. The proportion of patients exposed through homosexual behavior and household contact was higher in those 2 years than in other years. Nucleotide sequences could be determined for 58 patients. Fifty-seven of the 58 sequences belonged to genotype IA HAV, with less than 10% nucleotide diversity. Of the 27 sequences isolated during 1998 and 1999, 25 had an identical nucleotide sequence regardless of the suspected transmission route. In contrast, sequences obtained in the other years differed from one another. A phylogenetic tree constructed from sequences recovered from patients without a history of travel abroad showed several clusters. CONCLUSIONS: Our results suggest that (1) HAV acquired through homosexual activity may be transmitted to nonhomosexual individuals; (2) hepatitis A in metropolitan areas in Japan is caused mainly by sporadic infection with genotype IA HAV; and (3) several subtypes of genotype IA HAV are endemic in Japan.
Adult↗
Analysis of HIV-1 sequences before and after co-infecting syphilis.
Increasing syphilis incidence among men who have sex with men (MSM) has been reported. The index case was a human immunodeficiency virus type 1 (HIV-1)-positive MSM who presented coincidentally with the secondary syphilis and a rebound of plasma viral load after complete suppression of HIV-1 (below 50 copies/ml) for 13 months with potent antiretroviral therapy (PART), suggesting a possibility of HIV-1 superinfection. We analyzed HIV-1 sequences before and after syphilis in four HIV-1-positive patients including the index case to explore drug resistance mutations (DRMs) and a possibility of HIV-1 superinfection. There were patients who obtained DRMs around syphilis infection but no evidence of HIV-1 superinfection was obtained. Our results underline the importance of strict adherence to PART.
Adult↗
Decrease in Epstein-Barr virus-positive AIDS-related lymphoma in the era of highly active antiretroviral therapy.
Recent introduction of highly active antiretroviral therapy (HAART) is reported to have reduced the incidence of lymphoma among HIV-infected individuals. A clinicopathological study was performed on 86 AIDS-related lymphoma patients who were treated in Tokyo area from 1987 to 2005. The incidence of lymphoma detected by autopsy was 27% (53 cases/198 autopsies). Diffuse large B cell lymphoma was the most predominant histological subtype throughout the period (78%). Burkitt's lymphoma (BL) increased from 2% in the pre-HAART era (before end-1997) to 13% in the HAART era, whereas incidence of BL did not vary between HAART users and non-users. Epstein-Barr virus (EBV)-positive lymphoma decreased from 88% in the pre-HAART era to 58% in the HAART era, but did not differ significantly between HAART users (73%) and non-users (74%). Nodal involvement of lymphoma increased from 14% in the pre-HAART era to 50% in the HAART era; however, central nervous system involvement decreased from 62 to 38%. Kaposi's sarcoma-associated herpesvirus infection was rare (4%) among all cases. These data suggest that HAART might play a partial role in these changes, and the alteration in immunological backgrounds, such as EBV prevalence, is suggested as another leading cause of these changes in Japanese AIDS-related lymphoma.
Adolescent↗
Peptide-loaded dendritic-cell vaccination followed by treatment interruption for chronic HIV-1 infection: a phase 1 trial.
Immune response enhanced by therapeutic HIV-1 vaccine may control viral proliferation after discontinuation of highly active antiretroviral therapy (HAART). Although which strategies for therapeutic vaccination are feasible remains controversial, application of dendritic cells (DCs) as a vaccine adjuvant represents a promising approach to improving deteriorated immune function in HIV-1-infected individuals. The safety and efficacy of DC-based vaccine loaded with HIV-1-derived cytotoxic T lymphocytes (CTL) peptides were thus investigated in this study. Autologous DCs loaded with seven CTL peptides with HLA-A*2402 restriction were immunized to four HIV-1-infected individuals under HAART. In terms of safety, peptide-loaded DCs were well tolerated, and only mild local and general symptoms were observed during vaccine administration. ELISPOT assays to detect IFN-gamma production in CD8(+) lymphocytes revealed a limited breadth of responses to immunized peptides in two of four participants, but no response in the remaining two participants. Differences in immunological response might be attributable to the fact that responders displayed higher nadir CD4 counts before starting HAART and were immunized with a larger number of DCs per reactive peptide than non-responders. Discontinuation of HAART after vaccination failed to lower viral set points compared to those before starting HAART. This early outcome warrants further exploration to elucidate the therapeutic value of vaccination with DCs in HIV-1 infection.
