Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy

BACKGROUND: Although untreated human immunodeficiency virus (HIV)-infected patients maintaining undetectable plasma HIV RNA levels (elite controllers) have high HIV-specific immune responses, it is unclear whether they experience abnormal levels of T cell activation, potentially contributing to immunodeficiency. METHODS: We compared percentages of activated (CD38(+)HLA-DR(+)) T cells between 30 elite controllers, 47 HIV-uninfected individuals, 187 HIV-infected individuals with undetectable viremia receiving antiretroviral therapy (antiretroviral therapy suppressed), and 66 untreated HIV-infected individuals with detectable viremia. Because mucosal translocation of bacterial products may contribute to T cell activation in HIV infection, we also measured plasma lipopolysaccharide (LPS) levels. RESULTS: Although the median CD4(+) cell count in controllers was 727 cells/mm(3), 3 (10%) had CD4(+) cell counts <350 cells/mm(3) and 2 (7%) had acquired immunodeficiency syndrome. Controllers had higher CD4(+) and CD8(+) cell activation levels (P < .001 for both) than HIV-negative subjects and higher CD8(+) cell activation levels than the antiretroviral therapy suppressed (P = .048). In controllers, higher CD4(+) and CD8(+) T cell activation was associated with lower CD4(+) cell counts (P = .009 and P = .047). Controllers had higher LPS levels than HIV-negative subjects (P < .001), and in controllers higher LPS level was associated with higher CD8(+) T cell activation (P = .039). CONCLUSION: HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4(+) T cell loss even without measurable viremia.     

Granule-dependent mechanisms of lysis are defective in CD8 T cells of HIV-infected, antiretroviral therapy-treated individuals

BACKGROUND: HIV-specific cytotoxic T-cell (CTL) responses are defective in HIV-infected patients undergoing antiretroviral therapy (ART). This defect has been attributed to the decreased antigenic burden secondary to ART-associated suppression of HIV-replication, and is responsible for the rebounds of viraemia that occur when patients interrupt therapy. CTL are stimulated by type 1 cytokines and can kill targets via granule-dependent (perforin and granzymes) and -independent (tumour necrosis factor-alpha, CD95) mechanisms. METHODS: Granule-dependent and granule-independent mechanisms of CTL killing, as well as type 1 cytokine production by CD4 T cells, were analysed in 57 chronically HIV-infected ART-treated or ART-untreated individuals. RESULTS: The results can be summarized as follows: the frequency of gp160 (env)-specific interferon-gamma-secreting CD8 T lymphocytes correlates positively with HIV viraemia in ART-treated and -untreated patients; Env-specific perforin- and granzymes-expressing CD8 T lymphocytes, and Env-stimulated perforin and granzymes mRNA, are reduced in ART-treated patients independently of HIV viral load and of type 1 cytokine production; tumour necrosis factor-alpha production is increased in ART-treated individuals; and Env-specific immature CD8+28+27+ cells are only marginally augmented in ART-treated patients, Similar results are observed in cytomegalovirus-specific CD8 T cells and peripheral blood mononuclear cells. CONCLUSIONS: A defect of CTL function that selectively affects the granule-dependent mechanisms of lysis is observed in ART-treated individuals. Because interferon-gamma production is higher in these patients, this could be a defect primarily involving CTL. These data suggest an independence of CD8 T-cell numbers and their lytic ability in HIV-infected, ART-receiving patients. Immunomodulants are needed to successfully treat HIV infection.     

CD38 expression on CD8 T lymphocytes as a marker of residual virus replication in chronically HIV-infected patients receiving antiretroviral therapy

