Bilateral cystoid macular edema following successful treatment of AIDS-associated CMV retinitis

Background: Cystoid macular edema (CME) in AIDS patients with inactive cytomegalovirus (CMV) retinitis is an uncommon but potentially sight-threatening complication. The pathogenesis of CME in these patients is unclear. This study tries to identify possible risk factors by analyzing the charts of five patients. Methods: Ten eyes of 5 patients that finally developed CME were followed for an average of 18 months. The initial retinal lesions, their response to antiviral treatment, the development of CME, and the patients' immune status were prospectively monitored. Results: CMV retinitis was diagnosed at a median CD4+ count of 3 cells/mm³ (range 0–11). All eyes responded to the initial systemic anti-viral treatment. At the onset of CME, CMV retinitis was controlled by antiviral maintenance therapy in all patients [ganciclovir (n = 2), cidofovir (n = 2), foscarnet (n = 1)]. The median time between diagnosis of CMV retinitis and onset of CME was 11.5 months (range 5–24). Development of CME was associated with significant visual loss: acuity ranged from 0.05 to 0.7 when CME was first noticed, compared to 0.8–1.25 at diagnosis of CMV retinitis. Duration of inflammation, size or zone of retinal necrosis did not favor the development of CME, neither did the antiviral therapy. A weak correlation of CME development and immune status (expressed as increase of CD4+ cells) was found. Due to systemic corticosteroids CME resolved. Conclusions: CME is a new visual threat to AIDS-patients with CMV retinitis whose immune status improved under the latest combined antiretroviral therapy. Therapy with oral corticosteroids may positively influence this condition.      

NK相关抗原在HIV/AIDS患者CD8+T淋巴细胞上的表达

目的　探讨NK相关抗原CD5 6、CD16在HIV AIDS患者CD8 T淋巴细胞上的表达。方法　取外周血细胞 ,用标记荧光的抗体进行染色 ,以CD8强阳 淋巴细胞为门 ,用流式细胞仪分析CD8 T淋巴细胞上CD5 6、CD16的表达。结果　HIV AIDS患者CD8 T淋巴细胞表达CD5 6 、CD5 6 CD16 - 、CD5 6 CD16 均明显低于HIV抗体阴性健康对照组 (P <0 .0 5 ) ;经高效抗逆转录病毒疗法 (HAART)治疗后CD8 T淋巴细胞表达的CD5 6 、CD5 6 CD16 - 、CD5 6 CD16 呈逐渐升高趋势。HIV AIDS患者表达CD5 6 CD16 - 的CD8 T淋巴细胞亚群绝对数与CD4 T淋巴细胞绝对数呈正相关 ,r=0 .393,P <0 .0 5 ;表达CD5 6 - CD16 的CD8 T淋巴细胞百分数与CD4 T细胞绝对数呈负相关 ,r=- 0 .32 4 ,P <0 .0 5。结论　表达CD5 6的CD8 T淋巴细胞在HIV AIDS患者中明显缺失 ,HAART治疗可恢复缺失。CD8 T淋巴细胞上CD5 6的表达是HIV感染中值得关注的重要指标之一 ,对评价抗病毒疗效具有指导意义。     

T cell responses to highly active antiretroviral therapy defined by chemokine receptors expression, cytokine production, T cell receptor repertoire and anti-HIV T-lymphocyte activity

The immunological correlates of highly active antiretroviral therapy (HAART)-induced suppression of human immunodeficiency virus type 1 (HIV-1) replication have been investigated. 20 HIV-1-infected patients with mean CD4+ T cell count of 298/microl, plasma viral load of 4.7 log10 copies/ml and naive for protease inhibitors (PI) were studied during12 months of HAART. An increased number of both CD4+ and CD8+ naive T cells and a normalization of the frequency of CCR5- and CXCR4-expressing CD4+ T cells were readily observed after starting therapy. Single cell analysis of cytokine production after 12 months of HAART showed an increased number of interleukin (IL)-2-, but not IL-4- and (IFN)-gamma-, producing T cells and a decreased percentage of CD8+ IFN-gamma + cells. A correlation between the frequency of IFN-gamma-producing T cells and that of memory, CCR5+ and CD95+ T cells was demonstrated in both CD4+ and CD8+ subsets. The diversity of T cell receptor (TCR) variable beta (BV) chain repertoire significantly increased after 12 months of HAART within the CD4+ but not the CD8+ T cell subset. However, the level of perturbation of the third complementarity-determining region (CDR3), was not significantly modified by effective therapy. The number of anti-HIV Gag and Pol cytotoxic T lymphocytes precursors (CTLp) decreased during HAART and highly correlated with the CD8 IFN-gamma response. Ameliorated clinical conditions were observed in all patients in absence of any opportunistic infections during all the study period. These observations indicate that a better restoration of immunity may be obtained in patients starting HAART at less advanced stages of the disease.     

