CMV plasma DNAemia and risk of cancer among HIV-infected patients: a case-control study nested in the ANRS CO3 Aquitaine Cohort, France, 2002-2007.

BACKGROUND: CMV reactivation, which enhances immune senescence, could be associated with a higher risk of cancer. OBJECTIVES: We compared the prevalence of positive CMV DNAemia in HIV-infected patients with and without cancer. STUDY DESIGN: This case-control study, nested in the ANRS-CO3 Aquitaine Cohort, included patients with a first diagnosis of cancer (2002-2007) as cases. Two controls were matched per case. Cancer risk was estimated using conditional logistic regression models, an Odds Ratio (OR) of 2 could be detected with 80% power. The variables considered were: ≥ 1 positive CMV DNAemia, CD4+ and CD8+ counts, HIV plasma load. Plasma CMV DNA was retrospectively quantified within the 3-year period preceding the endpoint. RESULTS: The 143 cases (93 non-AIDS-related and 50 AIDS-related cancers) and 284 controls had a median age of 47 years (IQR: 41-56). At the time of diagnosis or censorship, for cases and controls, median values were respectively, for CD4+ count: 327 cells/mm(3) (IQR: 164-514) and 416 (IQR: 275-582), and for HIV plasma load: 2.6 log(10)copies/mL (IQR: 1.7-4.7) and 1.7 log(10)copies/mL (IQR: 1.7-3.3). We performed 2056 CMV PCR; 14 cases (9.8% [95% CI: 4.9-14.7]) and 19 controls (6.7% [CI: 3.8-9.6]) presented ≥ 1 positive PCR. CMV DNAemia was not associated with the risk of cancer (unadjusted and adjusted p-values=0.19 and 0.54, respectively). HIV load >500 copies/mL was independently associated with a higher risk of cancer (OR=2.02; p=0.002; 95% CI: 1.29-3.17). CONCLUSION: This large case-control study did not show any differential exposure to positive CMV plasma DNAemia between cancer cases and controls.

Variability and recombination of clinical human cytomegalovirus strains from transplantation recipients.

BACKGROUND: Human cytomegalovirus (HCMV) is the first cause of viral infection in immunocompromised transplanted patients. OBJECTIVES: Here, five HCMV genes were studied to investigate the existence of recombination events in clinical strains ex vivo. STUDY DESIGN: Sequencing and phylogenetic analysis were conducted on 21 strains from 16 renal and 5 lung transplant recipients. RESULTS: Nucleotidic polymorphism ranged from 6.6% (US3) to 12% (UL40), with a significant proportion of missense mutations (39-69%), some of which could have a functional impact. Analysis of the concatenated sequence (4804 nucleotides for each strain) evidenced two clusters of sequences presenting a reticulate topology suggestive of recombination events (SplitsTree). Phi-test pointed numerous phylogenetically conflicting signals indicating a high statistical probability of recombination. The subsequent bootscan analysis was consistent with these data. CONCLUSIONS: These results reinforce the prominent role of recombination in HCMV evolutionary history and adaptation to its host.

UL40 human cytomegalovirus variability evolution patterns over time in renal transplant recipients.

BACKGROUND: Human cytomegalovirus (HCMV) is the most common opportunistic pathogen infecting immunocompromised patients after transplantation. Although its immunomodulatory capacities and genomic variability participate in immune system evasion, they are poorly studied in clinical strains without culture amplification. One of HCMV immunomodulatory genes, UL40, confers HCMV-infected cells' protection from natural killer-mediated lysis through its encoded nonapeptide presented in the context of human leukocyte antigen-E. METHODS: In three renal transplant recipients with different HCMV serostatus, we aimed to evidence the co-evolution of mixtures of HCMV variants over time with sequencing and cloning of HCMV UL40 gene. RESULTS: Six months after renal transplantation in patient 1Bx, D+/R+, UL40 phylogenetic and bootscan analysis suggested the emergence of a recombination between two previous viral strains. In patient 8Bx, initially D+/R-, distribution of variants in five samples over 43 months was notably stable, with no visible emerging variants despite two renal engraftments and extended episodes of active infection. In patient 9Bx, also D+/R-, phylogenetic tree of viral variants revealed in the first sample a minor clone, confirmed by a specific polymerase chain reaction, related to the three subsequent dominant clones. CONCLUSIONS: In three HCMV-infected renal transplant recipients, we have evidenced different viral evolutive polymorphisms including point mutations, recombination, and occasionally suggesting the intervention of several HCMV strains or a quasispecies-like distribution. This variability could contribute to viral adaptability in pathogenesis.