Virological outcomes of various first-line ART regimens in patients harbouring HIV-1 E157Q integrase polymorphism: a multicentre retrospective study.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are recommended as first-line ART for people living with HIV (PLWH) in most guidelines. The INSTI-resistance-associated mutation E157Q, a highly prevalent (2%-5%) polymorphism of the HIV-1 (human immunodeficiency virus type 1) integrase gene, has limited data on optimal first-line ART regimens. We assessed the virological outcomes of various first-line ART regimens in PLWH with E157Q in real-world settings. METHODS: A multicentre retrospective observational study was conducted on PLWH who underwent integrase genotypic drug-resistance testing before ART initiation between 2008 and 2019 and were found to have E157Q. Viral suppression (<50 copies/mL) rate at 24 and 48 weeks, time to viral suppression and time to viral rebound (≥100 copies/mL) were compared among the first-line ART regimens. RESULTS: E157Q was detected in 167 (4.1%) of 4043 ART-naïve PLWH. Among them, 144 had available clinical data after ART initiation with a median follow-up of 1888 days. Forty-five started protease inhibitors + 2 NRTIs (PI group), 33 started first-generation INSTI (raltegravir or elvitegravir/cobicistat) + 2 NRTIs (INSTI-1 group), 58 started once-daily second-generation INSTI (dolutegravir or bictegravir) + 2 NRTIs (INSTI-2 group) and eight started other regimens. In the multivariate analysis, the INSTI-2 group showed similar or favourable outcomes compared with the PI group for viral suppression rates, time to viral suppression and time to viral rebound. Two cases in the INSTI-1 group experienced virological failure. CONCLUSIONS: The general guideline recommendation of second-generation INSTI-based first-line ART for most PLWH is also applicable to PLWH harbouring E157Q.

Clinical characteristics of HIV-1-infected patients with high levels of plasma interferon-γ: a multicenter observational study.

BACKGROUND: Circulating interferon-γ (IFN-γ) concentration may be sustained at a high level regardless of the initiation of antiretroviral therapy (ART) in some patients with HIV-1 infection. In the present study, we examined the clinical characteristics of HIV-1-infected patients with high levels of plasma IFN-γ. METHODS: The study subjects were patients infected with HIV-1 who were either naïve to ART with CD4+ cell count > 200 cells/µL (n = 12), or had achieved viral suppression after ART for over a year (n = 188). The levels of plasma IFN-γ and interleukin-6 (IL-6) were measured by the enzyme-linked immunosorbent assay. Patients were divided into high IFN-γ and low IFN-γ groups based on a cutoff level of 5 pg/mL. RESULTS: The high IFN-γ group included 41 patients (21%). Compared to the patients on ART with low IFN-γ levels, those on ART in the high IFN-γ group were more likely to be younger than 50 years of age (P = 0.0051) and less likely to have dyslipidemia (P = 0.0476) or to be on a protease inhibitor (P = 0.0449). There was no significant difference between groups in the median increase of CD4+ cell counts from the initiation of ART for up to 3 years. However, after 4 years, the increase in CD4+ cell counts was significantly lower in the high IFN-γ group compared with that in the low IFN-γ group. There were no such significant differences between patients with low and high (> 2 pg/mL) levels of plasma IL-6. CONCLUSION: We concluded that HIV-1-infected patients with high levels of circulating IFN-γ did not have a higher rate of comorbidities related to immune activation. However, they exhibited lower CD4+ cell count recovery after 4 years of being on ART. This deficit could be a consequence of persistent immune activation.

Addition of maraviroc to antiretroviral therapy decreased interferon-γ mRNA in the CD4+ T cells of patients with suboptimal CD4+ T-cell recovery.