An update on the neuropathology of HIV in the HAART era

This review compares the neuropathology of highly active antiretroviral therapy (HAART)-treated HIV+ individuals with the reported central nervous system (CNS) findings from the pre-HAART era. HAART has had considerable success in combating HIV-related immune collapse and has prevented many of the former end-stage complications of AIDS. However, with increased survival times the prevalence of minor HIV-associated cognitive impairment appears to be rising among treated patients and this may be a particular risk for older individuals. HIV encephalitis (HIVE) is still prevalent in treated patients although attenuated forms of HIVE and CNS opportunistic disorders are also observed. Some subjects show very significant CNS lymphocytic infiltrates in the context of HAART-induced immune reconstitution. HIV-associated cognitive impairment correlates best with the increased presence of activated, though not necessarily infected, microglia and CNS macrophages. This suggests that indirect mechanisms of neuronal injury and loss occur in HIV/AIDS as a basis for dementia since neurones are not themselves productively infected. Research to elucidate the mechanisms of neuronal injury in HIV/AIDS may contribute to the understanding of CNS function not only in HAART-treated subjects but also in other neurodegenerative disorders.     

Proliferation and telomere length in acutely mobilized blood mononuclear cells in HIV infected patients

The aim of the study was to investigate the mobilization of T cells in response to a stressful challenge (adrenalin stimulation), and to access T cells resided in the peripheral lymphoid organs in HIV infected patients. Seventeen patients and eight HIV seronegative controls received an adrenalin infusion for 1 h. Blood was sampled before, during and 1 h after adrenalin infusion. Proliferation and mean telomere restriction fragment length (telomeres) of blood mononuclear cells (BMNC) and purified CD8+ and CD4+ cells were investigated at all time points. In patients, the proliferation to pokeweed mitogens (PWM) was lower and decreased more during adrenalin infusion. After adrenalin infusion the proliferation to PWM was restored only in the controls. In all subjects telomeres in CD4+ cells declined during adrenalin infusion. Additionally, the patients had shortened telomeres in their CD8+ cells, and particularly HAART treated patients had shortened telomeres in all cell-subtypes. The finding that patients mobilized cells with an impaired proliferation to PWM during and after adrenalin infusion has possible clinical relevance for HIV infected patients during pathological stressful conditions, such as sepsis, surgery and burns. However, this study did not find a correlation between impaired proliferation and telomeres. It is concluded that physiological stress further aggravates the HIV-induced immune deficiency.     

Reconstitution of CD4+ T cell responses in HIV-1 infected individuals initiating highly active antiretroviral therapy (HAART) is associated with renewed interleukin-2 production and responsiveness

Reconstitution of functional CD4(+) T cell responsiveness to in vitro stimuli is associated with continuous highly active antiretroviral therapy (HAART). Thirty-six antiretroviral naive patients received HAART over 16 weeks. Antigen-specific, mitogen and interleukin (IL)-2 induced lymphocyte proliferative responses and specific IL-2 and IL-4 production were assessed at each time-point, together with quantification of HIV-1 RNA load and lymphocyte populations. Reconstitution of recall responses was limited largely to persistent antigens such as Herpes simplex virus and Candida, rather than to HIV-1 or neo-antigens. Recall antigens, mitogens and IL-2-induced renewed responses were associated with in-vitro production of IL-2, but not IL-4. Differential responsiveness to low versus high concentration IL-2 stimulus increases in a stepwise manner, suggesting normalization of IL-2 receptor expression and improved functionality. These increases in in-vitro proliferative responses thus probably reflect short lived effector clones, driven by ongoing antigenic stimulus associated with persisting long-term organisms. In this context non-responsiveness to HIV-1 antigens suggests ongoing HIV-1 specific clonal T cell anergy.     