Adult↗
The pro-apoptotic human BH3-only peptide harakiri is expressed in cryptococcus-infected perivascular macrophages in HIV-1 encephalitis patients.
In the central nervous system (CNS), HIV-1 targets mainly microglia/macrophages. Like the CD4+ T cell depletion and neuronal loss in AIDS, apoptosis is thought to be involved in eliminating infected macrophages. In this study, we examined the expression of the pro-apoptotic BH3-peptide harakiri (Hrk) in brain tissues of AIDS patients. Immunoreactivity against Hrk was positive in perivascular macrophages infiltrated into some restricted lesions. Most of these immunopositive cells contained small inclusions positive for Grocott's methenamine silver staining. Confocal laser microscopy demonstrated that Hrk expression coincided with immunoreactivities against HIV-1 and Cryptococcus neoformans. Expression of Hrk mRNA was demonstrated in these cells by in situ hybridization, which indicated that Hrk is not phagocytosed material. Some pro-apoptotic bcl-family members, including Hrk, may contribute to the delayed hypersensitive reaction in AIDS, in macrophages eliminating opportunistic infection.
Adult↗
Catalase plays a critical role in the CSF-independent survival of human macrophages via regulation of the expression of BCL-2 family.
M-colony-stimulating factor (M-CSF)-induced monocyte-derived macrophages (M-Mphi) required continuous presence of M-CSF for their survival, and depletion of M-CSF from the culture induced apoptosis, whereas human alveolar macrophages (A-Mphi) and granulocyte-macrophage (GM)-CSF-induced monocyte-derived macrophages (GM-Mphi) survived even in the absence of CSF. The expression of BCL-2 was higher in M-Mphi, and M-CSF withdrawal down-regulated the expression. The expression of BCL-X(L) was higher in A-Mphi and GM-Mphi, and the expression was CSF-independent. The expression of MCL-1 and BAX were not different between M-Mphi and GM-Mphi and were CSF-independent. Down-regulation of the expression of BCL-2 and BCL-X(L) by RNA interference showed the important role of BCL-2 and BCL-X(L) in the survival of M-Mphi and GM-Mphi, respectively. Human erythrocyte catalase (HEC) and conditioned medium obtained from GM-Mphi or A-Mphi cultured in the absence of GM-CSF prevented the M-Mphi from apoptosis and restored the expression of BCL-2. The activity of the conditioned medium was abrogated by pretreatment with anti-HEC antibody. Anti-HEC antibody also induced the apoptosis of M-Mphi cultured in the presence of M-CSF and GM-Mphi and A-Mphi cultured in the presence or absence of GM-CSF and down-regulated the expression of BCL-2 and BCL-X(L) in these Mphis. GM-Mphi and A-Mphi, but not M-Mphi, can produce both extracellular catalase and cell-associated catalase in a CSF-independent manner. Intracellular glutathione levels were kept equivalent in these Mphis, both in the presence or absence of CSF. These results indicate a critical role of extracellular catalase in the survival of human macrophages via regulation of the expression of BCL-2 family genes.
Apoptosis↗
Questionnaire-based analysis of mefloquine chemoprophylaxis for malaria in a Japanese population.
