Apolipoprotein E (APOE) alleles have been associated with the severity of, or susceptibility to, infection by various microbes. We investigated the potential association between the APOE-ϵ4 allele and the rate of recurrence of genital herpes in patients who were HIV positive and herpes simplex virus type 2 (HSV-2) seropositive. The APOE-ϵ4 allele was significantly associated with recurrent genital ulceration independent of ethnicity, antiretroviral therapy and CD4 count (OR 8.3; 95% CI 2.4 to 28.5). To our knowledge, this is the first published study to demonstrate this association and suggests that APOE-ϵ4 may represent a future prognostic marker for symptomatic recurrence of genital herpes in individuals with HIV.
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Herpes simplex virus type 2 (HSV-2) is the most common cause of recurrent genital ulceration. It is also associated with increased risk of HIV transmission and acquisition.1 Apolipoprotein E (ApoE) is a serum protein involved in several biological processes, including lipid metabolism, tissue repair and immunoregulation.2 Different isoforms of this protein are coded for by three alleles (APOE-ϵ2, ϵ3 and ϵ4), which have been shown to influence the severity of, or susceptibility to, certain infectious agents. In herpes labialis, caused by herpes simplex virus type 1 (HSV-1), the type 4 allele is a risk factor for recurrent disease.3 Here we report an association between the APOE type 4 allele (APOE-ϵ4) and the rate of recurrence of genital herpes in a cohort of patients who are HIV positive.
A total of 100 consecutive patients who were HIV positive known to be co-infected with HSV-2 on baseline serological testing (Colindale Laboratories (UK) in-house blocking enzyme immunoassay (EIA)) were identified and recruited during their routine attendance to HIV outpatients between April and October 2007. At study entry, we established the number of recurrences of genital ulceration experienced by each patient over the past 12 months. Any history of genital ulceration prior to this time period was also recorded.
Recurrent disease was defined as two or more symptomatic outbreaks of genital herpes in the preceding 12 months. Patients taking continuous, suppressive anti-herpetic treatment for a previous history of recurrent genital ulceration were included in this group. All patients had syphilis serology tested as part of their routine clinic blood tests—screening by EIA (Abbott ICE) followed by Venereal Disease Research Laboratory test (VDRL) (Abbott, Dartford, UK), Treponema pallidum particle agglutination (TPPA) (Mast) and IgM (EIA, Mast, Bootle, UK) if positive. APOE genotyping was performed as previously described4 on DNA prepared from buccal swabs, using the Nucleospin tissue preparation kit (Abgene, Epsom, UK). Statistical analysis was undertaken using the SPSS software (V.15).
Of 100 patients recruited, data were complete and available for 96. The study results are summarised in table 1. The balance of ethnicities in the study is representative of our HIV cohort with 47% black Africans and 42% caucasian. No association was seen between CD4 count and recurrent disease, although this may have been due to the small numbers of patients with very low CD4 counts. A relationship could be inferred between recurrent disease and antiretroviral use but this did not reach statistical significance.
The presence of APOE-ϵ4 was significantly associated with recurrent disease (p = 0.001), independent of ethnicity, anti-retroviral treatment and CD4 count (multivariate analysis: hazard ratio (HR) 8.3; 95% CI 2.4 to 28.5). Stratifying by ethnicity revealed a preponderance of APOE4 in the recurrent compared with the non-recurrent group for both caucasian and black Africans (see table 2 in the supplementary material).
Further, a significant association was seen between APOE-ϵ4 and patients who had “ever” (in their lifetime) experienced genital ulceration compared with those who were asymptomatic carriers (p = 0.04) (fig 1). A total of 88.5% of patients were co-infected with HSV-1 on baseline serology. Nonetheless, APOE-ϵ4 remains an independent risk factor for recurrence despite the inclusion of HSV-1 status in a multivariate analysis (p = 0.001) (multivariate analysis: HR 9.7; 95% CI 2.6 to 36.9). During the study period only 11 patients reported two or more episodes of orolabial ulceration. Of these patients, eight were APOE-ϵ4 carriers and three were not. One patient had a syphilitic chancre (genital HSV PCR negative) diagnosed during the period of study.
This pilot study demonstrates a highly significant adverse association between the presence of the APOE-ϵ4 allele and recurrent genital ulceration in a cross-sectional sample of clinic attendees who were HIV positive. The study assumes that the ulcerative episodes described were attributable to genital herpes due to HSV-2. Despite being the predominant cause of recurrent genital ulceration worldwide, without a PCR diagnosis at time of ulceration we cannot verify this. Nonetheless, the clinical significance of APOE-ϵ4 and symptomatic recurrence of genital ulceration remains. As a retrospective study, it is also reliant on patient reporting of episodes, although, again, any bias is likely to be in support of the association as more frequent episodes are more likely to be recalled.
Previously published data suggest that APOE-ϵ4 is a risk factor for recurrent orolabial herpes,3 reversible dementia and peripheral neuropathy in patients who are HIV positive5 and Alzheimer’s disease in those harbouring HSV-1 in their brain.3 APOE-ϵ4 homozygosity is a risk factor for infectious mononucleosis and shingles.4 However, in contrast, APOE-ϵ4 protects against liver damage in hepatitis C virus-positive individuals.6 These diseases were studied on the basis that the microorganisms involved use the same cell surface molecules for binding and/or entry as does the apoE protein and that, consequently, the protein and microbe might compete for cell entry—the degree of competition being isoform-specific and dependent on the cell type involved.7 The extent of viral cell-entry could then influence the extent of tissue damage caused. A similar mechanism may explain the influence of APOE-ϵ4 on neuronal uptake of HSV-2 and/or subsequent reactivation.
Our study suggests that APOE-ϵ4 may represent a prognostic marker for genital herpes in individuals who are HIV positive. This potentially has clinical utility in improving patient counselling and could also permit identification of patients likely to benefit from earlier suppressive treatment; thereby, additionally reducing transmission risk of HSV to serodiscordant sexual contacts.8
To our knowledge, this is the first published study demonstrating an association between APOE-ϵ4 and symptomatic genital herpes. We studied this in a HIV positive cohort for practical reasons as well as having a particular interest in individuals co-infected with HSV-2 and HIV. It would be interesting to investigate whether the described association is also seen in patients who were HIV negative. A prospective controlled study is now warranted, ideally with PCR-based identification and quantification of HSV-2 shedding in genital ulcers during recurrences.
In a cohort of individuals with herpes simplex virus type 2 (HSV-2) and HIV, apolipoprotein E (APOE)-ϵ4 was significantly associated with a history of recurrent genital ulceration.
APOE-ϵ4 was also significantly associated with any past history of genital ulceration in this group.
APOE-ϵ4 warrants further investigation as a potential clinical prognostic marker for HSV-2 recurrence.
The authors would like to acknowledge the patients and staff at Birmingham Heartlands Hospital who contributed to this study and Dr B Shaw for reviewing the statistical analyses.
Figure 1 and table 2 are published online only at http://sti.bmj.com/content/vol84/issue7
Funding: The Birmingham Heartlands Hospital Hawthorn House Trust Fund.
Competing interests: None.
Ethics approval: Ethics approval was obtained from the East Birmingham Local Research Ethics Committee.
Contributors: ANJ designed the study, collected and analysed the data and wrote the paper. RFI designed the study and reviewed the paper. MAW was the principal scientist. RP contributed to the study design and reviewed the paper. EJS contributed to the study design and practical implementation. RN performed the allele typing. GG recruited patients and collected samples. ST contributed to study design and reviewed the paper. DJW designed the study and reviewed the paper.