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Effect of host genetics on the development of cytomegalovirus retinitis in patients with AIDS.

ABSTRACT: 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 = 1284). RESULTS:In European Americans (n = 750), a haplotype carrying an amino acid changing variation in the cytoplasmic domain (S420L) of IL-10R1 can be protective (OR, 0.14; 95% CI, 0.02-0.94; P = .04) against, whereas 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; P = .03) to CMV retinitis. In African Americans (n = 534), potential effects of IL-10 variants are observed. CONCLUSION:Host genetics may have a role in the occurrence of CMV retinitis in patients infected with HIV.

SUBMITTER: Sezgin E

PROVIDER: S-EPMC2932829 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Effect of host genetics on the development of cytomegalovirus retinitis in patients with AIDS.

Sezgin Efe E Jabs Douglas A DA Hendrickson Sher L SL Van Natta Mark M Zdanov Alexander A Lewis Richard Alan RA Smith Michael W MW Troyer Jennifer L JL O'Brien Stephen J SJ

The Journal of infectious diseases 20100801 4

<h4>Background</h4>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.<h4>Methods</h4>Effects of IL-10R1, IL-10 and previously described AIDS rest ...[more]

PMID: 20617924

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Project description:Human cytomegalovirus (HCMV) is a ubiquitous herpes virus (human herpes virus 5) with the highest morbidity and mortality rates compared to other herpes viruses. Risk groups include very young, elderly, transplant recipient, and immunocompromised individuals. HCMV may cause retinitis, encephalitis, hepatitis, esophagitis, colitis, pneumonia, neonatal infection sequelae, inflammatory, and age-related diseases. With an arsenal of genes in its large genome dedicated to host immune evasion, HCMV can block intrinsic cellular defenses and interfere with cellular immune responses. HCMV also encodes chemokines, chemokine receptors, and cytokines. Therefore, genes involved in human viral defense mechanisms and those encoding proteins targeted by the CMV proteins are candidates for host control of CMV infection and reactivation. Although still few in number, host genetic studies are producing valuable insights into biological processes involved in HCMV pathogenesis and HCMV-related diseases. For example, genetic variants in the immunoglobulin GM light chain can influence the antibody responsiveness to CMV glycoprotein B and modify risk of HCMV-related diseases. Moreover, CMV infection following organ transplantation has been associated with variants in genes encoding toll-like receptors (TLRs), programmed death-1 (PD-1), and interleukin-12p40 (IL-12B). A KIR haplotype (2DS4+) is proposed to be protective for CMV activation among hematopoietic stem cell transplant patients. Polymorphisms in the interferon lambda 3/4 (IFNL3/4) region are shown to influence susceptibility to CMV replication among solid organ transplant patients. Interestingly, the IFNL3/4 region is also associated with AIDS-related CMV retinitis susceptibility in HIV-infected patients. Likewise, interleukin-10 receptor 1 (IL-10R1) variants are shown to influence CMV retinitis development in patients with AIDS. Results from genome-wide association studies suggest a possible role for microtubule network and retinol metabolism in anti-CMV antibody response. Nevertheless, further genetic epidemiological studies with large cohorts, functional studies on the numerous HCMV genes, and immune response to chronic and latent states of infection that contribute to HCMV persistence are clearly necessary to elucidate the genetic mechanisms of CMV infection, reactivation, and pathogenesis.

Project description:PurposeTo describe the outcomes of different treatment approaches for cytomegalovirus (CMV) retinitis in the era of highly active antiretroviral therapy (HAART).DesignProspective cohort study, the Longitudinal Study of the Ocular Complications of AIDS.ParticipantsA total of 250 patients with CMV retinitis and a CD4+ T-cell count <100 cells/μl (n = 221) at enrollment or incident retinitis (n = 29) during cohort follow-up.MethodsThe effects of systemic therapy (vs. intraocular therapy only) on systemic outcomes and the effect of intraocular therapies (ganciclovir implants, intravitreal injections) on ocular outcomes were evaluated.Main outcome measuresMortality, CMV dissemination, retinitis progression, and treatment side effects.ResultsRegimens containing systemic anti-CMV therapy were associated with a 50% reduction in mortality (adjusted hazard ratio [HR], 0.5; 95% confidence interval [CI], 0.3-0.7; P = 0.006), a 90% reduction in new visceral CMV disease (adjusted HR, 0.1; 95% CI, 0.04-0.4; P = 0.004), and among those with unilateral CMV retinitis at presentation, an 80% reduction in second eye disease (adjusted HR, 0.2; 95% CI, 0.1-0.5; P = 0.0005) when compared with those using only intraocular therapy (implants or injections). Compared with systemic treatment only, regimens containing intravitreal injections had greater rates of retinitis progression (adjusted HR, 3.4; P = 0.004) and greater visual field loss (for loss of one half of the normal field, adjusted HR, 5.5; P < 0.01). Intravitreal implants were not significantly better than systemic therapy (adjusted HR for progression, 0.5; P = 0.26; adjusted HR for loss of one half of the visual field, 0.5; P = 0.45), but the sample size was small. Hematologic and renal side effect rates were similar between those groups with and without systemic anti-CMV therapy. The rate of endophthalmitis was 0.017 per eye-year (EY) (95% CI, 0.006-0.05) among those treated with intravitreal injections and 0.01 per EY (95% CI, 0.002-0.04) among those treated with an implant.ConclusionsIn the HAART era, systemic anti-CMV therapy, while there is immune compromise, seems to provide benefits in terms of longer survival and decreased CMV dissemination.Financial disclosure(s)Proprietary or commercial disclosure may be found after the references.