The CCR5 antagonist, maraviroc (MVC), is associated with an enhanced CD4+ T-cell response independent of virological suppression; however, its mechanism of action has not been elucidated. In this study, we confirmed the effect of MVC on CD4+ T-cell count recovery in immunological non-responders, and compared the conventional combination antiretroviral therapy (cART) with MVC-intensified cART. We also investigated the effect of MVC on interferon-γ (IFN-γ) production in CD4+ T cells in vitro and in vivo, and evaluated the relationship between the mRNA level of IFN-γ and the degree of CD4+ T-cell count recovery. In vitro analysis indicated that MVC significantly decreased mRNA levels of IFN-γ in HIV-Tat stimulated CD4+ T cells from healthy donor peripheral blood mononuclear cells. Of the 18 HIV-infected patients treated with MVC-intensified cART, 12 had a significantly increased CD4+ T-cell count after 24 weeks of additional treatment with MVC. In patients exhibiting a response in CD4+ T-cell counts, mRNA levels of IFN-γ in CD4+ T cells were lower than those in patients showing a non-response at baseline and at week 24, while mRNA levels of IFN-γ decreased in both groups at 24 weeks. In conclusion, MVC decreased the mRNA level of IFN-γ in CD4+ T cells in vitro and in vivo, especially in patients whose CD4+ T-cell count increased significantly. We also found that the lower baseline IFN-γ mRNA level and the larger decreased rate of IFN-γ mRNA in CD4+ T cells were associated with a good response to MVC regarding CD4+ T-cell recovery.

[The Usefulness of the Scan with 67Ga-citrate to Assess the Therapeutic Effect on Pneumocystis pneumonia with HIV-1 Infection].

OBJECTIVE: Peumocystis pneumonia (PCP) is one of the common opportunistic infections with severe respiratory failure, and is sometimes life-threatening in patients with the acquired immunodeficiency syndrome. Although treatment for PCP is established, an appropriate treatment period has not been evaluated to clarify the risk factors for immune reconstitution inflammatory syndrome (IRIS) associated with PCP. METHOD: We retrospectively analyzed the clinical characteristics of risk factor, which are the treatment period for PCP, and 67Ga scintigraphy (Ga-S) at the 21st day from the start of the treatment for PCP, with 21 cases of PCP and HIV infection treated during 2005-2012 at Kyushu Medical Center. RESULT: The rate of residual uptake by Ga-S was assessed in 17 cases (81%). Four cases were diagnosed as being PCP-IRIS, and residual uptake by Ga-S was detected in all PCP-IRIS cases. The durations of the therapy were classified into three groups: 21 days, 28 days, and 35 days. All PCP-IRIS cases were treated in the period of 28 days. In contrast, in 11 cases that showed residual uptake by Ga-S, and were treated for PCP in 35 days, PCP-IRIS did not occur. Additionally, there were 4 cases in which residual uptake by Ga-S did not occur. They were treated with PCP for only 21 days, but did not show PCP-IRIS. CONCLUSION: In this study, we showed that Ga-S is useful to evaluate the therapeutic effect. Furthermore, we found that the occurrence of PCP-IRIS could be prevented with the early start of cART after 21 days treatment for PCP, when residual uptake by Ga-S after the first treatment for PCP was not detected. It may also be possible to start cART in the early phase after its treatment without the occurrence of PCP-IRIS with the appropriate additional treatment of PCP for 14 days. These guidelines for treatment of PCP in HIV-infected adults and adolescents have been recommended for the duration of 21 days since 1984. We propose that for the prevention of PCP-IRIS, it is nessecory to reconsider recommendation for the treatment duration of 21 days, and meanwhile to evaluate the treatment effect of PCP with Ga-S, because PCP resistance to sulfa drugs, namely are trimethoprim-sulfamethoxazole, is beginning to appear.

Exacerbation of microcytic anemia associated with cessation of anti-retroviral therapy in an HIV-1-infected patient with beta thalassemia.

We report a patient with Japanese minor ß thalassemia and HIV-1 infection. The patient showed prolonged anemia, which was originally attributed to chronic parvovirus B19 infection. Twelve years later, the patient presented with exacerbation of microcytic anemia following cessation of anti-retroviral therapy; the exacerbation resolved when anti-retroviral therapy was resumed. Sequencing of the ß globin gene revealed heterozygosity for a four-nucleotides deletion at codon 41/42 and minor ß thalassemia was confirmed. Because HIV-1-infected patients frequently show anemia due to nutritional deficiencies, opportunistic infections, AIDS-related malignancies, drug treatment and a direct effect of HIV-1 on the bone marrow, it is likely to overlook other causes of anemia. Thalassemia should be considered in the differential diagnosis of anemia even in HIV-1 infected patients, when microcytic anemia without iron deficiency is observed. Our case suggested that active HIV infection may have worsened ß thalassemia, and early introduction of anti-retroviral therapy is beneficial for the recovery of anemia.