The level of CD8+ CD38+ T lymphocytes in blood correlates with disease progression in HIV-infected individuals, independently of the CD4 count. Effective antiretroviral therapy reduces this lymphocyte subset in parallel with plasma viremia, although CD38 expression on CD8+ cells does not normalize completely in most subjects, and might reflect residual HIV replication. The expression of CD38 on CD8+ cells (as number of CD38 molecules per CD8+ cell) was measured quantitatively by flow cytometry in 200 individuals, of whom 170 were HIV positive and 30 were HIV-uninfected controls. Forty-six HIV-infected subjects were on antiretroviral therapy and had undetectable viral load. The remaining 124 HIV-positive persons were not on therapy and had detectable plasma viremia. The mean level of CD38 on CD8+ cells was higher in HIV-positive, untreated patients than in subjects on antiviral therapy and controls (5023, 2029, and 1978 molecules per CD8+ cell, respectively, p < 0.01). In HIV-positive, untreated subjects, the higher CD38 expression mainly occurred on CD45RO+ CD8+ cells. The level of CD38 strongly correlated with plasma HIV-RNA (r = 0.63, p < 0.001). The levels of CD38 on CD8+ cells declined steadily in HIV-positive subjects after beginning antiretroviral therapy. A few individuals presented viral blips whereas being on antiviral treatment, levels of CD38 on CD8+ cells increased transiently in parallel with episodes of viral replication. Levels of CD38 on CD8+ cells are increased in chronic HIV infection, and strongly correlate with plasma viremia. The slow decline of CD38 expression on CD8+ cells over time in subjects with undetectable plasma viremia while being on antiretroviral therapy suggests that CD38 expression on CD8+ cells could be used as a marker of residual virus replication.     

Relationship between the frequency of HIV-specific CD8+ T cells and the level of CD38+CD8+ T cells in untreated HIV-infected individuals

CD8+ T cells are critical for effective host defenses against viral infections. Studies addressing HIV-induced immune responses in infected individuals have suggested that CD8+ T cells play an important role in controlling viral replication. However, despite an abundance of HIV-specific CD8+ T cells, HIV is not contained in many untreated patients. Active HIV replication is associated with numerous immunologic changes, the most notable and consistent of which is an increase in CD8+ T cells expressing CD38. Previous studies have demonstrated that the expression of CD38 on CD8+ T cells is associated with poor prognostic outcome in infected individuals with detectable plasma viremia; however, the relationship between the expression of CD38 and the frequency of HIV-specific CD8+ T cells is unclear. We demonstrate a correlation between levels of HIV-specific CD8+ T cells and levels of CD8+ T cells expressing CD38 in untreated patients. The distribution of HIV-specific CD8+ T cells was heavily skewed toward CD38+CD8+ T cells in patients with a high percentage of CD38+CD8+ T cells. Spontaneous/Fas-mediated apoptosis in CD38+CD8+ T cells was significantly higher in patients with high percentages of CD38+CD8+ T cells. Our data suggest that a substantial proportion of the HIV-specific CD8+ T cells present in CD38+CD8+ T cells in patients with active viral replication arise by HIV-driven aberrant immune activation and may not manifest effective cytolytic activity against infected targets due to a high degree of susceptibility to apoptosis, thus providing an explanation of why HIV is not successfully contained by CD8+ T cells in such individuals.     

HIV disease progression: immune activation, microbes, and a leaky gut

Recent findings indicate that the majority of all CD4+ T lymphocytes are lost during acute HIV infection, with mucosal compartments being most severely affected. The frequency of infection is very high in gut CD4+ T cells, and depletion of these cells persists into the chronic phase of infection. Infection is associated with increased gut permeability, with microbial translocation being evidenced by increased circulating lipopolysaccharide (LPS) levels. Plasma LPS levels correlate with systemic immune activation, which drives chronic HIV infection. Antiretroviral therapy reduces plasma LPS, and greater CD4+ T cell reconstitution is associated with lower LPS levels. These findings have a number of implications for therapeutic strategies. This article summarizes a presentation on HIV disease progression made by Daniel Douek, MD, PhD, at an International AIDS Society-USA Continuing Medical Education course in San Francisco in May 2007. The original presentation is available as a Webcast at www.iasusa.org.     

抗病毒治疗早期艾滋病病人CD4+ T细胞亚群与免疫重建的关系

目的研究抗病毒治疗(ART)早期阶段,艾滋病(AIDS)病人CD4+T细胞亚群的变化及其与免疫重建的关系。方法前瞻性分析21例接受ART规律治疗的艾滋病病人,收集病人服药前及服药第2、4、8、12周时的静脉血,采用流式细胞仪染色技术检测CD4+T细胞的水平,分析其在治疗过程中的变化规律,以及与免疫活化间的相关性。结果 ART后,CD4中心记忆细胞(CD4CM)和CD4幼稚细胞两种形式的CD4+T细胞增加,且在前4周治疗增长迅速。治疗4周时CD4CM的变化与治疗12周时CD4+T细胞的变化呈正相关关系,而与CD8+CD3+8T细胞的变化呈负相关关系。结论 ART能有效地重建AIDS病人的T淋巴细胞免疫,并且CD4CM可能是免疫重建的早期指标。     

