Annual and Interim Progress Report Summaries

Principal Investigator: James Wilson

Project: Impact of Adenovirus Infections on Vaccine Efficacy for HIV-1

Submitted October 16, 2009

The goal of this project is to (a) understand the biology of gut-associated lymphocytes (GALT) in the human gastro-intestinal tract with respect to their reactivity to adenovirus antigens, especially as it pertains to gay men and (b) to model the fate of GALT (in macaques) following vaccination with adenovirus vaccines using adenoviruses obtained from macaques in order to determine whether this might lead to a possible increased susceptibility to HIV infection. In the first part of the study, we have obtained GI tissues from eight macaques and have extensively defined the status of GALT with respect to their ability to be stimulated by adenovirus antigens, using an adenovirus that we have found to be endemic in captive macaque colonies in the US. Additionally, we have analyzed the mononuclear cells present in the blood from twenty-five macaques and have analyzed their capacity to be stimulated by a selection of adenoviruses belonging to different species originally isolated from humans, chimpanzees, and macaques. Both these data sets have shown that macaques show a measurable albeit low memory response to adenovirus antigens. Importantly, we have also validated the reagents and assays that were part of this determination because they will be used to determine the change in reactivity that may occur following vaccination. An important goal of this project is to create an SIV challenge model in macaques where the immunizing vector is a macaque adenovirus (and not a human adenovirus vector, as has been done before) because the T-cell response to a macaque adenovirus against which a recall reaction may be mounted may be different than when using an adenovirus that the macaque has not previously “seen”. We have previously observed that macaques chronically shed adenovirus DNA in their stools, although the frequency with which these viruses can be cultured is quite low. In this project we aim to isolate and sequence 12 macaque adenoviruses from stool cultures and to construct vectors using three of them. We have so far obtained 6 adenoviruses in this manner that may be vectored and have begun to sequence 3 additional adenoviruses.