By 2015, approximately half of people living with HIV in the US will be >50 yr. of age but median life expectancy of HIV infected persons continues to lag behind that of HIV uninfected by approximately 10 years. What HIV infection and aging have in common is increased pro-inflammatory state and compromised immune function with demonstrable deficits in antibody (Ab) responses to influenza vaccines. Whether HIV accelerates aging or has additive effect on adverse effects of aging is unclear, but presence of HIV infection greatly increases inflammaging, immune senescence and increased risk of end-organ disorders termed HIV-associated non-AIDS (HANA) conditions that occur at younger ages than uninfected persons. This application is based on our pilot observations in three cohorts. First, virally suppressed menopausal HIV- infected women on combination antiretroviral therapy (cART) exhibited higher inflammatory cytokine profile, gut microbial translocation (MT) and cellular immune activation of CD4 T cells, CD8 T cells and macrophages in comparison to uninfected menopausal women; importantly, the immune activation status was negatively associated with influenza Ab response. Second, in a younger cohort of HIV infected patients with poor responses to influenza vaccines we identified a potential defect in the function of a novel peripheral CD4 helper subset designated as T follicular helper cell (pTfh) that bears functional resemblance to the germinal center Tfh (GC Tfh) cells, which are prime drivers of B cell differentiation into antibody secreting cells. Third, in HIV negative aged adults, B cell intrinsic TNF-alpha and higher microRNA-155 were predictive of B cell functional defects and poor antibody response to influenza vaccine. These observations underscore the implications of the inflammation/immune activation on immune dysfunction. We hypothesize that inflammation/immune activation negatively impacts the immune response to influenza vaccines in physiologic aging and in HIV disease, and the effect is compounded in the aging HIV infected population. We will conduct the proposed studies in virologicallly suppressed HIV infected patients on cART (and control HIV uninfected populations) in age strata 18- 40, 41-60, and >60 years with peripheral blood samples collected pre-vaccination, at 7 days, at 3-4 weeks and 6 month post-vaccination.
Our specific aims are: 1. To investigate the nature and mechanism of the effect of immune activation on Ab responses to seasonal flu vaccination; 2. To characterize the function of peripheral T follicular helper cells in influenza antibody responses and role of immune activation on their function; and 3. To characterize B cells, T- independent responses and role of immune activation on their function. Understanding these issues is fundamentally important in the HIV+ elderly to improve vaccines and prevent vaccine preventable infectious complications.

Public Health Relevance

Aging is associated with poor antibody responses to influenza vaccines and the same phenomenon is noted in younger HIV-infected patients. Excessive inflammation is associated with poor responses in the uninfected elderly and in HIV+ people, but whether the underlying basis is the same is not known. This project will use the influenza vaccine as a tool to investigate important components of the immune response, in particular, B cells that make the antibody and a subset of CD4 T helper cells that are important for helping B cells but also are targets for HIV infection. This research has important implications for improving vaccines against influenza and other pathogens, including HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
4R01AI108472-04
Application #
9064747
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kuo, Lillian S
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Moysi, Eirini; Pallikkuth, Suresh; De Armas, Lesley R et al. (2018) Altered immune cell follicular dynamics in HIV infection following influenza vaccination. J Clin Invest 128:3171-3185
Rinaldi, Stefano; Pallikkuth, Suresh; George, Varghese K et al. (2017) Paradoxical aging in HIV: immune senescence of B Cells is most prominent in young age. Aging (Albany NY) 9:1307-1325
de Armas, Lesley R; Pallikkuth, Suresh; George, Varghese et al. (2017) Reevaluation of immune activation in the era of cART and an aging HIV-infected population. JCI Insight 2:
de Armas, Lesley R; Cotugno, Nicola; Pallikkuth, Suresh et al. (2017) Induction of IL21 in Peripheral T Follicular Helper Cells Is an Indicator of Influenza Vaccine Response in a Previously Vaccinated HIV-Infected Pediatric Cohort. J Immunol 198:1995-2005
George, Varghese K; Pallikkuth, Suresh; Parmigiani, Anita et al. (2015) HIV infection Worsens Age-Associated Defects in Antibody Responses to Influenza Vaccine. J Infect Dis 211:1959-68
Parmigiani, Anita; Alcaide, Maria L; Freguja, Ricardo et al. (2013) Impaired antibody response to influenza vaccine in HIV-infected and uninfected aging women is associated with immune activation and inflammation. PLoS One 8:e79816
Pallikkuth, Suresh; Pahwa, Savita (2013) Interleukin-21 and T follicular helper cells in HIV infection: research focus and future perspectives. Immunol Res 57:279-91