Factors Associated with Neutralizing Antibody Responses following 2-Dose and 3rd Booster Monovalent COVID-19 Vaccination in Japanese People Living with HIV.

People living with HIV (PLWH) could be at risk of blunted immune responses to COVID-19 vaccination. We investigated factors associated with neutralizing antibody (NAb) responses against SARS-CoV-2 and variants of concern (VOCs), following two-dose and third booster monovalent COVID-19 mRNA vaccination in Japanese PLWH. NAb titers were assessed in polyclonal IgG fractions by lentiviral-based pseudovirus assays. Overall, NAb titers against Wuhan, following two-dose vaccination, were assessed in 82 PLWH on treatment, whereby 17/82 (20.73%) were classified as low-NAb participants. Within the low-NAb participants, the third booster vaccination enhanced NAb titers against Wuhan and VOCs, albeit to a significantly lower magnitude than the rest. In the multivariate analysis, NAb titers against Wuhan after two-dose vaccination correlated with age and days since vaccination, but not with CD4+ count, CD4+/CD8+ ratio, and plasma high-sensitivity C-Reactive protein (hsCRP). Interestingly, an extended analysis within age subgroups revealed NAb titers to correlate positively with the CD4+ count and negatively with plasma hsCRP in younger, but not older, participants. In conclusion, a third booster vaccination substantially enhances NAb titers, but the benefit may be suboptimal in subpopulations of PLWH exhibiting low titers at baseline. Considering clinical and immune parameters could provide a nuanced understanding of factors associated with vaccine responses in PLWH.

[CMV-induced duodenal papillitis in a patient with HIV-1 infection].

We present herein a case report of a 59-year-old patient with HIV-1 infection who developed a CMV-induced pseudotumor of the duodenum. The patient presented with oral pain and dysphagia. Physical examination revealed oral thrush. An EIA and a Western blot assay for antibodies to HIV were positive. His CD4-positive lymphocyte count was initially 49/microL with an HIV viral load of 2.6 x 10(5) copies/mL. Cytomegalovirus (CMV) reactivation was detected with the CMV antigenemia assay. He had CMV retinitis in both eyes with unilateral blurring. An endoscopic study revealed candida esophagitis, and a tumor-like lesion with an irregular ulcer at the papilla of Vater. Histological and immunohistochemical studies revealed a CMV-induced pseudotumor and severely inflamed duodenal mucosa with infiltration of CMV-positive cells. The patient was treated with oral valganciclovir and fluconazole for three weeks. As the oral thrush and retinitis showed improvement, he began antiretroviral therapy (ART), consisting of raltegravir and TDF/ FTC. One month later the patient's CD4-positive cells increased to 130/microL and the level of HIV-RNA decreased to 160 copies/mL, The CMV retinitis had transiently worsened because of an ART-induced inflammatory response, immune reconstitution inflammatory syndrome (IRIS). Six months after the ART initiation, an endoscopic study revealed that the esophagitis and the lesion at the papilla had improved. Biopsy showed no CMV-positive cells in the epithelium. The patient was now in a relatively healthy condition. CMV-induced pseudotumors of the duodenum are rare, and sometimes resemble malignancy. However, because this tomor responds to medical treatment physicians treating severely immunocompromised patients should be aware of its presentation and treatment.

Evaluation of Neutralizing Activity against Omicron Subvariants in BA.5 Breakthrough Infection and Three-Dose Vaccination Using a Novel Chemiluminescence-Based, Virus-Mediated Cytopathic Assay.

