A macaque model to study vaginal HSV-2/immunodeficiency virus co-infection and the impact of HSV-2 on microbicide efficacy.
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.


RESULTS
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 SHIV-RT infection (n = 6). Although cervical lesions were detected in only approximately 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(R) 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
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.
Crostarosa
Federica
F
Center for Biomedical Research, Population Council, New York, New York, United States of America.
Aravantinou
Meropi
M
Akpogheneta
Onome J
OJ
Jasny
Edith
E
Shaw
Andrew
A
Kenney
Jessica
J
Piatak
Michael
M
Lifson
Jeffrey D
JD
Teitelbaum
Aaron
A
Hu
Lieyu
L
Chudolij
Anne
A
Zydowsky
Thomas M
TM
Blanchard
James
J
Gettie
Agegnehu
A
Robbiani
Melissa
M
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000821:virology; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006678:HIV / Q000378:metabolism*; D015658:HIV Infections / Q000150:complications* / Q000821:virology; D006561:Herpes Simplex / Q000150:complications* / Q000821:virology; D018258:Herpesvirus 2, Human / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008251:Macaca; D011725:Pyridines / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014709:Vero Cells
D000890:Anti-Infective Agents; D016207:Cytokines; C510296:MIV 150; D011725:Pyridines; D007371:Interferon-gamma; D014508:Urea