Cited by 90HIV Research and TreatmentSARS-CoV-2 and COVID-19 ResearchHIV/AIDS Research and Interventions

Low-Dose Penile SIVmac251 Exposure of Rhesus Macaques Infected with Adenovirus Type 5 (Ad5) and Then Immunized with a Replication-Defective Ad5-Based SIV gag/pol/nef Vaccine Recapitulates the Results of the Phase IIb Step Trial of a Similar HIV-1 Vaccine

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Qureshi, Huma, Ma, Zhong-Min, Huang, Ying, Hodge, Gregory, Thomas, Michael A., DiPasquale, Janet, DeSilva, Veronique, Fritts, Linda +8 more·2012·Journal of Virology

Abstract

The Step Trial showed that the MRKAd5 HIV-1 subtype B Gag/Pol/Nef vaccine did not protect men from HIV infection or reduce setpoint plasma viral RNA (vRNA) levels but, unexpectedly, it did modestly enhance susceptibility to HIV infection in adenovirus type 5 (Ad5)-seropositive, uncircumcised men. As part of the process to understand the results of the Step Trial, we designed a study to determine whether rhesus macaques chronically infected with a host-range mutant Ad5 (Ad5hr) and then immunized with a replication defective Ad5 SIVmac239 Gag/Pol/Nef vaccine were more resistant or susceptible to SIV infection than unimmunized rhesus macaques challenged with a series of escalating dose penile exposures to SIVmac 251. The Ad5 SIV vaccine induced CD8(+) T cell responses in 70% of the monkeys, which is similar to the proportion of humans that responded to the vaccine in the Step Trial. However, the vaccine did not protect vaccinated animals from penile SIV challenge. At the lowest SIV exposure dose (10(3) 50% tissue culture infective doses), 2 of 9 Ad5-seropositive animals immunized with the Ad5 SIV vaccine became infected compared to 0 of 34 animals infected in the other animal groups (naive animals, Ad5-seropositive animals immunized with the empty Ad5 vector, Ad5-seronegative animals immunized with the Ad5 SIV vaccine, and Ad5-seronegative animals immunized with the empty Ad5 vector). Penile exposure to more concentrated virus inocula produced similar rates of infection in all animal groups. Although setpoint viral loads were unaffected in Step vaccinees, the Ad5 SIV-immunized animals had significantly lower acute-phase plasma vRNA levels compared to unimmunized animals. Thus, the results of the nonhuman primate (NHP) study described here recapitulate the lack of protection against HIV acquisition seen in the Step Trial and suggest a greater risk of infection in the Ad5-seropositive animals immunized with the Ad5 SIV vaccine. Further studies are necessary to confirm the enhancement of virus acquisition and to discern associated mechanisms.

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Authors
Qureshi, H., Ma, Z.-M., Huang, Y., Hodge, G., Thomas, M. A., DiPasquale, J., DeSilva, V., Fritts, L., Bett, A. J., Casimiro, D. R., Shiver, J. W., Robert-Guroff, M., Robertson, M. N., McChesney, M. B., Gilbert, P. B., & Miller, C. J.
Affiliations
  • University of California, Davis (US)
  • Fred Hutch Cancer Center (US)
  • National Institutes of Health (US)
  • Merck Research Laboratories, West Point, Pennsylvania, USA
Venue
Journal of Virology
Published
2012-02-15
Volume
86
Issue
4
Pages
2239-2250
ISSN
  • 0022-538X (ISSN-L)
  • 1098-5514
OpenAlex
W2092404330
Cited by
90
References
46
Citations by year
2025: 1 · 2024: 4 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 7 · 2017: 6 · 2016: 6 · 2015: 12 · 2014: 22 · 2013: 10 · 2012: 12
FWCI
5.57
Type
journal article
Language
en
Open access
Locations
  • Journal of Virology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (AI054165)
  • National Cancer Institute
  • National Institute of Allergy and Infectious Diseases (P01 AI8227, R01AI094620, P01AI082278, R37AI054165)
  • National Center for Research Resources (P51RR000169, P51-RR 00169)
  • California National Primate Research Center
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS Research and Interventions
Keywords
HIV-1 vaccine, SIVmac251, STEP trial, CD8+ T cell responses, rhesus monkeys, HIV acquisition
MeSH terms
Adenoviruses, Human, Animals, Antibodies, Viral, Defective Viruses, Disease Models, Animal, Genetic Vectors, HIV, Humans, Immunization, Macaca mulatta, Male, Simian Immunodeficiency Virus, HIV-1, HIV Infections, Gene Products, gag, Gene Products, env, Gene Products, nef, Simian Acquired Immunodeficiency Syndrome, AIDS Vaccines, SAIDS Vaccines

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