Neutralizing potency of humoral immune responses induced by prior infection or vaccination is vital for protecting of individuals and population against severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). However, the emergence of viral variants that can evade neutralization by vaccine- or infection-induced immunity is a significant public health threat and requires continuous monitoring. Here, we have developed a novel scalable chemiluminescence-based assay for assessing SARS-CoV-2-induced cytopathic effect to quantify the neutralizing activity of antisera. The assay leverages the correlation between host cell viability and ATP levels in culture to measure the cytopathic effect on target cells induced by clinically isolated, replication-competent, authentic SARS-CoV-2. With this assay, we demonstrate that the recently arisen Omicron subvariants BQ.1.1 and XBB.1 display a significant decrease in sensitivity to neutralization by antibodies elicited from breakthrough infections with Omicron BA.5 and from receipt of three doses of mRNA vaccines. Thus, this scalable neutralizing assay provides a useful platform to assess the potency of acquired humoral immunity against newly emerging SARS-CoV-2 variants. IMPORTANCE The ongoing global pandemic of SARS-CoV-2 has emphasized the importance of neutralizing immunity in protecting individuals and populations against severe respiratory illness. In light of the emergence of viral variants with the potential to evade immunity, continuous monitoring is imperative. A virus plaque reduction neutralization test (PRNT) is a "gold standard" assay for analyzing neutralizing activity for authentic viruses that form plaques, like influenza virus, dengue virus, and SARS-CoV-2. However, this method is labor intensive and is not efficient for performing large-scale neutralization assays on patient specimens. The assay system established in this study allows for the detection of a patient's neutralizing activity by simply adding an ATP detection reagent, providing a simple evaluation system for neutralizing activity of antisera as an alternative to the plaque reduction method. Our extended analysis of the Omicron subvariants highlights their increasing capability to evade neutralization by both vaccine- and infection-induced humoral immunity.

Association of demographics, HCV co-infection, HIV-1 subtypes and genetic clustering with late HIV diagnosis: a retrospective analysis from the Japanese Drug Resistance HIV-1 Surveillance Network.

INTRODUCTION: Late diagnosis of the human immunodeficiency virus (HIV) is a major concern epidemiologically, socially and for national healthcare systems. Although the association of certain demographics with late HIV diagnosis has been reported in several studies, the association of other factors, including clinical and phylogenetic factors, remains unclear. In the present study, we conducted a nationwide analysis to explore the association of demographics, clinical factors, HIV-1 subtypes/circulating recombinant form (CRFs) and genetic clustering with late HIV diagnosis in Japan, where new infections mainly occur among young men who have sex with men (MSM) in urban areas. METHODS: Anonymized data on demographics, clinical factors and HIV genetic sequences from 39.8% of people newly diagnosed with HIV in Japan were collected by the Japanese Drug Resistance HIV-1 Surveillance Network from 2003 to 2019. Factors associated with late HIV diagnosis (defined as HIV diagnosis with a CD4 count <350 cells/µl) were identified using logistic regression. Clusters were identified by HIV-TRACE with a genetic distance threshold of 1.5%. RESULTS: Of the 9422 people newly diagnosed with HIV enrolled in the surveillance network between 2003 and 2019, 7752 individuals with available CD4 count at diagnosis were included. Late HIV diagnosis was observed in 5522 (71.2%) participants. The overall median CD4 count at diagnosis was 221 (IQR: 62-373) cells/µl. Variables independently associated with late HIV diagnosis included age (adjusted odds ratio [aOR] 2.21, 95% CI 1.88-2.59, ≥45 vs. ≤29 years), heterosexual transmission (aOR 1.34, 95% CI 1.11-1.62, vs. MSM), living outside of Tokyo (aOR 1.18, 95% CI 1.05-1.32), hepatitis C virus (HCV) co-infection (aOR 1.42, 95% CI 1.01-1.98) and not belonging to a cluster (aOR 1.30, 95% CI 1.12-1.51). CRF07_BC (aOR 0.34, 95% CI 0.18-0.65, vs. subtype B) was negatively associated with late HIV diagnosis. CONCLUSIONS: In addition to demographic factors, HCV co-infection, HIV-1 subtypes/CRFs and not belonging to a cluster were independently associated with late HIV diagnosis in Japan. These results imply the need for public health programmes aimed at the general population, including but not limited to key populations, to encourage HIV testing.

A case of refractory adult-onset Still's disease with high serum interleukin-18 levels treated with monitoring of serum levels of cyclosporine.

