Rachel Schrier

Cytomegalovirus (CMV)–Specific CD4+ T Lymphocyte Immune Function in Long-Term Survivors of AIDS-Related CMV End-Organ Disease Who Are Receiving Potent Antiretroviral Therapy

To better understand the relation of cytomegalovirus (CMV)-specific CD4+ T lymphocyte immunity and clinical outcome in AIDS-related CMV end-organ disease, 2 patient groups were prospectively studied: patients recently diagnosed with active CMV end-organ disease and survivors of CMV retinitis who had responded to highly active antiretroviral therapy and had quiescent retinitis when anti-CMV therapy was discontinued. Most patients with active CMV disease had negative CMV-specific CD4+ T lymphocyte responses at diagnosis, as measured by lymphoproliferation (7/7) or cytokine flow cytometry (3/5) assays. In contrast, all 10 subjects with quiescent retinitis and >150 absolute CD4+ T lymphocytes/microL whose anti-CMV therapy was discontinued during 6 months of follow-up had positive CMV-specific immune responses at least once by each assay. However, 6 of these 10 subjects also had negative CMV-specific immune responses > or =1 time. Such patients may be at risk for future CMV disease progression and should be closely monitored.

Effect of Potent Antiretroviral Therapy on Immune Responses to Mycobacterium avium in Human Immunodeficiency Virus—Infected Subjects

To characterize the influence of highly active antiretroviral therapy (HAART) on cell-mediated immunity (CMI) to Mycobacterium avium complex (MAC), we measured immune responses to M. avium in human immunodeficiency virus (HIV)-infected individuals before and during HAART, in subjects with a history of disseminated MAC (DMAC), and in HIV-uninfected control subjects. Forty-seven percent of untreated HIV-infected patients and 78% of control subjects exhibited in vitro proliferative responses to M. avium (P=.03). Proliferative responses to M. avium increased after HAART for 3 months and were present in 77% of subjects after 6 months. Mean interferon-gamma production increased from 199 to 1156 pg/mL after HAART (P=.06). Proliferative responses to M. avium occurred in 76% of DMAC subjects receiving HAART. CD4 and CD8 but not gammadelta T cells expanded in response to M. avium. CMI to M. avium reconstitutes rapidly after HAART and appears sustained even with partial viral suppression.

Intraocular Viral And Immune Pathogenesis Of Immune Recovery Uveitis In Patients With Healed Cytomegalovirus Retinitis

Purpose: To investigate immune and viral contributions to the pathogenesis of immune recovery uveitis (IRU), which presents as vitritis, macular edema, or formation of epiretinal membranes, and develops in patients with acquired immunodeficiency syndrome (AIDS) who experienced cytomegalovirus (CMV) retinitis before antiretroviral treatment (ART) induced immune reconstitution. Methods: Aqueous and vitreous fluids from patients with IRU, active CMV retinitis, and control human immunodeficiency virus (HIV)-negative, noninflamed eyes were compared for presence of cytokines IL-6, IL12, interferon gamma using enzyme-linked immunosorbent assay techniques, and CMV DNA (by polymerase chain reaction). Results: IRU eyes (11 patients, 18 samples) had the highest levels of IL-12 (median 48 pg/mL), moderate levels of IL-6 (median 146 pg/mL), and low but significant interferon gamma (median 15 pg/mL), compared to controls (P < 0.01). All uveitis eyes tested (9/9) were CMV DNA negative. In contrast, active CMV retinitis eyes were CMV DNA positive, had higher levels of IL-6 (median 349 pg/mL) (25 patients, 41 samples) than both control (P = 0.0001) and uveitis eyes (P = 0.048), similar levels of interferon gamma (median 27 pg/mL) to uveitis eyes, but less IL-12 (median 0 pg/mL) than uveitis eyes. Conclusions: Inflammatory IRU can be differentiated from active CMV retinitis by the presence of IL-12, less IL-6, and absence of detectable CMV replication.

The Safety of Discontinuation of Maintenance Therapy for Cytomegalovirus (CMV) Retinitis and Incidence of Immune Recovery Uveitis Following Potent Antiretroviral Therapy

Abstract Background: Reconstitution of immune function during potent antiretroviral therapy can prompt discontinuation of maintenance cytomegalovirus (CMV) therapy but has also been associated with sight-threatening inflammatory conditions including immune recovery uveitis (IRU). Method: Patients with inactive CMV retinitis and a CD4+ cell count above 100/mm3, receiving CMV therapy and stable combination antiretroviral therapy, were assigned to one of two groups based on willingness to discontinue CMV therapy. Results: Thirty-eight participants were enrolled: 28 discontinued anti-CMV therapy (Group 1) and 10 continued CMV treatment (Group 2). Median on-study follow-up was 16 months. One Group 1 participant who experienced an increase in plasma HIV viral load and a decline in CD4+ cell count developed confirmed progression of CMV retinitis. Progression or reactivation CMV retinitis was not observed among Group 2. IRU was present at study entry in 3 participants. Six participants in Group 1 and 3 participants in Group 2 developed IRU on-study. CMV viremia was not detected in any participants, and urinary shedding of CMV was intermittent. Conclusion: Recurrence of CMV retinitis following discontinuation of anti-CMV therapy among patients with antiretroviral-induced increases in CD4+ cell count was rare. However, IRU was common in both those who maintained and discontinued anti-CMV therapy.

