A phase I clinical trial of replication-competent Ad4-HIVenv and Ad4-HIVmosaic gag vaccines was initiated in the NIH clinical center in collaboration with NIAID and Dr. Mark Connors as Principal Investigator. The study is evaluating the safety and immunogenicity of the vaccines formulated as enteric coated capsules for oral administration and as a liquid for administration to the upper respiratory tract. At the same time, new replication-competent Ad vectors are under development for future clinical use following pre-clinical evaluation in the rhesus macaque model. Studies in mice and a pilot study in rhesus macaques showed that Ad-HIV envelope recombinants with deletions of E1B55K and/or E4orf1-4 early region genes not only had greater carrying capacity but also exhibited enhanced cellular and humoral immunity. A further pilot study in macaques will repeat these initial results and also examine a recombinant with an E1B55K deletion along with an E4orf 1 deletion. This pilot study will be prelude to a larger study in which the optimal vector will be used in a pre-clinical vaccine study evaluating overall immunogenicity and protective efficacy. A current pre-clinical study in macaques is evaluating a novel vaccine/microbicide regimen. Microbicides have been shown to be effective in preventing HIV transmission, however, their effectiveness depends on appropriate use which is often compromised by human behavior. Combining a prophylactic vaccine with microbicide use might provide protection against infection in instances when microbicides are not used properly. Therefore, we are immunizing rhesus macaques with our Ad-recombinant priming/Env protein boosting regimen in order to elicit mucosal immunity. Subsequently, we will expose the vaccinated animals to infectious SIV following administration of a microbicide. The microbicide (SAMT-247) is a zinc finger inhibitor that results in expression of non-infectious viral particles which nevertheless have intact envelope on their surface. We have postulated that the non-infectious particles will boost the immune response already elicited by the vaccine regimen. Overall, we are testing the hypothesis that the combined vaccine plus microbicide regimen is beneficial by providing either additive or synergistic protection against SIV infection. We have recently reported the development of a new technology for sorting and characterization of HIV/SIV from clinical specimens using nanoFACS. The virions can be stained and sorted based on either cellular antigens incorporated into the virion particles or alternatively using specific antibodies to different envelope epitopes. The ability to sort infectious HIV from clinically relevant samples provides material for detailed molecular, genetic, and proteomic analyses applicable to future design of vaccine antigens and potential development of personalized treatment regimens.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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Musich, Thomas; Jones, Jennifer C; Keele, Brandon F et al. (2017) Flow virometric sorting and analysis of HIV quasispecies from plasma. JCI Insight 2:e90626
Qureshi, Huma; GenescĂ , Meritxell; Fritts, Linda et al. (2014) Infection with host-range mutant adenovirus 5 suppresses innate immunity and induces systemic CD4+ T cell activation in rhesus macaques. PLoS One 9:e106004
Thomas, Michael A; Song, Rui; Demberg, Thorsten et al. (2013) Effects of the deletion of early region 4 (E4) open reading frame 1 (orf1), orf1-2, orf1-3 and orf1-4 on virus-host cell interaction, transgene expression, and immunogenicity of replicating adenovirus HIV vaccine vectors. PLoS One 8:e76344
Qureshi, Huma; Ma, Zhong-Min; Huang, Ying et al. (2012) 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. J Virol 86:2239-50
Patterson, L Jean; Kuate, Seraphin; Daltabuit-Test, Mara et al. (2012) Replicating adenovirus-simian immunodeficiency virus (SIV) vectors efficiently prime SIV-specific systemic and mucosal immune responses by targeting myeloid dendritic cells and persisting in rectal macrophages, regardless of immunization route. Clin Vaccine Immunol 19:629-37
Hidajat, Rachmat; Kuate, Seraphin; Venzon, David et al. (2010) Construction and immunogenicity of replication-competent adenovirus 5 host range mutant recombinants expressing HIV-1 gp160 of SF162 and TV1 strains. Vaccine 28:3963-71
Demberg, Thorsten; Robert-Guroff, Marjorie (2009) Mucosal immunity and protection against HIV/SIV infection: strategies and challenges for vaccine design. Int Rev Immunol 28:20-48
Morgan, Cecilia; Marthas, Marta; Miller, Christopher et al. (2008) The use of nonhuman primate models in HIV vaccine development. PLoS Med 5:e173
Patterson, L Jean; Robert-Guroff, Marjorie (2008) Replicating adenovirus vector prime/protein boost strategies for HIV vaccine development. Expert Opin Biol Ther 8:1347-63