We report the case of a 31-year-old woman who developed adult-onset Still's disease (AOSD) with a high level of serum interleukin (IL)-18. Although treated with high dose steroids, she suffered repeated remissions and her condition deteriorated. After we administered oral cyclosporine A (CsA), 200 mg/d, monitoring C2 and trough levels, her symptoms improved significantly. We decreased the dose of methylprednisolone slowly without noting a relapse. The use of CsA accompanied by C2 and trough level monitoring should be considered for refractory AOSD patients with high levels of serum IL-18.

Cellular HIV-1 DNA levels in patients receiving antiretroviral therapy strongly correlate with therapy initiation timing but not with therapy duration.

BACKGROUND: Viral reservoir size refers to cellular human immunodeficiency virus-1 (HIV-1) DNA levels in CD4(+) T lymphocytes of peripheral blood obtained from patients with plasma HIV-1-RNA levels (viral load, VL) maintained below the detection limit by antiretroviral therapy (ART). We measured HIV-1 DNA levels in CD4(+) lymphocytes in such patients to investigate their clinical significance. METHODS: CD4(+) T lymphocytes were isolated from the peripheral blood of 61 patients with a VL maintained at less than 50 copies/ml for at least 4 months by ART and total DNA was purified. HIV-1 DNA was quantified by nested PCR to calculate the copy number per 1 million CD4(+) lymphocytes (relative amount) and the copy number in 1 ml of blood (absolute amount). For statistical analysis, the Spearman rank or Wilcoxon signed-rank test was used, with a significance level of 5%. RESULTS: CD4 cell counts at the time of sampling negatively correlated with the relative amount of HIV-1 DNA (median = 33 copies/million CD4(+) lymphocytes; interquartile range [IQR] = 7-123 copies/million CD4(+) lymphocytes), but were not correlated with the absolute amounts (median = 17 copies/ml; IQR = 5-67 copies/ml). Both absolute and relative amounts of HIV-1 DNA were significantly lower in six patients in whom ART was initiated before positive seroconversion than in 55 patients in whom ART was initiated in the chronic phase, as shown by Western blotting. CD4 cell counts before ART introduction were also negatively correlated with both the relative and absolute amounts of HIV-1 DNA. Only the relative amounts of HIV-1 DNA negatively correlated with the duration of VL maintenance below the detection limit, while the absolute amounts were not significantly correlated with this period. CONCLUSIONS: The amounts of cellular HIV-1 DNA in patients with VLs maintained below the detection limit by the introduction of ART correlated with the timing of ART initiation but not with the duration of ART. In addition, CD4(+) T lymphocytes, which were newly generated by ART, diluted latently infected cells, indicating that measurements of the relative amounts of cellular HIV-1 DNA might be underestimated.

Comparison of the influence of four classes of HIV antiretrovirals on adipogenic differentiation: the minimal effect of raltegravir and atazanavir.

Antiretroviral therapy for HIV infection is associated with lipodystrophy. However, raltegravir (RAL), a new integrase inhibitor, and atazanavir (ATV), a new generation of protease inhibitor (PI), have not been reported to significantly induce metabolic abnormalities in some clinical studies. The aim of this study was to investigate the influence and molecular mechanisms of RAL and compared it with the other three classes of ARVs (nucleoside reverse-transcriptase inhibitors; NRTI, nonnucleoside reverse-transcriptase inhibitor; NNRTI, and PI) on adipogenesis using 3T3-L1 cells. RAL and ATV had minimal effects on the lipid metabolism of 3T3-L1 cells. NRTI induced a moderate change, and NNRTI and some PIs induced a severe reduction in cell lipid content. These ARVs induced a decrease in the expression of genes associated with lipogenic transcription factors (sterol regulatory-element-binding protein-1c, CAAT box enhancer-binding protein-α, and peroxisome proliferator-activated receptor-γ). The differentiated 3T3-L1 cells were less sensitive to ARV-induced metabolic disturbance than were predifferentiated cells. RAL and ATV did not significantly affect the lipid metabolism in our in vitro study. The other ARVs had a direct influence on adipocytes. Degree and underlying mechanisms of metabolic disturbance differed among different ARVs. These data suggest that the distinct metabolic side-effect profiles of ARVs are a consequences of their differential effects on the adipocyte physiology. A better understanding of the mechanism of ARV-induced metabolic abnormalities could lead to safer use of ARVs or selection of alternative agents for further clinical development.

