Longitudinal Viral Dynamics in Semen During Early HIV Infection

Abstract

Background: Multiple viruses coinfect the male genital tract, influencing each other’s replication and perhaps affecting human immunodeficiency virus (HIV) pathogenesis and disease progression.

Methods: This study included 453 longitudinal seminal samples from 195 HIV-infected men from the San Diego Primary Infection Resource Consortium and 67 seminal samples from HIV-negative healthy controls. Seminal HIV RNA and DNA from 7 human herpesviruses (HHVs) were measured by real-time polymerase chain reaction. Longitudinal shedding rates were determined by Kaplan-Meier survival analysis. Predictors of viral shedding were determined using backwards selection in a multivariable generalized estimating equation model.

Results: HIV-infected participants presented significantly increased rates of seminal HHV shedding compared with HIV-uninfected controls. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) were the most commonly detected HHV in semen of HIV-infected participants. Persistent shedding was more common for CMV and EBV when compared to other HHVs. With exception of HHV-7, HHV shedding was not significantly influenced by HIV RNA levels, CD4+ cell counts, or antiretroviral therapy. Presence of CMV, EBV, and herpes simplex virus (HSV) were independent predictors of genital HIV RNA shedding after adjusting for plasma HIV RNA and longitudinal measurements.

Conclusions: Seminal replication of multiple HHVs is common in our HIV primary infection cohort. Genital replication of CMV and EBV was the most common and was significantly associated with seminal HIV RNA shedding. Prevalence of HSV shedding was lower and mostly intermittent, but its association with seminal HIV RNA was the strongest. Understanding the complex viral milieu in semen is important for HIV transmission but might also play a role in HIV pathogenesis and disease progression.

Figure 1.

Kaplan-Meier analysis of time to herpesvirus shedding (n=195), evaluated over the course of 365 days from baseline. This figure represents the cumulative shedding rate for each human herpesvirus using a survival curve to indicate the probability of viral shedding over 1 year. For example, although at any given time point only about half of men are shedding cytomegalovirus (CMV) in semen, over the period of a year almost all men will eventually shed CMV. Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpesvirus; HSV, herpes simplex virus 1/2.

Figure 2.

Shedding patterns of human herpesviruses, evaluated for participants with at least 1 follow-up visit with at least 30 days between visits. Shedding was classified as intermittent if shedding for a particular herpesvirus was undetectable during 1 or more time points. Otherwise, shedding was classified as persistent. Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpesvirus; HSV, herpes simplex virus 1/2.