Virus in Semen and the Risk of Sexual Transmission

Sexual contact is the primary route of human transmission for sexually transmitted infections (STIs). Traditional STIs are caused by a variety of pathogens, and classic examples of STIs include chlamydia, gonorrhea, syphilis, the acquired immunodeficiency syndrome, and genital herpes. Recently, reports showing virus detection in the semen of men infected with viruses that had previously been unknown to be sexually transmitted have caught the attention of infectious disease specialists, public health officials, and the media. Two of the more prominent examples are Zika virus (ZIKV) and Ebola virus (EBOV), which have been found in symptomatically infected patients and disease survivors.^1,2 Contrary to prevalent belief, the detection of viral genomes in semen tends to be more common among viruses that are typically not sexually transmitted, such as certain adenoviruses, bunya-viruses, flaviviruses, hepadnaviruses, herpes-viruses, paramyxoviruses, and retroviruses.³ However, although such detection should not come as a surprise, the contribution of it to virus transmission and consequently to epidemiology, disease burden, and public health needs to be defined.

Infectivity is a prerequisite for pathogen transmission, which also depends on factors such as infectious dose and exposure route. These days, virus detection seems to be achieved largely by means of molecular methods and the use of state-of-the-art technologies, such as polymerase-chain-reaction and deep-sequencing approaches. These methods have replaced more traditional approaches, especially in field diagnostic testing, because they provide more rapid, highly sensitive, and specific means of pathogen discovery. In the past, virus isolation, whether in cell culture or laboratory animals, was considered to be a standard procedure, but it seems almost neglected in diagnostic testing today because it is slower, more laborious, and potentially more hazardous than the newer molecular methods. In addition, the isolation of highly pathogenic viruses, such as EBOV, requires complex biosafety and biosecurity measures that can be lowered for most molecular approaches. Yet, virus isolation remains the only direct and definitive approach for proving infectivity.

The article by Mead and colleagues⁴ in this issue of the Journal shows the potential shortcomings of current virus-detection standards when it comes to the relevance for infectious disease and public health. In this study, 4% of the ZIKV RNA-positive semen samples were found to be infectious, and infectivity was observed only in samples that were obtained within 30 days after illness onset and that had a viral load of more than 7.0 log₁₀ RNA copies per milli-liter. This finding suggests that there is a short period during which ZIKV-infected men might transmit this virus through sexual contact. Likewise, the fact that sexual transmission could rarely be confirmed for EBOV, despite the detection of RNA in the semen of survivors more than 1 year after acute infection, further shows the shortcomings of molecular detection alone in understanding transmissibility.⁵ In some contexts, current practice calls for the sequential testing of semen samples until at least two consecutive negative results are found. However, this algorithm is controversial because it may not address the potential for virus latency and reactivation (if it exists for a given pathogen) driven by undefined factors, which means that a person could be shedding virus intermittently. This also raises the question of whether modern molecular approaches are properly positioned to detect virus latency rather than persistence. Nevertheless, the goal should be the determination of infectivity, which is probably best assessed by means of viral isolation, which is considered to be less sensitive than molecular detection. Thus, the diagnostic situation is far more complicated than it seems.

For public health purposes, all the scenarios above might be less applicable. For communicable diseases, such as those caused by EBOV or similar viruses, preventive reactive measures must be taken on the basis of the potential for transmission. The World Health Organization reacted to the new risk of EBOV being sexually transmitted by revising the guidelines regarding sexual practices of survivors.⁶ Similarly, public health entities have quickly issued recommendations for safer sex to prevent the spread of ZIKV and the potentially devastating complication of fetal infection.^7,8 These recommendations leverage the best data available and have been implemented but ought to be updated as new data emerge.

On the research front, we need more rapid approaches for detection that measure virus infectivity rather than genome presence. Even though it will be difficult to conduct this work, it should be feasible.⁹ We must further understand the source and mechanism leading to virus latency or persistence in semen, which organelles and cell types produce virus, and the viral load in seminal fluid. These are just a few important research questions to be addressed.

Finally, the provocative notion that many pathogenic viruses in humans can be detected in the semen of infected men should be contemplated. The presence of such viruses in semen may potentially contribute to additional risks of transmission and complicate our understanding of the epidemiology of these emerging pathogens. Lassa virus, a rising public health concern in West Africa, might be the next example on the growing list of emerging viruses that are typically not sexually transmitted.¹⁰ Do these viral diseases then all become STIs? This is unlikely, because potential STIs with distinct primary routes of transmission will probably be separated from the traditional STIs.