Herpes Simplex Virus Infection: Epidemiological Aspects and Analysis of the Type-specific Antibody Response

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are ubiquitous viruses belonging to the Herpes viridae family, which consists of over 100 known viruses infecting organisms from oysters to humans. HSV-1 and HSV-2 often lead to asymptomatic infections in humans, nevertheless different clinical presentations can be seen including recurring oral and genital lesions, meningitis and less commonly neonatal herpes and encephalitis. HSV type 1 and type 2 are closely related viruses carrying a genetic homology of ~50% and this resemblance has hampered the attempts to differentiate between the two types serologically. Due to the recurring and often asymptomatic nature of the HSV infection, type-specific serology can be the only way to diagnose an HSV infection and it can also be employed for epidemiological studies, for counseling in the clinical situation and in evaluating HSV vaccine trials. The only known HSV-glycoproteins inducing type-specific antibody responses are the envelope glycoproteins G-1 (gG-1) from HSV1 and gG-2 from HSV-2 and they have therefore been utilized as discriminating ELISA antigens. However, a prerequisite for type-specific seroassays is that these test are based on genetically stable antigens inducing only type-specific antibodies and this prerequisite is not yet fulfilled for the type-specific HSV ELISA antigen gG-1. In the present work, the B-cell epitopes, including an immunodominant region, were outlined for gG-1 by investigating the reactivity of purified human anti-gG-1 antibodies to cellulose-bound synthetic peptides spanning the entire gG-1 sequence, employing the pepscan method. It was demonstrated that the epitopic regions of gG-1 were localized to regions carrying a high degree of homology to gG-2, from HSV-2. In spite of this, an analysis of purified human antigG-1 antibodies displayed no crossreactivity to the gG-2 antigen or to virus-infected cell-membranes from HSV-2. During the epitope-mapping, two corresponding highly homologous epitopic regions in gG-1 and gG-2 were found. However, despite this similarity a retained type-specific antibody-response was demonstrated. The molecular basis for this finding was explored and mutational analysis demonstrated that the human polyclonal antibody response was dependant on the structural presentation of these regions and relied on single or dual key residues. The DNA sequence of gG-1 in 108 clinical isolates was further examined, showing that missense mutations, leading to amino acid shifts, affected the immunodominant region in almost 40% of the investigated viral isolates. Two different genotypes were established by phylogenetic comparison, but when investigating the serological response in patients infected with either of these two genotypes their IgG reactivity did not differ when compared. The type-specific HSV serology was applied in the clinical setting, using it as a tool for classifying first episodes of genital herpes and clarifying transmission routes. In an investigation of 97 consecutive patients with first episodes of genital herpes, virus isolation demonstrated that 44% of all cases were found to be caused by HSV-1, while over 60% of the cases of true primary genital infections were due to HSV-1. In 17% the first episode of genital herpes corresponded to the first clinical recurrence of an earlier acquired HSV-2 infection. A suggested explanation to the rise in genital infections caused by HSV1 has been a decrease of HSV-1 among children. An epidemiological study was therefore conducted in sera from 2106 Swedish children and