中国人类免疫缺陷病毒-1 vpr基因多态性及其临床意义

目的 分析来自中国不同地区HIV-1感染者的vpr基因序列变异位点及与国外以往研究的异同,为进一步研究HIV-1 vpr基因变异的意义及其与感染者临床病情的关系奠定基础.方法 RT-PCR及套式PCR法对398例HIV-1感染者行HIV-1 vpr基凶扩增,并进行氨基酸序列分析,了解HIV vpr基冈的多念性、离散率和常见变异位点.同时将发现常见变异位点感染者的相应病毒水平、淋巴细胞亚群及临床病程的进展进行对比分析.结果 对398份血标本行HIV-1 vpr基因扩增,分析后可用氨基酸序列为153份.HIV-1 Vpr氨基酸序列分型主要足CRF01_AE 51,63%,C亚型24.84%,B亚型17.65%,CRF03_AB 3.92%,CRF08_BC 1.31%.HIV Vpr序列中第77位氨基酸84.3%为谷氨酸,与以往国外报道的R77Q变异与AIDS长期病情无进展(LTNP)璃彳切卡廿关的观点有明显差异.HIV Vpr第、63、70、85、86、89、94位氨基酸的变异,有可能使感染者的临床进展趋缓.结论 我围HIV Vpr分型仍以M组为主,其中 CRF01_AE占优势.HIV-1 Vpr中氨基酸序列某些位点的变异可能与感染者临床表现相关.     

Serum Vpr regulates productive infection and latency of human immunodeficiency virus type 1.

In human immunodeficiency virus (HIV)-positive individuals, the vast majority of infected peripheral blood cells and lymph node cells may be latently or nonproductively infected. The vpr open reading frame of HIV-1 encodes a 15-kDa virion-associated protein, Vpr. The vpr gene has been shown to increase virus replication in T cells and monocyte/macrophages in vitro. We have previously reported that vpr expression in various tumor lines leads to growth inhibition and differentiation, indicating that Vpr may function as a regulator of cellular permissiveness to HIV replication. Here we show that Vpr protein is present in significant amounts in the serum of AIDS patients. Purified serum Vpr activated virus expression from five latently infected cell lines, U1, OM.10.1, ACH-2, J1.1, and LL58. Serum Vpr also activated virus expression from resting peripheral blood mononuclear cells of HIV-infected individuals. Together, these findings implicate serum Vpr in the activation of HIV replication in vivo and in the control of latency. Anti-Vpr antibodies inhibited Vpr activity, suggesting that humoral immunity modulates Vpr activity in vivo. These results have broad implications for the virus life cycle and for the prospective control of HIV replication and pathogenesis.     

Human immunodeficiency virus vpr gene encodes a virion-associated protein

The vpr gene of human immunodeficiency virus type 1 (HIV-1) is one of the seven accessory genes that are believed to have roles in the virus replication cycle. We report here the detection of a 13 kD vpr protein in sucrose gradient-purified HIV-1. This protein was not detected in cells infected with a virus having a truncated vpr gene that lacks the potential to encode for 26 C-terminal amino acid residues. These findings raise the possibility that virion-associated vpr proteins may be involved in the early life cycle of HIV-1 replication and suggest that the C-terminal region of the vpr gene is essential for its expression.     

Strain-dependent productive infection of a unique eosinophilic cell line by human immunodeficiency virus type 1

Eosinophils are granulocytic leukocytes that function in both protective and pathological immune responses. They can be infected by HIV-1, but characterization of the infection has been hindered by lack of a productive cell culture model. In the present study, the unique eosinophilic cell line AML14.3D10 was used as a model to test the hypothesis that HIV-1 productively infects eosinophilic cells in a strain-dependent fashion. The AML14.3D10 cell line was cultured with one T cell-tropic (T-tropic) strain and two macrophage-tropic (M-tropic) strains of HIV-1 (HTLV-IIIB, HIV-1AdaM, and HIV-1Ba-L strains, respectively). Cytopathic effects were evident in living cultures and in stained slide preparations of AML14.3D10 cells infected with the T-tropic strain of HIV-1. Culture supernatants from infected AML14.3D10 cells contained high levels of HIV-1 p24 protein that peaked at approximately 7-10 days postinfection. A line of AML14.3D10 cells chronically infected with HTLV-IIIB and continuously producing high levels of virus was established. In contrast to the T-tropic strain, the M-tropic strains of HIV-1 did not productively infect the eosinophilic cell line. Thus, the AML14.3D10 eosinophilic cell line was permissive for a T-tropic strain but not for M-tropic strains of HIV-1. Flow cytometry revealed that uninfected AML14.3D10 cells were positive for the HIV-1 receptor CD4 and coreceptors CXCR4 and CCR5; the cell line was negative for CCR3. The lack of productive infection by M-tropic strains despite CCR5 expression indicates that strain-dependent infection may not be determined at the coreceptor level in AML14.3D10 cells.     