CD4+CD38+HLA-DR+ cells: a predictor of viral set point in Chinese men with primary HIV infection who have sex with men

Twenty-three Chinese men with primary HIV infection (PHI) who have sex with men, and 17 asymptomatic HIV-infected patients participated in this study. The effect of different initial activation parameters on viral set points and the immunologic progression of subjects with PHI were determined. We found that the proportions of CD38+DR+ and CD38-DR+ T cells were lower while those of CD38+DR- and CD38-DR- T cells were higher in patients with PHI than in the asymptomatic HIV-infected patients. The initial proportion of CD4+CD38+DR+ T cells emerged as a statistically significant predictor (P < 0.05) of viral set points by multivariate least squares regression. In addition, individuals with a higher initial proportion of CD4+CD38+DR+ cells were more likely to have CD4+ T cell counts decrease to ≤ 350 cells/μl (P = 0.015), as determined by Kaplan-Meier curve analysis. We concluded that the initial CD4+CD38+DR+ T cell level in PHI patients is an important prognostic parameter of viral set points and is therefore related to disease progression.     

Antiretroviral treatment of HIV infection does not influence HIV-specific immunity but has an impact on non-specific immune activation

HIV-specific and non-specific immune responses are crucial in the immunopathogenesis of HIV infection. Therefore, the objective of our study was to analyse the frequency and functional status of HIV-specific CD8+ T cells and the expression of non-specific activation markers on CD8+ T cells in HIV+ patients, and to assess the effects of combined antiretroviral treatment (cART). We examined 28 HIV+ patients, including 13 patients not receiving therapy and 15 patients on cART therapy using ELISpot assay and flow cytometry with intracellular and MHC tetramer staining. MHC tetramers detected HIV-specific CD8+ T cells in 6 HIV+ patients on cART and in 7 untreated individuals; the ELISpot method detected these cells in 5 untreated HIV+ individuals only. Reduced intracellular IFN-γ and IL-2 production by HIV-specific CD8+ T cells was detected in both treated and untreated HIV+ patients, and multifunctional CD8+ T cells simultaneously producing these cytokines were not found in any patient. In contrary to these findings, the percentage of CD8+ T cells expressing CD38 and HLA-DR was significantly higher in untreated patients as compared to HIV+ patients on cART. Together, these results suggest that the alterations of HIV-specific immunity are not influenced by the therapy of HIV infection; whereas, the non-specific chronic immune activation is down-regulated by cART.     

Relationship of frequency of CD4+CD25+Foxp3+ regulatory T cells with disease progression in antiretroviral-naive HIV-1 infected Chinese

Forty-five antiretroviral-naive HIV-1 infected patients and 14 healthy controls in North China were enrolled in this study. The frequency of CD4+CD25+Foxp3+ regulatory T cells (Tregs) and levels of expression of CD95, HLA-DR and CD38 in T cells were detected by flow cytometry. We found that the frequency of Tregs was higher in AIDS patients than in asymptomatic HIV-1 infected patients (P=0.004). The frequency of Tregs was significantly correlated with absolute CD4 count, viral load, CD4+CD95+ T cells and CD8+CD95+ T cells (P<0.05). The relationship between the frequency of Tregs and immune activation was not found in HIV-infected patients. We concluded that the frequency of Tregs in HIV-infected Chinese patients was significantly correlated with disease progression.     

