Population Council Research that makes a difference

Abstract

A macaque model to study vaginal HSV-2/immunodeficiency virus co-infection and the impact of HSV-2 on microbicide efficacy (HTML) 
Crostarosa,Federica; Aravantinou,Meropi; Akpogheneta,Onome J.; Jasny,Edith; Shaw,Andrew; Kenney,Jessica; Piatak Jr.,Michael; Lifson,Jeffrey D.; Teitelbaum,Aaron; Hu,Lieyu; Chudolij,Anne; Zydowsky,Thomas M.; Blanchard,James; Gettie,Agegnehu; Robbiani,Melissa
PLoS ONE 4(11): e8060 (1)-e8060 (14)
Publication date: 2009


Background
Herpes simplex virus type-2 (HSV-2) infection enhances the transmission and acquisition of human immunodeficiency virus (HIV). This occurs in symptomatic and asymptomatic stages of HSV-2 infection, suggesting that obvious herpetic lesions are not required to increase HIV spread. An animal model to investigate the underlying causes of the synergistic action of the two viruses and where preventative strategies can be tested under such complex physiological conditions is currently unavailable.




Methodology/Principal Findings
We set out to establish a rhesus macaque model in which HSV-2 infection increases the susceptibility to vaginal infection with a model immunodeficiency virus (simian-human immunodeficiency virus, SHIV-RT), and to more stringently test promising microbicides. HSV-2 exposure significantly increased the frequency of vaginal SHIVRT infection (n = 6). Although cervical lesions were detected in only ,10% of the animals, long term HSV-2 DNA shedding was detected (in 50% of animals followed for 2 years). Vaginal HSV-2 exposure elicited local cytokine/chemokine (n = 12) and systemic low-level HSV-2-specific adaptive responses in all animals (n = 8), involving CD4+ and CD8+ HSV-specific T cells (n = 5). Local cytokine/chemokine responses were lower in co-infected animals, while simian immunodeficiency virus (SIV)-specific adaptive responses were comparable in naý¨ve and HSV-2-infected animals (n = 6). Despite the increased frequency of SHIV-RT infection, a new generation microbicide gel, comprised of CarraguardH and a non-nucleoside reverse transcriptase inhibitor MIV-150 (PC-817), blocked vaginal SHIV-RT infection in HSV-2-exposed animals (n = 8), just as in naive animals.

Conclusions/Significance
We established a unique HSV-2 macaque model that will likely facilitate research to define how HSV-2 increases HIV transmission, and enable more rigorous evaluation of candidate anti-viral approaches in vivo.