Co-infection with opportunistic pathogens promotes human immunodeficiency virus type 1 infection in macrophages

Human immunodeficiency virus type 1 (HIV-1) infection is dependent on susceptible host cells that express both CD4 and chemokine co-receptors. The co-receptor CCR5 is associated with primary infection by macrophage-tropic virus isolates, whereas CXCR4 is commonly associated with T cell- and dual-tropic viruses. Once infected, lymphocytes and macrophages may replicate HIV-1 or harbor latent virus, depending on environmental factors and cellular activation. Immune activation is often associated with viremia, which is consistent with enhanced infection and viral replication in activated cells harboring virus. In this regard, opportunistic infections activate the immune system with the detrimental sequelae of enhanced viral replication and viremia. Under these conditions, viral expansion extends beyond T cells to tissue macrophages, many of which are co-infected with opportunistic pathogens. The opportunistic infections promote macrophage susceptibility to HIV-1 through cytokine modulation and altered chemokine co-receptors, potential targets for intervention.     

Autonomic neuropathy is common in human immunodeficiency virus infection.

We prospectively evaluated autonomic nervous system function in 17 consecutive ambulant patients with HIV infection [mean age (S.D.) 34.5 (5.5) years] and 17 controls matched for sex and age [31.2 (7.4) years]. A questionnaire was administered, and neurological examination and standard bedside autonomic function tests were performed. Eleven of 17 HIV-infected individuals (64.7%) had symptoms suggestive of autonomic dysfunction, particularly urogenital problems. Thirteen of 17 (76.5%) had autonomic neuropathy (one or more abnormal tests), including nine of 11 symptomatic individuals. Only two controls had any autonomic symptoms, and all had normal tests. Autonomic dysfunction is common in those with HIV infection and AIDS.     

The replication of human immunodeficiency virus type 1 in macrophages is enhanced after phagocytosis of apoptotic cells

Clearance of apoptotic cells increases macrophage secretion of antiinflammatory mediators and might modulate viral replication in human immunodeficiency virus (HIV) type 1-infected macrophages. To study this, primary macrophages were infected with HIV-1 and exposed to apoptotic cells. It was found that phagocytosis of apoptotic cells potently enhanced HIV-1 growth. The peptide Arg-Gly-Asp-Ser, which binds to integrin receptors, inhibited the uptake of apoptotic cells and the subsequent enhancement of HIV-1 replication. Viral replication was preceded by increased secretion of transforming growth factor (TGF)-beta1 and partially reverted by anti-TGF-beta1 antibodies. Moreover, anti-TGF-beta1 antibodies inhibited HIV-1 replication in macrophages not exposed to apoptotic cells. A positive correlation was observed between TGF-beta1 production and HIV-1 growth, and the addition of TGF-beta1 amplified HIV-1 replication in macrophages from low TGF-beta1 producers. The findings suggest that TGF-beta1 favors HIV-1 replication in macrophages and that the clearance of apoptotic cells by HIV-1-infected macrophages contributes to persistent viremia in patients infected with HIV-1.     

Interferon gamma and interleukin 6 modulate the susceptibility of macrophages to human immunodeficiency virus type 1 infection

The effect of interferon gamma (IFN-gamma) and interleukin 6 (IL-6) on infection of macrophages with human immunodeficiency virus type 1 (HIV-1) was investigated. By using a polymerase chain reaction-based viral entry assay and viral infectivity assay, it was demonstrated that IL-6 and IFN-gamma augmented susceptibility of monocyte-derived macrophages (MDMs) to infection with T-cell tropic CXCR4-utilizing (X4) HIV-1 strains. Consistent with this finding, IFN-gamma and IL-6 augmented fusion of MDMs with T-tropic envelope-expressing cells. The enhanced fusion of cytokine-treated MDMs with T-tropic envelopes was inhibited by the CXCR4 ligand, SDF-1, and by T22 peptide. IFN-gamma and IL-6 did not affect expression of surface CXCR4 or SDF-1-induced Ca(++) flux in MDMs. In contrast to the effect of IFN-gamma on the infection of MDMs with X4 strains, IFN-gamma inhibited viral entry and productive infection of MDMs with macrophage-tropic (M-tropic) HIV-1. Consistent with this finding, IFN-gamma induced a decrease in fusion with M-tropic envelopes that correlated with a modest reduction in surface CCR5 and CD4 on MDMs. It was further demonstrated that macrophage inflammatory protein (MIP)-1alpha and MIP-beta secreted by cytokine-treated MDMs augmented their fusion with T-tropic-expressing cells and inhibited their fusion with M-tropic envelope-expressing cells. These data indicate that proinflammatory cytokines, which are produced during opportunistic infections or sexually transmitted diseases, may predispose macrophages to infection with X4 strains that, in turn, could accelerate disease progression.     