APOE ε4 and MBL-2 O/O genotypes are associated with neurocognitive impairment in HIV-infected plasma donors

Background:Host genetic factors are important determinants for risk of HIV-1 infection and disease progression. This study examined associations of host genetic variants and neurocognitive impairment in Chinese individuals infected through contaminated blood products. Methods:Two hundred and one HIV-infected patients from Anhui, China, had neuropsychological tests at baseline and 12 months. DNA was genotyped for APOE ϵ2, ϵ3 and ϵ4 alleles; MBL2-A/O; CCR5-wt/Δ32; CCR5-59029-G/A; CCR2-180-G/A; SDF-1-G/A; IL4-589-C/T; MCP-1-2518-A/G; CX3CR1-745-G/A; −849-C/T polymorphisms and CCL3L1 copy number variants using real-time PCR. Univariate and multivariate analyses were performed. Results:The cohort included 61% men, with mean education 5.5 years, AIDS diagnosis 113 (55%), on antiretrovirals 114 (56%), mean baseline CD4+ cell count 349 cells/μl and mean log10 RNA 4.09. At baseline, 37% had global neuropsychological impairment increasing to 44% after 12 months. Of 43 patients with the APOE ϵ4 allele, 58% were cognitively impaired compared with 31% without the ϵ4 allele (P = 0.001, odds ratio 3.09, 95% confidence interval 1.54–6.18). The mean global deficit score (GDS) for ϵ4-positive participants on antiretrovirals for 12 months was 0.88 (0.55) compared with 0.63 (0.54) for ϵ4-negative participants (P = 0.053, 95% confidence interval −0.004 to 0.51). For MBL2, 52% of patients with the O/O genotype declined in cognitive function over 12 months compared with 23% with A/A (odds ratio 3.62, 95% confidence interval 1.46–9.03, P = 0.004). No associations were observed for the other genetic variants. Conclusion:The APOE ϵ4 allele was associated with increased risk for cognitive deficits, whereas the MBL2 O/O genotype was associated with increased risk for progressive cognitive decline in Chinese individuals infected with HIV through contaminated blood products.

Cerebrospinal Fluid (CSF) CD8+ T-Cells That Express Interferon-Gamma Contribute to HIV Associated Neurocognitive Disorders (HAND)

Background HIV associated neurocognitive disorders (HAND) continue to affect cognition and everyday functioning despite anti-retroviral treatment (ART). Previous studies focused on mechanisms related to monocyte/macrophage mediated inflammation. However, in the ART era, there is increasing evidence for the involvement of CD8+ T-cells in CNS pathogenesis. Methods To investigate the relationship between T-cell responses and neurocognitive impairment (NCI), cerebrospinal fluid (CSF) and peripheral blood CD4+ and CD8+ T-cell intracellular cytokine (IFNγ, IL-2, TNFα) and lytic marker (CD107a) expression were assessed in HIV infected subjects who underwent comprehensive neurocognitive (NC) evaluation and either initiated or changed ART. Results Data were collected from 31 participants at 70 visits. The frequency of cytokine expressing T-cells in CSF was significantly higher than in peripheral blood for CD4+T-cells: TNFα, IL-2, IFNγ and CD8+T-cells: IL-2 and IFNγ. Analysis of T-cell activity and NCI as a function of CSF HIV RNA levels suggested a general association between NCI, high CSF CD8+ (but not CD4+T-cell) cytokine expression and CSF HIV RNA <103 copies/ml (p<0.0001). Specifically, CSF CD8+ T-cell IFNγ expression correlated with severity of NCI (r = 0.57, p = 0.004). Multivariable analyses indicated that CSF CD8+T-cell IFNγ and myeloid activation (CD163) contributed equally and independently to cognitive status and a composite variable produced the strongest correlation with NCI (r = 0.83, p = 0.0001). In contrast, CD8+ cytolytic activity (CD107a expression) was negatively correlated with NCI (p = 0.05) but was dependent on CD4 levels >400/μl and low CSF HIV RNA levels (<103 copies/ml). In our longitudinal analysis of 16 subjects, higher CSF CD8+IFNγ expression at baseline predicted NC decline at follow-up (p = 0.02). Severity of NCI at follow-up correlated with level of residual HIV RNA in CSF. Conclusions Presence of IFNγ expressing CD8+ T-cells, absence of cytolytic CD8+ T-cells, high myeloid activation, and failure of ART to suppress HIV replication in CSF contribute to increased risk of HAND.