未经高效抗逆转录病毒治疗的HIV感染者血管内皮损伤及血浆脂肪细胞因子的研究

目的 研究未经高效抗逆转录病毒治疗(HAART)的HIV感染者血管内皮损伤、血浆脂肪细胞因子及血栓形成因子的水平,以探讨单纯HIV感染者体内是否存在心血管病高危因素.方法 收集2009年2-10月在我中心就诊的HIV感染者43例和17例同期院内正常体检者的一般资料并采集外周静脉血,ELISA法检测血浆瘦素、脂联素、可溶性细胞间黏附分子1(sICAM-1)、D-二聚体水平,在两组人群中比较这4项指标及TC、TG、空腹血糖等指标.流式细胞仪检测病例组CD4+T淋巴细胞计数、CD8+CD38+/CD8+、CD8+HLA-DR+/CD8+,用病毒定量检测仪和分支DNA技术检测HIV病毒载量,两组人群中有统计学差异的指标与CD4+T淋巴细胞计数、CD8+CD38+/CD8+、CD8+HLA-DR+/CD8+、HIV病毒载量进行Spearman相关性分析.结果 43例HIV感染者CD4+T淋巴细胞为(133±82)个/μl,HIV RNA为(4.42±0.66)lg拷贝/ml,瘦素[11.41(7.91,14.53)μg/L]、脂联素[1.79(1.40,4.00)mg/L]水平显著低于对照组[55.31(16.49,229.65)μg/L,3.36(2.92,4.18)mg/L,P值均＜0.005],sICAM-1[1.71(1.11,2.40)mg/L]显著高于对照组[0.69(0.57,0.80)mg/L,P=0.0000],并且sICAM-1与HIV病毒载量及免疫激活指标CD8+ CD38+/CD8+显著正相关(r=0.3378,P=0.0267和r=0.3904,P=0.0096).结论 未经HAART治疗的HIV感染者体内存在某些心血管病高危因素的显著变化,应进一步研究其内在机制,寻求预防和处理方法.

Abstract：

Objectives To investigate the markers of endothelial injury, adipocytokine and thrombotic activity and explore whether there are cardiovascular disease risk factors in antiretroviral-naive HIV patients. Methods Clinical data and venous blood samples were collected from 43 anti-retroviral naive HIV-infected patients during February -October 2009 in our center, and compared with 17 healthy subjects.Plasma leptin, adiponectin, soluble intercellular adhesion molecule-1 ( sICAM-1 ), D-dimer were measured by ELISA. Four markers and cholesterol, triglyceride, fasting plasma glucose were compared between the two groups. The CD4+ T cells and percentages of CD38, HLA-DR on CD8+ T were determined by flow cytometry and plasma HIV copies were detected with bDNA analyzer among HIV-infected participants.Spearman correlations between the significant markers and CD4+ T cells, CD8+ CD38+/CD8+, CD8+ HLA-DR +/CD8+, HIV viral load were examined among HIV-infected participants. Analyses were conducted by using Stata version 7. Results Thirty-eight of the 43 patients were sexually infected by HIV and the median absolute CD4+ T cell count was ( 133 ± 82 ) cells/μl, HIV RNA was (4. 42 ± 0. 66 ) lg copies/ml. HIV-infected patients, compared with healthy subjects, had lower leptin [11.41 (7.91,14. 53 )μg/L vs 55.31( 16. 49,229.65 ) μg/L, P= 0. 0005], adiponectin [1.79 ( 1.40,4. 00 ) mg/L vs 3.36 ( 2. 92,4. 18 ) mg/L,P =0. 003] and higher sICAM-1 [1.71 (1.11,2.40) mg/L vs 0. 69 ( 0. 57, 0. 80 ) mg/L, P = 0. 0000].No significant differences exist in cholesterol, triglyceride, fasting plasma glucose. For HIV-infected participants, sICAM-1 tended to correlate with CD8+ CD38+/CD8+ and HIV viral load ( r= 0.3378, P= 0.0267;r = 0.3904,P = 0.0096). Conclusion Patients with untreated HIV infection have lower leptin, adiponectin and higher sICAM-1 levels and the relationship of these markers to HIV-mediated atherosclerotic risk requires further study.     

Immunological changes after highly active antiretroviral therapy with lopinavir-ritonavir in heavily pretreated HIV-infected children

