Patterns of human herpesvirus-8 oral shedding among diverse cohorts of human herpesvirus-8 seropositive persons

Abstract

Background: Human herpesvirus-8 (HHV-8), the etiologic agent of Kaposi sarcoma (KS), establishes lifelong latent infection with periodic lytic replication ("shedding") at mucosal sites, especially the oropharynx. Patterns of HHV-8 shedding are not well understood, and require elucidation to better predict risk of HHV-8 related malignancies in those infected. We sought to characterize patterns of HHV-8 oropharyngeal shedding among diverse cohorts that enrolled HHV-8 seropositive persons.

Methods: We quantified HHV-8 oral shedding using PCR among HHV-8 seropositive persons who collected at least 14 days of oral swabs in 22 studies on 3 continents. We excluded persons taking antivirals during sampling or any prior use of antiretrovirals in those who were HIV-infected.

Results: 248 participants were enrolled from the US, Peru, Cameroon, Uganda, and Kenya; 61 % were men, 58 % were HIV seropositive, and 16 % had KS. Overall, 3,123 of 10,557 samples (29.6 %) had HHV-8 detected. Quantity of virus shed was highly correlated with shedding rate, (ρ = 0.72, p < 0.0001). HHV-8 was detected in ≥1 sample in 55 % of participants with a median of 7 % of days in the US and Kenya, 0 % in Uganda and Peru, and 18 % in Cameroon. Median episode duration was three days, and episodes with high median quantity lasted longer (42 vs 3 days, p < 0.0001). In persons with multiple observations over time, 66 % of shedding rate variance was attributable to differences between individuals.

Conclusions: In HHV-8 infected individuals from diverse settings, oral mucosal shedding rate, quantity, and duration were correlated; individual shedding was highly variable. Studies are needed to determine factors accounting for between-person variation and the relationship of HHV-8 shedding to development of associated diseases.

Keywords: HIV infections; Herpesviridae infections; Herpesvirus 8, Human; Kaposi sarcoma-associated herpesvirus (KSHV); Sarcoma, Kaposi; Virus replication.

Fig. 1

Flow diagram of study participant inclusion. Numbers listed are n = number of participants (“sessions” = number of observation periods contributed). Abbreviations: ART, antiretroviral therapy; US: United States

Fig. 2

Heterogeneity of participant characteristics within the cohorts included in this study

Fig. 3

Quantity of HHV-8 DNA (Log₁₀ copies/mL) within swabs positive for HHV-8. 2.17 Log₁₀ copies/mL represents the lower limit of accurate detection (150 copies/mL). The label for each bin represents a range including the value listed and all values up to but not including the value listed in the next highest bin

Fig. 4

Correlation of HHV-8 DNA quantity and shedding rate: Scatterplot of HHV-8 quantity (median HHV-8 DNA copy number by qPCR during shedding session) vs. HHV-8 shedding rate (number of days HHV-8 is detectable at any level by qPCR divided by number of days of shedding session). Best-fit regression line is shown (ρ = 0.72, p < 0.0001)

Fig. 5

Patterns of HHV-8 Shedding. Included participants had HHV-8 detectable by PCR on at least one day during the first 60 days of observation and were observed for a minimum of 30 days. Each row represents one participant, ordered by shedding rate from lowest to highest over the shedding session. Sixty participants with at least 30 days of observation who never shed were omitted. Time is represented on the x-axis (in days) such that each box represents the HHV-8 PCR result from a single daily swab for an individual. DNA quantity is graded by color (in log₁₀ copies/mL). Asterisks (*) denote participants with Kaposi Sarcoma and plus signs (+) denote participants with HIV. White indicates no swab collected; other colors as per legend

Fig. 6

Variation in oral shedding rate of HHV-8 by participant across multiple shedding sessions. All cohort participants with 2–5 sessions within two years were included in the analysis of shedding variation over time, representing 39 participants with 112 total sessions. Four persons had shedding rates increase by at least 30 % on an absolute scale over time (red), 7 persons had rates decrease by the same amount (blue), and 28 had no consistent pattern (black)