Although mefloquine is the only drug licensed for malaria chemoprophylaxis in Japan, there have been few reports describing the effects of and adverse events in the prophylactic usage of mefloquine in a Japanese population. We therefore performed a questionnaire-based study in 21 travelers who were prescribed mefloquine for malaria chemoprophylaxis between October 2001 and December 2003. The study revealed that only 8 out of 21 (38.1%) of the travelers could complete the prophylaxis schedules. Another 8 travelers (38.1%) with incomplete adherence stated that they did not take mefloquine because of either actually experienced or anticipated adverse events. Twelve of the 16 travelers (75.0%) who took mefloquine complained of at least one adverse event probably related to mefloquine. As an overall impression about mefloquine chemoprophylaxis, 14 of the 21 travelers stated that they would take mefloquine again for the next travel to malaria-endemic areas, although 5 of them were concerned about adverse events. These results suggest that, although mefloquine is an indispensable drug for malaria prevention, other effective and well-tolerated chemoprophylactic antimalarials should be available for Japanese travelers who do not tolerate mefloquine.
Antimalarials↗
Frequent detection of Epstein-Barr Virus and cytomegalovirus but not JC virus DNA in cerebrospinal fluid samples from human immunodeficiency virus-infected patients in northern Thailand.
Applying nested-PCRs, we frequently detected DNA of Epstein-Barr virus and cytomegalovirus but not JC virus in cerebrospinal fluid samples from 140 human immunodeficiency virus-infected patients with central nervous system symptoms in northern Thailand. Despite the low incidence of primary central nervous system lymphoma or cytomegalovirus encephalitis among Thai AIDS patients, Epstein-Barr virus and cytomegalovirus infections in the central nervous system are common.
Adult↗
Clinical characteristics of imported malaria in Japan: analysis at a referral hospital.
Imported malaria remains an important problem in Japan. We have reviewed the medical records of 170 cases of malaria in our hospital, which corresponds to 14.9% of the total cases in Japan. The predominant malarial species was Plasmodium falciparum (52.3%), and the most frequent area of acquisition was Africa (54.2%), followed by Asia (20.9%) and Oceania (19.6%). The most common reason for travel among Japanese patients was business. A significant proportion (22.2%) of vivax malaria cases experienced relapse despite standard primaquine therapy. Most primaquine failures were from Oceania. We also found that a substantial number of Japanese patients contracted malaria without chemoprophylaxis and consulted medical facilities with an unfavorably long delay from initial symptoms (median: 3.0 days). Direct education of travelers and travel companies, in addition to health care providers, is likely necessary to improve outcomes of imported malaria.
Adult↗
[Emerging virus infections--present status, countermeasures and future aspects (discussion)].
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Animals↗
A CCR2-V64I polymorphism affects stability of CCR2A isoform.
OBJECTIVE: A valine to isoleucine substitution at position 64 of CCR2 (CCR2-64I) is associated with a delay in progression to AIDS in HIV-1-infected individuals. The aim of the present study is to elucidate the molecular mechanism underlying the effect of this allele. DESIGN: We analysed the effect of the 64I substitution on levels of expression of CCR2A and CCR2B, two CCR2 isoforms produced by alternative splicing. METHODS: Sendai virus vector was used to express CCR2 molecules. RESULTS: While CCR2B trafficked well to the cell surface, CCR2A, which differs from CCR2B only by the sequence of its C-terminal cytoplasmic tail, was detected predominantly in the cytoplasm. The level of expression of CCR2A-64I was significantly higher than that of CCR2A without the substitution. On the other hand, the 64I substitution did not affect levels of CCR2B expression. Pulse-chase experiments revealed that the 64I substitution increased the half-life of CCR2A in cells. When co-expressed with CCR5, CCR2A-64I interfered more severely with cell surface expression of CCR5 than did wild-type CCR2A. Furthermore, immunoprecipitation experiments showed that CCR2A co-precipitated with an immature form of CCR5. CONCLUSION: These results suggest that CCR2A binds to CCR5 in the cytoplasm and down-modulates its surface expression. We propose that the increased ability of CCR2A-64I to down-modulate CCR5 expression might be a possible cause of a delay in HIV-1 disease progression in patients with this allele.