We evaluated the effect of salvage antiretroviral therapy with lopinavir/ritonavir (LPV/r) on the immune system of heavily antiretroviral pretreated HIV-infected children. We carried out a longitudinal study in 20 antiretroviral experienced HIV-infected children to determine the changes in several immunological parameters (T cell subsets, thymic function) every 3 months during 18 months of follow-up on salvage therapy with LPV/r. Statistical analyses were performed with the Wilcoxon test, taking as a reference the basal value at the entry in the study. HIV-infected children showed an increase of CD4+ T cells, a decrease in CD8+ T cells, and an increase in T cell rearrangement excision circle (TRECs) levels. The percentage of HIV children with undetectable viral load (VL < or = 400 copies/ml) increased significantly (p = 0.007) and the percentage with SI viral phenotype decreased significantly (p = 0.002) at the end of the study. Thus, the viral phenotype changed to NSI/R5 after salvage therapy with LPV/r. Interestingly, we observed a significant decrease of memory (CD4+ CD45RO+) and a moderate decrease of activated (CD4+ HLA-DR+, CD4+ HLA-DR+CD38, CD4+, CD45RO+HLA-DR+) CD4+ T cells during the follow-up. On the other hand, memory (CD8+ CD45RO+ and CD8+ CD45RO+CD38+), activated (CD8+ HLA-DR+CD38+, CD8+ HLA-DR+, CD8+ CD38+), and effector (CD8+ CD57+, CD8+ CD28(-)CD57+) CD8+ T cells had a very significant decrease during follow-up. Our data indicate an immune system reconstitution in heavily pretreated HIV-infected children in response to salvage therapy with LPV/r as a consequence of a decrease in immune system activation and an increase in thymic function.     

Markers of Gut Barrier Function and Microbial Translocation Associate with Lower Gut Microbial Diversity in People with HIV

People with human immunodeficiency virus (HIV) (PWH) have reduced gut barrier integrity (“leaky gut”) that permits diffusion of microbial antigens (microbial translocation) such as lipopolysaccharide (LPS) into the circulation, stimulating inflammation. A potential source of this disturbance, in addition to gut lymphoid tissue CD4+ T-cell depletion, is the interaction between the gut barrier and gut microbes themselves. We evaluated the relationship of gut barrier integrity, as indexed by plasma occludin levels (higher levels corresponding to greater loss of occludin from the gut barrier), to gut microbial diversity. PWH and people without HIV (PWoH) participants were recruited from community sources and provided stool, and 16S rRNA amplicon sequencing was used to characterize the gut microbiome. Microbial diversity was indexed by Faith’s phylogenetic diversity (PD). Participants were 50 PWH and 52 PWoH individuals, mean ± SD age 45.6 ± 14.5 years, 28 (27.5%) women, 50 (49.0%) non-white race/ethnicity. PWH had higher gut microbial diversity (Faith’s PD 14.2 ± 4.06 versus 11.7 ± 3.27; p = 0.0007), but occludin levels were not different (1.84 ± 0.311 versus 1.85 ± 0.274; p = 0.843). Lower gut microbial diversity was associated with higher plasma occludin levels in PWH (r = −0.251; p = 0.0111), but not in PWoH. A multivariable model demonstrated an interaction (p = 0.0459) such that the correlation between Faith’s PD and plasma occludin held only for PWH (r = −0.434; p = 0.0017), but not for PWoH individuals (r = −0.0227; p = 0.873). The pattern was similar for Shannon alpha diversity. Antiretroviral treatment and viral suppression status were not associated with gut microbial diversity (ps > 0.10). Plasma occludin levels were not significantly related to age, sex or ethnicity, nor to current or nadir CD4 or plasma viral load. Higher occludin levels were associated with higher plasma sCD14 and LPS, both markers of microbial translocation. Together, the findings suggest that damage to the gut epithelial barrier is an important mediator of microbial translocation and inflammation in PWH, and that reduced gut microbiome diversity may have an important role.     

Functionally competent antigen-specific CD127(hi) memory CD8+ T cells are preserved only in HIV-infected individuals receiving early treatment

The importance of functional CD4+ T cells and antigen control in the maintenance of CD127 expression on antigen-specific CD8+ T cells is poorly understood in humans. We compared CD127 expression on antigen-specific CD8+ T cells in 4 groups of human immunodeficiency virus (HIV)-infected patients. This analysis demonstrated that HIV-specific CD8+ CD127(hi) T cells are maintained as long-lived memory cells only in HIV-infected individuals treated early with antiretroviral therapy (ART). This population of CD127(hi) T cells fluctuates with viral load (VL) such that the antigen-specific T cell pool oscillates from a CD127(hi) memory to a CD127(lo) effector phenotype depending on the levels of plasma VL. In individuals with chronic infection, the CD127(hi) pool diminishes or is lost with time despite virologic control while receiving ART. These studies show that functionally competent subsets of antigen-specific memory CD8+ T cells in HIV-infected individuals are maintained but only if control of viremia is attained early during the course of infection.     

