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Despite effective antiretroviral therapy (ART), individuals infected with human immunodeficiency virus (HIV) remain at higher risk for mortality and morbidities commonly associated with aging than the general population [1]. Chronic immune activation is thought to mediate this increased risk [2]. Many have hypothesized that the chronic inflammatory state of HIV infection may drive T-cell senescence, as seen with chronic cytomegalovirus (CMV) infection and among elderly HIV-uninfected individuals [3–5], potentially increasing the risk of infections and malignancies, and further fueling the persistent inflammatory state. T-cell senescence is typically characterized by the accumulation of terminally differentiated CD8+ T cells with shortened telomeres, loss of the costimulatory molecule CD28, and increased expression of CD57, a marker of proliferative history and poor proliferative capacity [6]. Even during suppressive ART, HIV-infected individuals have increased frequencies of CD28−CD8+ T cells [7, 8], but the impact of HIV on CD57 expression on CD8+ T-cell subsets—particularly the effector memory CD8+ T-cell subsets that normally express CD57—is less well documented. We recently demonstrated that although CMV promotes terminal differentiation and the expression of CD57 on CD28−CD8+ T cells, consistent with the “immunosenescent” phenotype of aging, HIV is associated with enrichment for less well-differentiated transitional CD8+ T cells and abnormally low proportions of CD28−CD8+ T cells expressing CD57 [9, 10]. In the current study, we sought to determine whether abnormally low proportions of CD28−CD8+ T cells expressing CD57 (ie, the %CD57+ of CD28−CD8+ T cells) are evident during the first few months of HIV infection, whether early ART initiation (

Background. Cytomegalovirus (CMV) retinitis is a common opportunistic infection among patients with AIDS and still causes visual morbidity despite the wide spread usage of highly active antiretroviral therapy (HAART). The ubiquitous CMV pathogen contains a human interleukin-10 (IL-10) homolog in its genome and utilizes it to evade host immune reactions through an IL-10 receptor mediated immune-suppression pathway. Methods. Effects of IL-10R1, IL-10 and previously described AIDS restriction gene variants are investigated on the development of CMV retinitis in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort ( ). N p 1284 Results. In European Americans ( ), a haplotype carrying an amino acid changing variation in the n p 750 cytoplasmic domain (S420L) of IL-10R1 can be protective (OR, 0.14; 95% CI, 0.02–0.94; ) against, whereas P p .04 another haplotype carrying an amino acid changing variation in the extracellular domain (I224V) of IL-10R1 can be more susceptible (OR, 6.21; 95% CI, 1.22– 31.54; ) to CMV retinitis. In African Americans ( P p .03 n p ), potential effects of IL-10 variants are observed. 534

To determine potential correlates of immune recovery from AIDS-related cytomegalovirus retinitis (CMVR), multiparameter flow cytometry was used to characterize CMV-specific T cells from subjects with CMVR. Individuals with active retinitis were compared with those who had been clinically immunorestored by antiretroviral therapy and had > or =2 years of ophthalmologic follow-up without anti-CMV therapy or retinitis reactivation or progression. In comparison with patients with active retinitis, immunorestored patients had higher circulating CD4(+) and CD8(+) T cells expressing interleukin-2 and interferon- gamma in response to combined CMV pp65 and IE1 peptide pool stimulation. CD4(+) T cell responses were predominantly to pp65, whereas CD8(+) T cell responses were predominantly to IE. Immunorestored patients, compared with patients with active retinitis, had increased levels of circulating CMV-specific CD8(+) T cells with "early" (CD27(+)CD28(+)CD45RA(+), CD27(+)CD28(+)CD45RA(-)) and "intermediate" (CD27(-)CD28(+)CD45RA(-)) phenotypes. Recovery from AIDS-related CMVR after the initiation of antiretroviral therapy may be mediated by CMV-specific CD4(+) and CD8(+) T cells capable of promoting antigen-specific CD8(+) T cell proliferation.

Filgrastim, or granulocyte colony-stimulating factor, reverses neutropenia associated with human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus (CMV) infections. During a trial of anti-CMV retinitis therapies coadministered with antiretroviral therapy, 2-4 plasma specimens of HIV-1 RNA were collected from 36 HIV-1-infected patients receiving filgrastim to prevent neutropenia and from 36 patients not receiving filgrastim. For both groups, the crude mean and mean rate of change of HIV-1 log(10) RNA levels were similar. Adjustment for covariates (CD4(+) T cell lymphocytes, virus load at enrollment, level of neutropenia and antiretroviral therapy [mainly non-highly active antiretroviral therapy], and anti-CMV therapy during follow-up) resulted in a mean log(10) HIV-1 RNA level for individuals receiving filgrastim versus those not receiving the drug of 5.11 versus 4.87 (P=.12) and respective log mean rates of change per month of -0.08 versus -0.21 (P=.08). This latter difference has borderline statistical significance, which suggests that filgrastim may reduce the decline of HIV-1 RNA loads.

To evaluate the potential clinical utility of a cytomegalovirus (CMV)-specific CD8+/interferon (IFN)- gamma+ cytokine flow cytometry (CFC) assay for patients with CMV retinitis (CMVR), stored peripheral blood mononuclear cell specimens were obtained from patients with active CMVR (i.e., having clinical evidence of absent CMV-protective immunity), as well as from highly active antiretroviral therapy-treated patients with CMVR who were able to discontinue anti-CMV therapy without subsequent progression of retinitis (i.e., having clinical evidence of restored CMV-protective immunity). Positive CD8+/IFN- gamma+ T lymphocyte responses to CMV phosphoprotein 65 or immediate early peptide-pool stimulation were present in specimens from only 3 of 10 patients with active CMVR but were present in at least 1 specimen from all 20 patients with immunorestored CMVR, with a mean of 2.4 specimens/patient tested, spanning up to 6 months of observation (P = .0001). Among the patients with immunorestored CMVR, positive responses were present in all longitudinal specimens from 15 of the 20 patients. These data suggest that further testing of the CMV-specific CD8+/IFN- gamma+ CFC assay, for clinical utility in predicting incident and progressive CMVR disease, is warranted.