Herpes Simplex Virus Type 2 (HSV-2) is a widespread sexually transmitted infection that causes recurring genital lesions. This double-stranded DNA virus establishes a lifelong latent infection in nerve cells, periodically reactivating to cause outbreaks or silent viral shedding. The idea of different “strains” of HSV-2 is relevant to understanding the virus’s biology, global spread, and interaction with the human body. Investigating subtle genetic differences helps researchers and clinicians understand variations in disease presentation and response to treatment.
Genetic Typing and Variability of HSV-2
The term “strain” in the context of HSV-2 can be misleading, as it implies distinct, highly divergent viruses like those seen in influenza. Herpes simplex viruses have a relatively stable DNA genome, and genetic variability between different HSV-2 isolates is quite low, generally less than 0.5%. Despite this low diversity, analysis of the viral genome reveals measurable differences that group isolates into distinct lineages known as clades.
Scientists use whole-genome sequencing and phylogenetic analysis to identify these clades, which often show a pattern of geographic clustering. For instance, research has described two distinct clades of HSV-2, with isolates corresponding to those collected from regions like Tanzania and Scandinavia. This genetic typing confirms that while all isolates are the same species, HSV-2, they have subtle evolutionary differences that reflect their history and global spread.
These genetic differences arise from the virus’s ability to mutate during replication, although its polymerase enzyme is more stable than the enzymes of RNA viruses. HSV-2 populations can generate genetic diversity, sometimes generating a higher number of nonconservative genetic variants than HSV-1. This ability to evolve, combined with recombination, contributes to the subtle genomic mosaicism observed in individual HSV-2 isolates. Analyzing these molecular variations allows researchers to map the virus’s evolution and track its movement through human populations.
Correlation Between Variability and Clinical Presentation
The existence of genetic variability raises the question of whether different clades or variants lead to different experiences for the infected person. The severity of genital herpes infection varies widely among individuals; some experience frequent, painful outbreaks while others remain largely asymptomatic. This variation is driven by a complex interplay of host factors, such as immune status, and the genetic makeup of the infecting virus.
Research has begun to link specific viral genetic variations to clinically important phenotypes, particularly the rate of viral shedding. Viral shedding, the release of virus particles from the skin or mucosa, serves as a surrogate marker for disease severity and is responsible for transmission. Higher rates of shedding are associated with more frequent symptomatic outbreaks.
In one study, specific minor genetic variants within the HSV-2 genome were associated with a higher rate of genital shedding. For example, a nonsynonymous change in the UL22 gene, which codes for glycoprotein H, was identified as being associated with a higher shedding rate. This suggests that while host immunity plays a large role, certain viral genetic signatures can predispose a person to a more biologically active infection.
Different isolates of HSV-2 exhibit diverse behaviors in laboratory settings, such as differences in how quickly they spread in cell culture. In cases of severe neonatal infection, viruses isolated from newborns with encephalitis contained protein-coding variations not found in viruses causing noninvasive disease. These findings indicate that while the impact of clades on the average person’s symptoms may be subtle, specific genetic changes can influence disease severity and tissue tropism, particularly in vulnerable populations.
Implications for Diagnosis and Antiviral Treatment
The genetic variability of HSV-2 is an important consideration for medical management, affecting both diagnostic testing and the effectiveness of antiviral drugs. Molecular diagnostic tests, such as polymerase chain reaction (PCR), target specific conserved regions of the viral genome to detect the virus. Although the overall genomic diversity of HSV-2 is low, genetic changes in the target region could theoretically affect the sensitivity of a diagnostic assay.
The primary practical implication of genetic variability is the potential for developing antiviral drug resistance. Standard treatments for HSV-2, such as acyclovir, valacyclovir, and famciclovir, work by targeting the viral enzymes thymidine kinase (TK) and DNA polymerase. Mutations in the genes encoding these two enzymes, UL23 (TK) and UL30 (DNA polymerase), are the primary mechanism by which HSV-2 develops resistance.
Fortunately, the vast majority of HSV-2 isolates remain susceptible to these first-line antivirals. However, in immunocompromised patients, the virus has a greater opportunity to replicate under drug pressure, increasing the chance of selecting for a resistant variant. Genotypic testing, which involves sequencing the TK and DNA polymerase genes, is used to identify these specific resistance mutations and guide the use of alternative drugs like foscarnet.
Genetic variability also complicates the development of a preventative vaccine, a major global health goal. A vaccine must generate an effective immune response against all circulating genetic variants of HSV-2 to be widely effective. If a vaccine is designed based on a conserved sequence, it may be less effective if genetic differences in surface proteins, such as glycoprotein G (gG-2), affect the body’s recognition of the virus.