Downregulation of Bcl-2, but not of Bax or Bcl-x, is associated with T lymphocyte apoptosis in HIV infection and restored by antiretroviral therapy or by interleukin 2.

The role of Bcl-2, Bax, and Bcl-x in the apoptosis of T lymphocytes in HIV-infected individuals was investigated. A strong correlation between Bcl-2 downregulation and spontaneous apoptosis has been reported by various groups in short-term cultures of CD8+ but not of CD4+ T lymphocytes. We describe a similar correlation in CD4+ T cells and provide an explanation why Bcl-2 downregulation in these cells has not been detected so far. In apoptotic cells not only Bcl-2, but also the CD4 surface receptors, are downregulated, preventing the detection of these cells in flow cytometric analysis. In contrast to Bcl-2, no correlation is detectable between Bax or Bcl-x expression and apoptosis. T lymphocytes of HIV-infected, but not of control, individuals display ex vivo a heterogeneous Bcl-2 expression pattern with a low and a high Bcl-2-expressing lymphocyte fraction. The proportion of low Bcl-2-expressing T cells correlates with a higher viral load in these individuals. Antiretroviral therapy significantly reduces the proportion of low Bcl-2-expressing lymphocytes, which is associated with a decrease in apoptosis. Bcl-2 downregulation and spontaneous apoptosis of T lymphocytes from HIV-infected individuals can be partially prevented by the exogeneous addition of IL-2, but not of IL-12, IL-4, or antibodies that prevent the CD95/CD95 ligand pathway of apoptosis.     

Lack of the CD8+ cell anti-HIV factor in CD8+ cell granules

In HIV infection, CD8+ cells show cytotoxic and noncytotoxic anti-HIV activity. The latter function is mediated, at least in part, by a secreted antiviral protein, the CD8+ cell antiviral factor (CAF). Because antiviral effector molecules, such as perforin and granzymes, reside in the exocytic granules of CD8+ T cells, we examined the possibility that granules contain CAF-like activity. CD8+ cells from HIV-infected individuals showing strong CAF-mediated antiviral activity were induced to release their granule constituents into culture media. Within 1 hour of stimulation, high levels of granzyme B (a primary granule constituent) were found in the culture fluids of previously activated CD8+ cells. The same culture fluids contained no or very low amounts of CAF activity, as measured with HIV-infected CD4+ cells. Maximal levels of CAF activity were not observed until 5 or 7 days after stimulation, consistent with typical CAF production kinetics. In addition, extracts of granules purified from antiviral CD8+ cells did not show any CAF activity, whereas the cytoplasmic fraction of these cells showed substantial levels of antiviral activity. These findings suggest that CAF does not reside at appreciable levels in the exocytic granules of antiviral CD8+ T cells.     

Prospective study of CD8+ lymphocyte activation in relation to viral load in HIV-infected patients with > or = 400 CD4+ lymphocytes per microliter.

To investigate the temporal relationship between CD8+ lymphocyte phenotypic alterations, the CD4+ T cell decline, and plasma HIV RNA levels during the natural history of HIV infection, 33 treatment-naive HIV-infected patients with > or =400 CD4+ cells/microl were studied prospectively for 3 years. During the study period, 20 patients remained untreated, and only 6 received more than 6 months of therapy. A significant relationship was found between changes in plasma HIV RNA and changes in the proportion of CD38+CD8+ cells. Conversely, the number of CD4+ T cells lost per year was strongly related to the increase in the proportion of CD28-CD8+ T cells. A strong relationship between mean yearly changes in CD4+ T cell numbers and changes in HIV RNA was also observed. CD4+ T cell changes were associated with changes in both viral load and CD8+ T cell activation. These results provide support for the use of both virologic and immunologic parameters for prognosis and management during HIV infection.     

Immune activation in the female genital tract during HIV infection predicts mucosal CD4 depletion and HIV shedding

Plasma viral load predicts genital tract human immunodeficiency virus (HIV) shedding in HIV-infected women. We investigated whether local mucosal T-cell activation (HLA-DR, CD38, CCR5, and Ki67) contributed to HIV shedding in the genital tracts of HIV-infected women. We showed that cervical cytobrush-derived T cells expressed higher frequencies of T-cell activation markers (CD38+ and HLA-DR+) than blood-derived T cells. Expression was significantly higher in HIV-infected women than in uninfected women. We found that the frequency of activated proliferating cervical T cells (Ki67+; Ki67+CCR5+) broadly predicted HIV shedding in the genital tract in HIV-infected women, independently of plasma viral loads. Furthermore, activated cervical T cells (HLA-DR+CD38+ and HLA-DR+CCR5+) and local HIV shedding were independently associated with CD4 depletion in the genital tract. These data suggest that the presence of high frequencies of activated T cells in the female genital mucosa during HIV infection facilitates both local HIV shedding and CD4 T-cell depletion.     