Churg-Strauss syndrome associated with elevated levels of serum interleukin-5 and T cell receptor-Cß gene rearrangement.

A 58-year-old woman was diagnosed with Churg-Strauss syndrome (CSS) based on the symptoms of bronchial asthma, eosinophilia, mononeuritis multiplex and histological examination of the right sural nerve. Prior to treatment, the serum interleukin (IL)-5 level was high, and rearrangement of the T cell receptor (TCR) gene was identified. This is the first report of TCR gene rearrangement in a patient with CSS. The expanded T cell clone may be responsible for the overproduction of IL-5. Further studies are warranted to disclose a prevalence of TCR gene rearrangement in CSS patients and its pathophysiological roles in the development of this disease.

A case of relapsing polychondritis associated with auricular cartilage infiltration of immunoglobulin G4-positive plasma cells and lung cancer.

A 79-year-old man was diagnosed with relapsing polychondritis, from symptoms of bilateral auricular deformity and pigmentation, polyarthralgia, and audiovestibular damage, and from histological examination of the left auricular cartilage. The left auricular cartilage biopsy specimen revealed cartilage destruction with infiltration of plasmacytes expressing IgG4. This case suggests that IgG4 may be involved in the pathogenesis and etiology of relapsing polychondritis.

Resistance of SARS-CoV-2 variants to neutralization by antibodies induced in convalescent patients with COVID-19.

Administration of convalescent plasma or neutralizing monoclonal antibodies (mAbs) is a potent therapeutic option for coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, SARS-CoV-2 variants with mutations in the spike protein have emerged in many countries. To evaluate the efficacy of neutralizing antibodies induced in convalescent patients against emerging variants, we isolate anti-spike mAbs from two convalescent COVID-19 patients infected with prototypic SARS-CoV-2 by single-cell sorting of immunoglobulin-G-positive (IgG+) memory B cells. Anti-spike antibody induction is robust in these patients, and five mAbs have potent neutralizing activities. The efficacy of most neutralizing mAbs and convalescent plasma samples is maintained against B.1.1.7 and mink cluster 5 variants but is significantly decreased against variants B.1.351 from South Africa and P.1 from Brazil. However, mAbs with a high affinity for the receptor-binding domain remain effective against these neutralization-resistant variants. Rapid spread of these variants significantly impacts antibody-based therapies and vaccine strategies against SARS-CoV-2.

SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity.

Many SARS-CoV-2 variants with naturally acquired mutations have emerged. These mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains largely unexplored. Here, we demonstrate that two recently emerging mutations in the receptor-binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429 and B.1.617) and Y453F (in B.1.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce affinity toward the host entry receptor ACE2. Notably, the L452R mutation increases spike stability, viral infectivity, viral fusogenicity, and thereby promotes viral replication. These data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is escape from cellular immunity.

Influenza virus B-associated hemophagocytic syndrome and recurrent pericarditis in a patient with systemic lupus erythematosus.

We report a 24-year-old male with systemic lupus erythematosus (SLE) who developed influenza virus B-associated hemophagocytic syndrome and cardiac tamponade. Although the patient's general condition improved after steroid pulse therapy and pericardiocentesis, pericardial effusion re-accumulated. Colchicine and aspirin were administered, together with prednisolone, after which no further relapses occurred. This was a rare case of severe influenza-associated hemophagocytic syndrome and steroid-resistant pericardial effusion in an SLE patient.

Clinical analysis of cerebrospinal fluid interleukin-6 in neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: To clarify the clinical usefulness of cerebrospinal fluid (CSF) interleukin-6 (IL-6) measurement in patients with neuropsychiatric systemic lupus erythematosus (NPSLE), we studied CSF IL-6 levels in patients with NPSLE and analyzed the association between CSF IL-6 levels and other clinical findings of NPSLE. PATIENTS AND METHODS: We retrospectively analyzed records of 37 patients (33 females and four males) with NPSLE admitted to our hospital between January 2003 and December 2008. RESULTS: All patients showed neuropsychiatric symptoms. Fourteen patients showed abnormalities in brain magnetic resonance imaging (MRI) and 12 patients had abnormal findings in electroencephalography (EEG). Increased CSF cell counts and elevated levels of CSF IL-6 were found in 11 and 30 patients, respectively. Elevated levels of CSF IL-6 were not statistically correlated with specific abnormalities in the blood analysis, in increased CSF cell counts, and in abnormalities in the brain MRI and EEG. In addition, a group of NPSLE patients positive for antiphospholipid antibodies (aPL) showed lower CSF IL-6 than the patients negative for aPL. CONCLUSION: These results indicated that CSF IL-6 might be useful in diagnosis of NPSLE. However, general assessments of patients based on various factors (clinical manifestations, imaging findings and CSF examinations) are also required.