Immune reconstitution in human immunodeficiency virus type 1-infected children with different virological responses to anti-retroviral therapy

Immune repopulation, despite virological failure, often occurs in children under highly active anti-retroviral therapy (HAART). The aim of this study was to analyse the characteristics of immune repopulation and activation in children with and without virological response to HAART. Fourteen human immunodeficiency virus type 1 (HIV-1)-infected children with suppression of HIV-1 plasma viraemia (virological responders, VR) and 16 virological non-responders (VNR) to therapy were studied at baseline and after approximately 2 years of HAART. During therapy, CD4+ T cells increased in both groups, but were higher in the VR than in the VNR group. All CD4+ T cell subsets (naive, central memory, effector/memory and CD38+) increased significantly in VR children, while there was a significant increase only in naive cells in VNR children. Naive CD8+ T cells and T cell receptor rearrangement excision circles (TREC), an indicator of thymic output, increased in both VR and VNR children. Activated CD8+ CD38+ T cells decreased in VR but remained high in VNR children. Levels of circulating lipopolysaccharide (LPS), an indicator of microbial translocation, further increased in VNR children. In conclusion, HAART induced an increase in naive cells in all children, regardless of their virological response. However, the persistence of viraemia resulted in an impaired expansion of memory CD4+ T cells susceptible to HIV-1 infection, and together with the microbial translocation sustained the persistence of a high level of immune activation.     

Predictors and kinetics of occult hepatitis B virus infection in HIV-infected persons

It has been proposed that occult hepatitis B virus (HBV) infection, defined as detectable HBV‐DNA in serum with undetectable surface antigen (HBsAg^?), is associated with raised transaminases in HIV‐infected persons. The aim of this study was to determine the prevalence of occult HBV infection in two independent cohorts, and investigate its predictors, association with alanine‐aminotransferase (ALT) levels and response to antiretroviral therapy. Sera from HBsAg^? persons with core antibody (anti‐HBc⁺) were tested by real‐time PCR. Overall, 5.2% of patients were HBsAg⁺ and 39% HBsAg^?/anti‐HBc⁺. The prevalence of occult HBV infection was 48/343 (14.0%; 95% CI 10.7–18.1%), and 27/196 (13.8%) and 21/147 (14.3%) in the two cohorts. Median HBV‐DNA load was 342 (51–147,500) and 60 (25–33,850) copies/ml respectively. HBV‐DNA detection was associated with absence of surface antibody (anti‐HBs), but not with CD4 or ALT levels. Among 11 HBV‐DNA⁺ persons who started antiretroviral therapy containing lamivudine or lamivudine/tenofovir, HBV‐DNA was repeatedly undetectable over median 19 (3–43) months. However, HBV‐DNA detection was intermittent among drug‐naïve persons. Occult HBV infection is common in HBsAg^?/anti‐HBc⁺ HIV‐infected patients and predicted by undetectable anti‐HBs. The intermittent nature of HBV‐DNA detection poses a diagnostic challenge, but no association is observed with ALT levels. J. Med. Virol. 79:1464–1471, 2007. © Wiley‐Liss, Inc.     

Soluble human leukocyte antigen-G serum levels in patients with acquired immune deficiency syndrome affected by different disease-defining conditions before and after antiretroviral treatment

We have previously reported that the serum levels of soluble human leukocyte antigen (HLA)-A, -B, -C, and -G antigens are elevated in human immunodeficiency virus (HIV)-infected subjects and decrease after antiretroviral therapy. In this study, we measured soluble HLA-G serum levels in patients with acquired immune deficiency syndrome (AIDS) affected by different AIDS-defining conditions before and during antiretroviral therapy and correlated them with virologic and immunologic parameters of response to treatment. Soluble HLA-G levels were significantly higher in AIDS patients before treatment as compared with healthy controls and significantly decreased after 36 months of therapy. The decrease of soluble HLA-G correlated with the decrease of plasma HIV-RNA level and CD8(+) T-lymphocytes number and with the increase of CD4(+) T-lymphocytes number. Soluble HLA-G levels were significantly higher in patients with opportunistic infections and Kaposi's sarcoma compared with patients with the wasting syndrome. These data suggest that infections and neoplasms may trigger the shedding of soluble HLA-G molecules, and confirm that the level of soluble HLA-G in serum might represent a surrogate marker to monitor virologic response and immune reconstitution in HIV-positive individuals.