Amino Acid Sequence↗
Antibody-dependent cellular cytotoxicity via humoral immune epitope of Nef protein expressed on cell surface.
Antibodies against various proteins of HIV type 1 (HIV-1) can be detected in HIV-1-infected individuals. We previously reported that the level of Ab response against one Nef epitope is correlated with HIV-1 disease progression. To elucidate the mechanism for this correlation, we examined Ab-dependent cellular cytotoxicity (ADCC) against target cells expressing Nef. We observed efficient cytotoxicity against Nef-expressing target cells in the presence of patient plasma and PBMCs. This ADCC activity was correlated with the dilution of plasma from HIV-1-infected patients. Addition of a specific synthetic peptide (peptide 31:FLKEKGGLE) corresponding to the Nef epitope reduced cell lysis to approximately 50%. These results suggest that PBMCs of HIV-1-infected patients may exert ADCC via anti-Nef Abs in the patients' own plasma and serve as a mechanism used by the immune system to regulate HIV-1 replication.
Adult↗
Current concepts in SARS treatment.
The outbreak of severe acute respiratory syndrome (SARS) has drawn enormous attention and caused fear worldwide since early 2003. The disease appears to be under control now; however, the possible return of SARS must be emphasized. Although many clinical experiments have been reported, the treatment of SARS is largely anecdotal, and so far no treatment consensus has been reached. We summarize 14 clinical reports and attempt to assess the effectiveness of various treatment regimens. A combination treatment of steroids and ribavirin was widely used empirically from the outset of the epidemic. In general, the use of steroids for SARS seemed beneficial, but the optimal timing, dosage, and duration of treatment have not yet been determined. On the other hand, ribavirin administration apparently reduced neither the rate of intratracheal intubation nor that of mortality. Moreover, significant toxicity, such as hemolytic anemia, has been attributed to ribavirin. A few preliminary trials and in vitro data suggest the possibility of treating SARS with interferon. Other agents, including the HIV protease inhibitor glycyrrhizin and convalescent plasma, remain to be evaluated.
Antiviral Agents↗
Functional analysis of HIV-1 vif genes derived from Japanese long-term nonprogressors and progressors for AIDS.
We analyzed the function of human immunodeficiency virus type 1 (HIV-1) vif gene from Japanese long-term nonprogressors (LTNPRs) and progressors (PRs) for acquired immunodeficiency syndrome (AIDS). We constructed a basic HIV-1 infectious clone, which facilitated the incorporation and evaluation of vif from infected individuals. Proviral reporter clones carrying vif from six Japanese LTNPRs and seven PRs were then generated and their in vitro growth kinetics were analyzed. The vif clones, which could confer infectivity on reporter viruses, were considered active, and the ratio of the active clones to the number of clones examined per individual was determined. For the majority of LTNPRs, there was no correlation between presence or absence of functional vif with long-term nonprogression for AIDS. There was one exception in which all the clones examined had inactive vif, suggesting a probable association of inactive vif with the nonprogression. All PRs with high viral load had a high ratio of active vif clones. Our results suggest that the presence of functional vif would influence HIV-1 infectivity and disease progression in infected individuals.
Amino Acid Sequence↗
Phase I study of autologous tumor vaccines transduced with the GM-CSF gene in four patients with stage IV renal cell cancer in Japan: clinical and immunological findings.
