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

Irene Bukh Brody, Roberto Calcedo, Mary J. Connell, Diane G. Carnathan, Martha Nason, Benton O. Lawson, Melon T. Nega, Surina Boyd, Qiuyue Qin, Thomas H. Vanderford, Jolaine M. Wilson, James M. Wilson, Guido Silvestri, Michael R. Betts

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 vaccination 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 (1:10,000 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.

Keywords: vaccine; HIV; CD4; susceptibility


Keywords


vaccine; HIV; CD4; susceptibility

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