Susceptibility to SIV Infection After Adenoviral Vaccination in a Low Dose Rhesus Macaque Challenge Model.

ABSTRACT

BACKGROUND: Vaccination with the Merck human adenovirus serotype-5 (HAdV-5) vectored HIV-1 subtype B gag/pol/nef vaccine was unexpectedly associated with enhanced susceptibility to HIV-1 infection in uncircumcised HAdV-5 seropositive men. It has been hypothesized that vaccination may have resulted in activated CD4+ T lymphocytes trafficking to mucosal sites thereby increasing targets for HIV infection. We have previously shown that AdV-vector vacci-nation in rhesus macaques resulted in an increase in the frequency of activated mucosal CD4+ T cells. However, whether this increase in activation is sufficient to increase susceptibility to HIV/SIV infection is unclear. METHODS: To examine this scenario, we developed a preliminary, proof-of-concept vaccination-challenge model in order to examine vaccine-induced SIV susceptibility in rhesus macaques. Rhesus macaques (n = 10/group) were vaccinated with a simian AdV-7 (SAdV-7)-vector encoding an irrelevant insert (SARS spike) and challenged 5 weeks post-prime in an escalating dosing regimen starting with sub-infectious doses (110,000 or 2TCID50) of SIVmac251. RESULTS: In contrast to our previous study, the SAdV-7 vaccine regimen did not induce detectable mucosal CD4+ T cell activation at the time points assessed in animals obtained from a different vendor and housed in a different facility. Within the power of the study, we did not observe significantly increased SIV acquisition in SAdV-7-vaccinated (5/10) versus placebo-vaccinated (3/10) macaques after repeated low-dose intra-rectal SIVmac251 challenge (P < 0.2). CONCLUSIONS: These results lay groundwork for future experiments to assess vaccine-induced SIV susceptibility in rhesus macaques. Further larger-scale studies are necessary to confirm the AdV-vector vaccination associated trend towards increased SIV/HIV acquisition and clarify associated mechanisms.