We produced lethally irradiated retrovirally GM-CSF-transduced autologous renal tumor cell vaccines (GVAX) from six Japanese patients with stage IV renal cell cancer (RCC). Four patients received GVAX ranging from 1.4 x 10(8) to 3.7 x 10(8) cells on 6-17 occasions. Throughout a total of 48 vaccinations, there were no severe adverse events. After vaccination, DTH skin tests became positive to autologous RCC (auto-RCC) in all patients. The vaccination sites showed significant infiltration by CD4(+) T cells, eosinophils, and HLA-DR-positive cells. The kinetic analyses of cellular immune responses using peripheral blood lymphocytes revealed an enhanced proliferative response against auto-RCC in four patients, and cytotoxicity against auto-RCC was augmented in three patients. T cell receptor beta-chain analysis revealed oligoclonal expansion of T cells in the peripheral blood, skin biopsy specimens from DTH sites, and tumors. Western blot analysis demonstrated the induction of a humoral immune response against auto-RCC. Two of the four patients are currently alive 58 and 40 months after the initial vaccination with low-dose interleukin-2. Our results suggest that GVAX substantially enhanced the antitumor cellular and humoral immune responses, which might have contributed to the relatively long survival times of our patients in the present study.
Aged↗
Frequent transmission of cytotoxic-T-lymphocyte escape mutants of human immunodeficiency virus type 1 in the highly HLA-A24-positive Japanese population.
Although Japan is classified as a country with a low prevalence of human immunodeficiency virus type 1 (HIV-1), domestic sexual transmission has been increasing steadily. Because 70% of the Japanese population expresses HLA-A24 (genotype HLA-A*2402), we wished to assess the effect of the dominant HLA type on the evolution and transmission of HIV-1 among the Japanese population. Twenty-three out of 25 A24-positive Japanese patients had a Y-to-F substitution at the second position [Nef138-10(2F)] in an immunodominant A24-restricted CTL epitope in their HIV-1 nef gene (Nef138-10). None of 12 A24-negative Japanese hemophiliacs but 9 out of 16 patients infected through unprotected sexual intercourse had Nef138-10(2F) (P < 0.01). Two of two A24-positive but none of six A24-negative Australians had Nef138-10(2F). Nef138-10(2F) peptides bound well to the HLA-A*2402 heavy chain; however, Nef138-10(2F) was expressed poorly on the cell surface from the native protein. Thus, HIV-1 with Nef138-10(2F) appears to be a cytotoxic-T-lymphocyte escape mutant and has been transmitted frequently by sexual contact among the highly A24-positive Japanese population.
Amino Acid Sequence↗
Impaired processing and presentation of cytotoxic-T-lymphocyte (CTL) epitopes are major escape mechanisms from CTL immune pressure in human immunodeficiency virus type 1 infection.
Investigating escape mechanisms of human immunodeficiency virus type 1 (HIV-1) from cytotoxic T lymphocytes (CTLs) is essential for understanding the pathogenesis of HIV-1 infection and developing effective vaccines. To study the processing and presentation of known CTL epitopes, we prepared Epstein-Barr virus-transformed B cells that endogenously express the gag gene of six field isolates by adopting an env/nef-deletion HIV-1 vector pseudotyped with vesicular stomatitis virus G protein and then tested them for the recognition by Gag epitope-specific CTL lines or clones. We observed that two field variants, SLFNTVAVL and SVYNTVATL, of an A*0201-restricted Gag CTL epitope SLYNTVATL, and three field variants, KYRLKHLVW, QYRLKHIVW, and RYRLKHLVW, of an A24-restricted Gag CTL epitope KYKLKHIVW escaped from being killed by the CTL lines, despite the fact that they were recognized when the synthetic peptides corresponding to these variant sequences were exogenously loaded onto the target cells. Thus, their escape is likely due to the changes that occur during the processing and presentation of epitopes in the infected cells. Mutations responsible for this mode of escape were located within the epitope regions rather than the flanking regions, and such mutations did not influence the virus replication. The results suggest that the impaired antigen processing and presentation often occur in HIV-1 field isolates and thus are one of the major mechanisms that enable HIV-1 to escape from CTL recognition. We emphasize the importance of testing HIV-1 variants in an endogenous expression system.
Amino Acid Sequence↗