Detection systems for antibody responses against herpes B virus

Abstract

Abstract. Herpes B virus (BV) infection is highly prevalent among adult Asian macaques and rarely causes severe disease in infected animals. In contrast, BV infection of humans can induce fatal encephalitis in the absence of treatment. Therefore, the development of diagnostic tests for specific and sensitive detection of antibodies against BV is an important task. The cross-reactivity of antibodies against BV with related simplex viruses of other primates may afford an opportunity to obtain sensitive detection systems without the need to work with the highly pathogenic BV. Moreover, it has been proposed that use of recombinant viral glycoproteins may allow for a detection of antibody responses against BV with high specificity. However, limited data are available for both approaches to BV diagnostic. Here, we report that simian agent 8 (SA8; infects African green monkeys)-and herpesvirus papio 2 (HVP-2; infects baboons)-infected cells allow for a more sensitive detection of antibody responses against BV in macaques than lysates of herpes simplex virus type 1 and 2 (HSV-1/2; infect humans)-infected cells and a commercial HSV ELISA (Enzygnost ® Anti-HSV/IgG). In addition, we show that sera from BV-infected macaques frequently contain antibodies against the recombinant BV glycoprotein gD (BV gD) that has been previously proposed as a diagnostic target for discriminating BV-and HSV-induced antibodies. However, we found that antibodies of some HSV-infected human patients also reacted with BV gD. In contrast, only sera of HSV-1-and HSV-2-infected humans, but not sera from BV-infected macaques, reacted with HSV-1/2 gG. Collectively, these results suggest that both SA8 and HVP-2 allow for sensitive and comparable detection of BVdirected antibody responses in macaques and that the combination of BV gD and HSV-1/2 gG needs to be complemented by a least one additional viral glycoprotein for reliable discrimination between antibody responses against BV and HSV-1/2 in humans.

Seroprevalence of viral infections in captive rhesus and cynomolgus macaques

“…Here, we used a chip-based platform to analyze macaque colonies for the presence of blood serum antibodies against eight NHP viruses (SRV/D, SIV, STLV, SFV, BV, CMV, LCV, RRV) and a human virus (MV) that constitutes a threat to NHPs and human health. Our results indicate that infection with the herpesviruses CMV, RRV and LCV as well as the retrovirus SFV is frequent in the animal population studied and suggest that previous efforts, based on testing with in-house assays for BV-specific antibodies (Pöhlmann et al, 2017), to establish a BV-free colony were successful. Finally, our results suggest a potential transmission of MV to NHPs enrolled in research programs that involve frequent animal-human contact, although the unknown MV vaccination status of the NHPs in question precludes solid conclusions.…”

“…A commercial chip-based screening system was used to detect antibodies against SRV/D, SIV, STLV, SFV, BV, CMV, RRV, LCV and MV. The animals had previously been tested negative for BV antibodies using in-house assay systems Male 74 (32.0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 13.5 10 Infant 4 (1.7) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 75.0 (3) 100 (4) 100 (4) 50.0 (2) Juvenile 37 (16.0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 94.6 (35) 91.9 (34) 73.0 (27) 78.4 (29) Adolescent 47 (20.4) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 97.9 (46) 83.0 (39) 78.7 (37) 100 (47) Adult 104 (45.0) 0.0 (0) 0.0 (0) 0.0 (0) 1.9 (2) 10.6 (11) 100 (104) 90.4 (94) 92.3 (96) 98.1 (102) Aged 39 (16.9) 0.0 (0) 0.0 (0) 5.1 (2) 10.3 4 (Pöhlmann et al, 2017) and were also found to be negative employing the commercial detection system (Table 1). Similarly, all animals were negative for SIV antibodies.…”

“…However, the detection of BV-specific antibodies is challenging since antibody responses may develop only months after infection and antibody titers in infected animals maybe very low or undetectable at certain times after infection (Olson et al, 1991;Ward and Hilliard, 2002;Wolfensohn and Gopal, 2001). We had previously used an inhouse Enzyme Linked Immunosorbent Assay (ELISA) based on lysates from cells infected with herpesvirus papio 2 or a modified anti-HSV ELISA kit (Enzygnost ® Anti-HSV/IgG, Siemens) (Pöhlmann et al, 2017) to detect antibodies against BV in the colony studied here with negative results. Therefore, the finding that none of the macaques had BV antibodies as determined in the chip-based approach suggests that the in-house ELISAs might be highly sensitive.…”

“…MV infection of macaques recapitulates important aspects of MV pathogenesis and immune responses in humans, and the virus can be transmitted between animals (de Swart, 2009;de Vries et al, 2012;Choi et al, 1999;MacArthur et al, 1979;McChesney et al, 1989;Potkay et al, 1966;Remfry, 1976;Willy et al, 1999). We observed a significantly higher prevalence of MV antibodies in macaques in housing and experimental situations entailing more extensive and extended contact with humans (inside area, Table 1) than in the breeding groups (outside area, Table 1).…”

“…The following animal and human viruses are of relevance regarding the monitoring of NHP colonies for viral infections: the measles virus (MV), a human virus, can be transmitted to NHPs (Willy et al, 1999;Choi et al, 1999;MacArthur et al, 1979;McChesney et al, 1989;Potkay et al, 1966;Levy and Mirkovic, 1971;Remfry, 1976) and can cause fatal disease in marmosets (Callithrix jacchus) (Albrecht et al, 1980;Levy and Mirkovic, 1971;Fraser et al, 1978) and macaques (Choi et al, 1999;MacArthur et al, 1979;McChesney et al, 1989;Albrecht et al, 1977;Remfry, 1976), although morbidity and mortality in macaques vary. The herpes B virus (BV, Macacine alphaherpesvirus 1) naturally infects macaques, which usually do not develop disease, but the transmission of the virus to other NHPs and humans can induce severe disease Jones-Engel, 2017, 2018).…”