Immunopathogenesis of HIV Encephalitis

HIV infection leads to severe immunosuppression and in a sub‐population of patients, encephalitis. Whether systemic immunosuppression is required for CNS infection is still unclear. However, latent infection of monocytes/macrophages is an important mechanism by which HIV escapes immune surveillance and enters the CNS. Unlike other viral encephalitides, HIV predominantly infects macrophages/microglia and not neurons and glia. These cells produce retroviral proteins and cytokines which may be neurotoxic. Despite significant MHC expression within the CNS, there is a limited infiltration of immune cells, possibly due to a defect in systemic immunity. Anti‐retroviral therapy by decreasing viral replication and reversing immunosuppression, may arrest nervous system damage.

Serum Interleukin-6 (IL-6), IL-10, Tumor Necrosis Factor (TNF) Alpha, Soluble Type II TNF Receptor, and Transforming Growth Factor Beta Levels in Human Immunodeficiency Virus Type 1-Infected Individuals with Mycobacterium avium Complex Disease

ABSTRACT To characterize changes in serum cytokine levels in human immunodeficiency virus type 1 (HIV-1)-infected persons withMycobacterium avium complex (MAC) bacteremia, the levels of IL-1α (interleukin-1α), IL-6, IL-10, tumor necrosis factor alpha (TNF-α), soluble type II TNF receptor (sTNF-RII), and transforming growth factor β (TGF-β) in serum were measured in two cohorts of HIV-1-infected persons with MAC bacteremia. The first cohort was part of a MAC prophylaxis study. Patients with bacteremia were matched with controls without bacteremia. Elevated IL-6, IL-10, TNF-α, sTNF-RII, and TGF-β levels were noted at baseline for all subjects, a result consistent with advanced HIV-1 disease. IL-1α was not detected. No differences in cytokine levels in serum were noted at baseline and at the time of bacteremia between patients with MAC and controls. In the second cohort, subjects had serum samples collected at the time of MAC bacteremia and thereafter while on macrolide therapy. Serum samples at time of bacteremia were collected from HIV-1-infected persons at a time when neither highly active antiretroviral therapy (HAART) nor MAC prophylaxis was used routinely. MAC treatment resulted in decreased levels of IL-6 and TNF-α in serum, which were evident for IL-6 by 4 to 6 weeks and for TNF-α by 8 to 16 weeks. Thus, antibiotic treatment for MAC results in decreased levels of IL-6 and TNF-α in serum in HIV-1-infected persons who are not on HAART.

Relationship of cerebrospinal fluid immune activation associated factors to HIV encephalitis.

Objectives and designBecause macrophages are the predominant immune cell and the predominant infected cell in the brains of patients with HIV encephalitis, we studied macrophage and immune activation-associated factors in the cerebrospinal fluid (CSF) from 39 autopsied AIDS cases for whom complete neuropathologic evaluation of the brain was available. ResultsCSF HIV p24 antigen was present in less than one-third of cases (11 out of 39). Less than half of the autopsies with moderate to severe parenchymal infection by HIV had high levels of CSF p24, although all autopsies with elevated levels of HIV p24 had moderate to severe HIV encephalitis. Elevated levels of cytokines, β2-microglobulin, neopterin, and quinolinic acid were observed. ConclusionsAlthough many of the CSF findings showed a strong correlation with each other, none showed a strong correlation with the severity of HIV infection of the brain itself. The absence of a close association between CSF abnormalities and HIV encephalitis could reflect the abundance of complicating opportunistic infections in these terminally ill patients or the inadequacy of CSF as a marker of basal ganglia involvement in HIV encephalitis. These findings complicate interpretation of clinical studies of CSF in patients with AIDS where neuropathologic evaluation is unavailable.

Persistent HIV-1-specific cellular responses despite prolonged therapeutic viral suppression

Design Antiretroviral therapy (ART) currently represents the best way to avert the lethal consequences of chronic persistent HIV-1 infection. It leads to significant reductions of plasma viremia, often to undetectable levels, but it can also be linked with the reduction and disappearance of detectable HIV-specific CD8 T-cell responses. Results Here we describe a group of patients in whom ongoing replication of HIV, particularly transcription of Nef mRNA species, was detected despite prolonged and clinically successful antiretroviral treatment. Modest, but significant, numbers of HIV-specific CD8 T cells and CD4 T-cell responses were found in these subjects, with the strongest responses directed towards Nef epitopes. Detailed phenotypic analysis of the HIV-specific CD8 cells demonstrated low perforin levels and persistent expression of CD27, a phenotype associated with incomplete differentiation of cytotoxic T lymphocytes (CTL). Conclusion This immature CTL phenotype has been described previously in association with chronic HIV disease, but its continued persistence is surprising in the setting of prolonged viral suppression on therapy and the presence of HIV-specific CD4 cell activity.