New Strategy to Improve Gastrointestinal Health in SIV/HIV

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Abstract A coronavirus pandemic is currently in progress and a tremendous effort for developing effective vaccines to curb it is currently being made. Adenovirus (Ad)-based vaccines are in the lead in the clinical trials, and it is to be expected that at least one vaccine formulation will comprise of an Ad vector. These vectors are known for inducing massive activation of the immune responses at the mucosal sites. The gastrointestinal (GI) tract is the primary site of HIV replication and CD4+ T cell depletion. HIV induces major alterations at the mucosal sites, which impact their barrier function, permitting transfer of microbial products from the intestinal lumen into the surrounding tissues and general circulation. Microbial translocation is a key driver of the chronic immune activation and inflammation (IA/INFL) that are responsible for HIV disease progression. IA/INFL have a tremendous impact on the outcome of HIV infection and persist even in subjects on antiretroviral therapy (ART), preventing a proper recovery of the CD4+ T cells and thus being responsible for comorbidities and accelerated aging. Improving gut health and controlling chronic IA/INFL is thus one of the major goals both for prevention of HIV-associated comorbidities and for cure strategies. It is conceivable that the use of Ad-based vaccines for the SARS-CoV-2 in people living with HIV may result in high levels of IA/INFL at the mucosal sites, which may reverse HIV control provided by ART. Therefore, we teamedwith Dr. Andrea Gambotto from the University of Pittsburgh, who produced a recombinant type 5 Ad vector encoding the transgene for the antigen SARS-CoV-2 S1 subunit (Ad5.SARS-CoV-2-S1). We will use this vaccine in SIV-infected, ART-suppressed rhesus macaques (RMs) to induce effective mucosal immune responses to SARS-CoV2, and we will monitor the impact of these responses on the key pathogenic features of HIV infection: (a) T-cell immune activation, with particular attention given to the mucosal sites; (b) mucosal inflammation and gut integrity; (c) microbial translocation; (d) microbiome; (e) hypercoagulability; (f) impact on the drug metabolism and viral suppression; (g) impact on the viral reservoirs. Since severe SARS-CoV-2 infection disproportionately target older individuals, both young and old RMs will be included. Our specific aim is to test the impact of a SARS-CoV- 2 vaccine on the gut dysfunction and its consequences, systemic immune activation and inflammation and on the response to ART and viral reservoirs in ART-suppressed SIV infection of young versus old RMs. By directly probing the impact of an Ad5.SARS-CoV-2 S1 vaccine on key parameters of HIV infection, our approach will assess whether the planned COVID-19 vaccination has the potential of being deleterious to HIV- infected subjects. We will also assess the importance of a healthy gastrointestinal mucosa to the efficacy of the SARS-CoV-2 vaccine, which goes beyond the HIV infection field, covering all the inflammatory bowel disease pathology.