Project description:Background: Cytomegalovirus retinitis (CMVR) is a crucial blind-causing disease of AIDS-related ocular opportunistic infection. The CMVR lesions produced retinal necrosis. It is not entirely clear whether CMVR eyes without macular-involved necrotic lesions may have subtle macular damage. In this study, we conducted a cross-sectional study using optical coherence tomography angiography (OCTA) to evaluate macular microvasculature and structure in eyes with AIDS-related CMVR. Methods: Acquired immune deficiency syndrome (AIDS)-related CMVR patients (active and inactive CMVR) and healthy controls treated in the Department of Ophthalmology, Beijing Youan Hospital, Capital Medical University between August 25, 2019, and October 18, 2019, were recruited. All OCTA parameters, including the foveal avascular zone (FAZ), retinal vessel density (VD), choroidal vascularity index (CVI), retinal thickness, and choroidal thickness, were compared between groups after the signal strength was corrected. Results: Signal strength in the 3 × 3 and 6 × 6 mm scan patterns was significantly weaker in the inactive CMVR group than in the control group (both p < 0.001). After adjusting for signal strength, heterogeneity in the central fovea and parafoveal quadrants was present with a shift toward lower macular chorioretinal vasculature, decreased full choroidal thickness, and thicker retinal thickness in the active and inactive CMVR groups. The retinal nerve fiber layer (RNFL) and inner nuclear layer (INL) were significantly thicker in the active and inactive CMVR groups than in the control group (all p < 0.05). For photoreceptor-retinal pigment epithelium (PR-RPE) thickness, no significant differences were found in any quadrant between groups. Foveal avascular zone areas were not significantly different among the three groups (p = 0.053). Conclusions: Subtle macular structure and microvasculature damage still existed in CMVR eyes without macular-involved necrotic lesions. The results of our study are helpful for a deep understanding of the damage caused by CMVR.

Project description:PurposeTo evaluate risk factors for severity of cytomegalovirus (CMV) retinitis lesion whitening (opacity), using a standardized scoring system.MethodsWe performed a cross-sectional, observational investigation of all individuals with newly diagnosed AIDS-related CMV retinitis in three randomized clinical trials and one prospective observational study. Opacity was scored by masked readers, using a prospectively defined ordinal 6-point scale. Demographic factors, laboratory data (CD4+, CD8+ T-lymphocyte counts, human immunodeficiency virus [HIV] blood levels), and lesion characteristics (location, size) were compared to the highest opacity score assigned to either eye. Among eyes with active lesions (scores ≥3), factors associated with severe opacity (scores 5, 6) were identified.ResultsThere were 299 participants (401 eyes with CMV retinitis). In one or more comparisons, increased opacity was associated with lower CD4+ and lower CD8+ T-lymphocyte counts, higher HIV blood level, lack of antiretroviral therapy, male sex, race/ethnicity, and bilateral disease. In eyes with active disease, severe opacity was associated with lower CD4+ T-lymphocyte count, higher HIV blood level, older age, Karnofsky score, lesion size, and bilateral disease. No relationship was identified between opacity and lesion location.ConclusionsLesion border opacity (resulting from CMV activity) reflects level of immune function; as immunodeficiency becomes worse, CMV activity (and opacity) increases. The positive relationship between opacity and HIV blood level may reflect both immunodeficiency and increased CMV activity caused by transactivation of CMV by HIV. Scoring of opacity may be a useful, standard measure for continued study of CMV retinitis across different settings and populations. (Clinicaltrials.gov number for the HPMPC CMV Retinitis Trial: NCT00000142; Clinicaltrials.gov number for the Monoclonal Antibody CMV Retinitis Trial: NCT00000135; Clinicaltrials.gov number for the Ganciclovir-Cidofovir CMV Retinitis Trial: NCT0000014; Clinicaltrials.gov number for the Longitudinal Study of the Ocular Complications of AIDS: NCT00000168.).

Dataset Information

Effect of host genetics on the development of cytomegalovirus retinitis in patients with AIDS.

Publications

Effect of host genetics on the development of cytomegalovirus retinitis in patients with AIDS.

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