Higher seroprevalence of Entamoeba histolytica infection is associated with human immunodeficiency virus type 1 infection in Taiwan

We assessed the seroprevalence of Entamoeba histolytica infection using indirect hemagglutination antibody (IHA) assay among 667 HIV-infected persons (group A), 1,311 asymptomatic HIV-uninfected persons seeking anonymous HIV testing (group B), 616 HIV-uninfected controls with gastrointestinal symptoms (diarrhea and/or liver abscess) seeking medical care (group C), and 2,500 healthy controls undergoing health check-up (group D). An IHA titer >or= 128 was detected in 7.1% of group A, 2.5% of group B, 1.8% of group C, and 0.1% of group D (P < 0.0001). The highest seroprevalence (11.2%) was noted among HIV-infected persons who were men having sex with men (MSM) 30-39 years of age. Compared with persons with gastrointestinal symptoms, the adjusted odds ratio for having high IHA titers among HIV-infected persons was 3.206 (95% confidence interval, 1.433, 7.176; P = 0.005). These findings show that HIV-infected persons, especially MSM 30-39 years of age, are at significantly higher risk of E. histolytica infection.     

The nature of the autoimmune antibody repertoire in human immunodeficiency virus type 1 infection.

Human immunodeficiency virus type 1 (HIV-1) seropositive donors typically have high serum antibody titers to a range of autoantigens, and the corresponding autoantibodies have been suggested to be of importance in the pathogenesis of HIV-1 infection. We have prepared 38 IgG human monoclonal autoantibodies from asymptomatic HIV-1 seropositive donors with elevated serum titers to autoantigens by construction of Fab combinatorial libraries on the surface of phage and affinity selection using a range of autoantigens, including double-stranded DNA, major histocompatibility complex class II, CD14, epidermal growth factor receptor, and ganglioside GD2. The autoantibodies are shown to be of moderate affinity and exhibit marked cross-reactivity with a range of antigens. This contrasts with the specific high-affinity antibodies selected (i) against infectious agents using the same libraries and (ii) against one of the autoantigens using a library from a donor with established autoimmune disease. The results lend no support to the presence of specific autoantibodies in HIV-1 infection and instead suggest attention should be focused on the pathological significance of high serum levels of antibodies capable of interacting with multiple molecular species.     

Risk of human immunodeficiency virus infection in herpes simplex virus type 2-seropositive persons: a meta-analysis.

To determine the contribution of herpes simplex type 2 (HSV-2) infection to the risk of human immunodeficiency virus (HIV) acquisition, a systematic review of literature and data synthesis were done. Thirty-one studies addressed the risk of HIV infection in HSV-2-seropositive persons. For 9 cohort and nested case-control studies that documented HSV-2 infection before HIV acquisition, the risk estimate was 2.1 (95% confidence interval, 1.4-3.2). Thus, the attributable risk percentage of HIV to HSV-2 was 52%, and the population attributable risk percentage was 19% in populations with 22% HSV-2 prevalence but increased to 47% in populations with 80% HSV-2 prevalence. For 22 case-control and cross-sectional studies, the risk estimate was 3.9 (95% confidence interval, 3.1-5.1), but the temporal sequence of the 2 infections cannot be documented. Control strategies for HSV-2 need to be incorporated into control of sexually transmitted infections as a strategy for HIV prevention.     

There is an association between human immunodeficiency virus infection and spondyloarthropathies.

The presence of inflammatory musculoskeletal manifestations during the course of human immunodeficiency virus (HIV) infection is well established. A wide spectrum of rheumatic disorders have been reported since the first reports of Reiter's syndrome with HIV infection. Other reported associations include forms of arthropathies, psoriatic arthritis, Sj?gren's syndrome, polymyositis-dermatomyositis, vasculitis, and septic arthritis.     

Detection of human immunodeficiency virus type 2 in brain tissue.

