Abstract
BackgroundHerpes 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 FindingsWe 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 SHIV-RT 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 naïve and HSV-2-infected animals (n = 6). Despite the increased frequency of SHIV-RT infection, a new generation microbicide gel, comprised of Carraguard® 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 naïve animals.Conclusions/SignificanceWe 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.
Highlights
Herpes simplex virus type-2 (HSV-2) prevalence is between 19– 50% in adults worldwide [1,2] and increases the risk of human immunodeficiency virus (HIV) acquisition by,3 fold [3,4]
These findings correlate with the observation that, HSV-2 results in a chronic infection, the frequency of symptomatic genital herpes reactivation decreases with time since infection [6]
To study the impact of HSV-2 on immunodeficiency virus infection, macaques were challenged with HSV-2 and later cochallenged with HSV-2 and SHIV-RT (Fig. S1)
Summary
Herpes simplex virus type-2 (HSV-2) prevalence is between 19– 50% in adults worldwide [1,2] and increases the risk of human immunodeficiency virus (HIV) acquisition by ,3 fold [3,4]. Individuals with recently acquired HSV-2 infection showed a higher incidence of HIV acquisition (22.6% per 100 person-years) compared to chronically infected people (7.5% per 100 person-years) [5]. These findings correlate with the observation that, HSV-2 results in a chronic infection, the frequency of symptomatic genital herpes reactivation decreases with time since infection [6]. 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
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