Herpes Simplex Virus Type 1 (HSV-1) is commonly associated with oral herpes, while Herpes Simplex Virus Type 2 (HSV-2) is the primary cause of genital herpes. The presence of HSV-1 can indeed potentially lead to a false positive result when screening for HSV-2 infection. This diagnostic ambiguity arises from the fundamental way the human immune system creates antibodies against these two closely related viruses.
Understanding Antibody Screening Tests for HSV
Long-term HSV infection is typically diagnosed by detecting specific Immunoglobulin G (IgG) antibodies in the blood. These tests, often called enzyme immunoassays (EIA) or ELISA, search for IgG antibodies, which persist indefinitely after initial exposure, indicating a past or present infection.
Commercial screening tests are designed to be highly sensitive to ensure true infections are rarely missed. However, prioritizing sensitivity can reduce specificity, which is the test’s ability to distinguish accurately between similar targets. This trade-off can result in false positive outcomes, especially in populations with low infection rates. Assays report a numerical index value, where a result above a cutoff, such as 1.1, suggests the presence of HSV-2 IgG antibodies. A positive result indicates past exposure, not necessarily an active outbreak, and these tests are susceptible to misidentification when two related viruses are involved.
The Scientific Basis for Cross-Reactivity
The reason HSV-1 can generate a false positive for HSV-2 is rooted in the genetic and structural similarity between the two viruses. HSV-1 and HSV-2 are both members of the herpesvirus family and share many structural proteins. When the immune system encounters HSV-1, it generates antibodies that target various parts of the virus, including its glycoproteins.
A key factor in diagnosis is glycoprotein G (gG), a protein that differs significantly between the two types: gG-1 for HSV-1 and gG-2 for HSV-2. While current type-specific serological tests specifically use the unique gG-2 protein to detect HSV-2, antibodies produced against HSV-1 can still bind to other shared, non-gG proteins present in the test kit. This phenomenon is known as cross-reactivity.
When a person infected only with HSV-1 is tested for HSV-2, the high levels of antibodies generated against the shared proteins can mistakenly bind to the test’s reagents. This cross-binding generates a signal that the assay interprets as a positive result for HSV-2 antibodies, even though the body has only been exposed to HSV-1. This cross-reactivity is a major cause of false positives, especially when the index value is low.
Interpreting Ambiguous Results and Confirmation Testing
For patients who receive a positive result on an HSV-2 screening test, especially without a history of genital lesions, the index value reported by the laboratory is important for interpretation. A low-positive result, typically defined as an index value between 1.1 and 3.5, is the range most highly associated with potential false positives and cross-reactivity from HSV-1 antibodies. For these ambiguous results, healthcare providers should recommend confirmatory testing.
The gold standard for definitively differentiating between HSV-1 and HSV-2 antibodies is the Western Blot assay, often performed at specialized reference laboratories. The Western Blot separates all the viral proteins into distinct bands, allowing laboratory staff to identify the specific pattern of antibodies present. This detailed analysis can distinguish between the non-specific, cross-reactive antibodies and the truly type-specific antibodies.
Another confirmatory option is a supplemental type-specific test, such as the HSV-2 IgG inhibition assay, which is more sensitive and has a faster turnaround time than the Western Blot. This assay measures the ability of HSV type lysates to neutralize the reactivity of the patient’s antibodies to the gG-2 protein. These highly specific follow-up tests are designed to overcome the limitations of the initial screening EIA, providing a more accurate diagnosis. Patients should consult with their healthcare provider when a low-positive screening result is received.