Infection due to human immunodeficiency virus (HIV) type 2 is believed to cause a clinical picture similar to that of HIV-1, although extensive data are not available. In 2 patients with West African exposure and neurologic symptoms, HIV-2 was detected in the central nervous system using DNA and RNA polymerase chain reaction, in situ hybridization, and immunohistology. In the first patient, the neurologic disease was most likely due to productive infection with HIV-2. In the second, a combination of neuropathologic abnormalities (including the presence of HIV-2) explained the clinical features. Thus HIV-2, like HIV-1, can be readily detected in brain tissue in patients with neurologic abnormalities, although the exact role of HIV-2 in pathogenesis of AIDS-associated neurologic disease requires further study.     

Recent herpes simplex virus type 2 infection and the risk of human immunodeficiency virus type 1 acquisition in India

To estimate the impact of prevalent and incident herpes simplex virus type 2 (HSV-2) infection on the acquisition of human immunodeficiency virus type 1 (HIV-1), stored serum samples from a cohort of 2732 HIV-1-seronegative patients attending 3 sexually transmitted infection clinics and 1 reproductive tract infection clinic in Pune, India, were screened for HSV-2-specific antibodies. Incident HSV-2 infection was defined serologically as "recent" if a negative result of testing for HSV-2 could be documented within the previous 6 months or "remote" if >6 months had elapsed since the last negative test result. The prevalence of HSV-2 at enrollment was 43%. The HSV-2 incidence was 11.4 cases/100 person-years, and the HIV-1 incidence was 5.8 cases/100 person-years. The adjusted hazard ratios of HIV-1 acquisition from exposure to HSV-2 infection were 1.67 for prevalent HSV-2, 1.92 for remote incident HSV-2, and 3.81 for recent incident HSV-2. Recent incident HSV-2 infection was associated with the highest risk of HIV-1 in this study, which suggests that prevention of HSV-2 infection may reduce the risk of HIV-1 acquisition.     

Kinetics of cytokine expression during primary human immunodeficiency virus type 1 infection.

In the present study, we have determined the kinetics of constitutive expression of a panel of cytokines [interleukin (IL) 2, IL-4, IL-6, IL-10, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha)] in sequential peripheral blood mononuclear cell samples from nine individuals with primary human immunodeficiency virus infection. Expression of IL-2 and IL-4 was barely detected in peripheral blood mononuclear cells. However, substantial levels of IL-2 expression were found in mononuclear cells isolated from lymph node. Expression of IL-6 was detected in only three of nine patients, and IL-6 expression was observed when transition from the acute to the chronic phase had already occurred. Expression of IL-10 and TNF-alpha was consistently observed in all patients tested, and levels of both cytokines were either stable or progressively increased over time. Similar to IL-10 and TNF-alpha, IFN-gamma expression was detected in all patients; however, in five of nine patients, IFN-gamma expression peaked very early during primary infection. The early peak in IFN-gamma expression coincided with oligoclonal expansions of CD8+ T cells in five of six patients, and CD8+ T cells mostly accounted for the expression of this cytokine. These results indicate that high levels of expression of proinflammatory cytokines are associated with primary infection and that the cytokine response during this phase of infection is strongly influenced by oligoclonal expansions of CD8+ T cells.     

Thyroid function in children with perinatal human immunodeficiency virus type 1 infection.

OBJECTIVE: To study thyroid function in children with perinatal HIV-1 infection retrospectively and determine whether thyroid abnormalities are correlated with clinical condition, disease progression, immunological impairment, and viral load. STUDY DESIGN AND SETTING: Total (TT4) and free (FT4) thyroxine, total (TT3) and free (FT3) triiodothyronine, reverse triiodothyronine (rT3), thyrotropin (TSH), thyroglobulin (TG), and thyroid binding globulin (TBG) were measured twice in 56 children with perinatal human immunodeficiency virus type 1 (HIV-1) infection. Median age at first determination was 13.5 (range: 0.03-127.0) months; median age at second determination was 66.2 (range 3.42-147.4) months. Antithyroglobulin, antimicrosomal, thyroid peroxidase, and thyrotropin receptor antibodies were also evaluated. Fifty-three healthy children were selected as controls. RESULTS: TT3, TT4, FT4, and TG were significantly reduced and rT3, TBG, and TSH increased in children with HIV-1 infection when compared with controls. Thyroid dysfunction correlated with severe immunosuppression and high viral load early in life preceded the onset of the disease and worsened over time. Autoantibodies were negative in all children with HIV-1 infection in all determinations. CONCLUSION: Thyroid abnormalities are observed early in the course of perinatal HIV-1 infection; thyroid dysfunction is particularly pronounced in children with severe immunosuppression and high viral load. Modifications of thyroid function precede worsening of clinical course in HIV-1 infected children.