[A case of HIV-1 infection that showed Western blot analysis for HIV-1 negative after antiretroviral therapy].

Western blot (WB) is the most widely accepted confirmatory assay for detecting antibodies to the human immunodeficiency virus 1 (HIV-1). We report the case of an HIV-1 patient whose WB was negative for over two years. A 41-year-old Japanese man with Pneumocystis pneumonia (PCP) and pulmonary tuberculosis referred in March 2005 was found to have positive HIV-1 ELISA and HIV RNA PCR, but HIV-1 WB with only two bands, at gp160 and p18, and no WB HIV-2 band. The CD4 count was 37/microL, and total immunoglobulin, IgG, IgM, and IgG subclasses were normal. The man was treated for PCP and pulmonary tuberculosis, then underwent antiretroviral therapy. He had taken short-terms steroids to treat a drug allergy and immune reconstitution syndrome. Six months later, his serological ELISA tests for HIV-1 and HIV DNA PCR were negative and WB showed no positive band. The CD4 count recovered gradually, and exceeded 350/microL two years later, but WB remained negative. Lymphoproliferative assays and interferon y expression against HIV-pl7, p24, and p41 were studied and compared to those of other HIV-1 infected patients. Our patient showed no response to p17 or p24 and only a weak response to p41. Other patients showed a response to HIV-antigens, but patients with antiretroviral therapy or with histories of steroid use responded more weakly than those with neither. These findings show that HIV-specific lymphocytes decline with antiretroviral therapy and steroid treatment within early HIV infection. It is therefore important to interpret negative serological tests carefully in patients such as ours.

Correlates of telomere length shortening in peripheral leukocytes of HIV-infected individuals and association with leukoaraiosis.

Telomere length (TL) is a marker of cellular and biological aging. Human immunodeficiency virus (HIV) infection has been reported to be associated with short TLs, which suggests that accelerated biological aging occurs in some cellular compartments of HIV+ individuals. In this study, we measured the TLs of peripheral leukocytes of HIV+ and healthy individuals and examined the biological and environmental correlates of TL. We also investigated the influence of TL on leukoaraiosis, an indicator of cerebral small vessel disease, in HIV+ individuals. Three hundred and twenty-five HIV+ individuals who received stable combination antiretroviral therapy (cART) for >1 year and achieved viral loads of <40 RNA copies/mL were enrolled along with 147 healthy individuals. Relative TLs of leukocytes were estimated by quantitative real-time polymerase chain reaction. Leukoaraiosis was assessed in 184 HIV+ individuals by fluid-attenuated inversion recovery magnetic resonance imaging. We analyzed several covariates, including markers of HIV infection, cART, and social/environmental factors; variables associated with TL length in univariate analyses were incorporated into multivariate models. The TLs of peripheral leukocytes of HIV+ individuals were significantly shorter than those of healthy individuals, and the rate of LT length decline with increasing age was greater. Linear regression analysis showed that in HIV+ individuals, increasing age, cART without integrase-stand transfer inhibitors (INSTI), failure to achieve viral loads of <40 copies/mL within 1 year of initiating cART, and substance use were significantly associated with shorter TLs, even after adjustment for the effects of age. Logistic regression analysis indicated an increasing risk of leukoaraiosis was associated with older age, shorter TLs, hypertension, and carotid artery plaque. Multivariate regression analysis indicated that older age and shorter TLs were significant risk factors for leukoaraiosis. In summary, our data showed that TL shortening in HIV+ individuals was independently associated with leukoaraiosis, and was associated with age, control of viral loads, use of INSTI, and substance use. Our results suggest that effective viral control and less toxic cART can help reduce TL shortening and improve outcomes among HIV+ individuals.