Deregulation of the expression of the fractalkine/fractalkine receptor complex in HIV-1-infected patients

Fractalkine is the only member of the CX3C chemokine family. Polymorphism of the fractalkine receptor gene may influence the prognosis of human immunodeficiency virus (HIV) infection, but the nature of the cells expressing fractalkine or its receptor in HIV-infected patients remains unknown. We show that, in contrast to HIV-uninfected individuals, a large number of cells expressed fractalkine in T-cell zones of lymph nodes from HIV-infected patients. CD83(+) mature and CD123(+) plasmacytoid dendritic cells as well as plasma cells are involved in this increased expression of fractalkine. Increased numbers of plasmacytoid dendritic cells and plasma cells were present in T-cell zones of HIV-infected patients. CD83(+) dendritic cells were present in similar number in HIV-infected patients and controls, but an increased fraction of these cells produced fractalkine in HIV-infected patients. Many plasma cells in the gut-associated lymphoid tissue from HIV-infected patients also produced fractalkine, whereas few cells produced fractalkine in the gut of controls. The fraction of CD45RO(+) and CD45RO(-) T helper (Th) cells expressing the fractalkine receptor CX3CR1 was higher in HIV-infected patients than in healthy individuals, and these cells were abnormally sensitive to fractalkine stimulation. This increased response correlated with HIV viremia, and it returned to normal levels in patients successfully treated with antiretroviral drugs. The increased expression of the fractalkine/fractalkine receptor complex associated with HIV infection may affect adhesion and migration of Th lymphocytes and their interaction with dendritic cells. Thus, it may influence the equilibrium between depletion and renewal of the Th lymphocyte compartment.     

Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load

Although generalized T-cell activation is an important factor in chronic HIV disease pathogenesis, its role in primary infection remains poorly defined. To investigate the effect of immune activation on T-cell changes in subjects with early HIV infection, and to test the hypothesis that an immunologic activation "set point" is established early in the natural history of HIV disease, a prospective cohort of acutely infected adults was performed. The median density of CD38 molecules on CD4+ and CD8+ T cells was measured longitudinally in 68 antiretroviral-untreated individuals and 83 antiretroviral-treated individuals. At study entry, T-cell activation was positively associated with viremia, with CD8+ T-cell activation levels increasing exponentially at plasma HIV RNA levels more than 10,000 copies/mL. Among untreated patients, the level of CD8+ T-cell activation varied widely among individuals but often remained stable within a given individual. CD8+ T-cell activation and plasma HIV RNA levels over time were independently associated with the rate of CD4+ T-cell loss in untreated individuals. These data indicate that immunologic activation set point is established early in HIV infection, and that this set point determines the rate at which CD4+ T cells are lost over time.     

Production of CD8+ T cell nonlytic suppressive factors by CD28, CD38, and HLA-DR subpopulations

HIV infection may be modified by CD8(+) T cells by the production of nonlytic antiviral factors. To determine subpopulations that mediate nonlytic, antiviral activity, we examined the production of beta chemokines and of CD8 antiviral factor (CAF) by different subsets, using CD8(+) cells derived from 24 HIV-1-infected and 25 uninfected individuals. Subjects with CD8(+) cell counts greater than 200/microl produced increased levels of MIP-1alpha by CD8(+)CD28(+), CD8(+)CD38(-), and CD8(+)HLA-DR(+) subsets as compared with uninfected controls. CD8(+)CD38(-) cells produced higher levels of MIP-1beta and RANTES. CAF production was increased by CD8(+)CD38(+) and CD8(+)HLA-DR(+) cells of HIV-infected individuals as compared with uninfected controls. Chemokine production was increased by cells that do not express activation markers, whereas CAF activity was increased by cells expressing CD38 or HLA-DR. These findings shed light on CD8(+) T cell noncytotoxic antiviral factor production during HIV infection.