Tfh and B cells in HIV/SIV pathogenesis and vaccination

Koup, Richard A.

Abstract

We have investigated the phenotype, function, location and molecular signature of follicular CD4 T helper cells (TFH) in rhesus macaques. Similar to human TFH, they are characterized by a CCR7lowPD-1highCTLA-4highICOShighCXCR4high phenotype and represent a heterogeneous population with respect to cytokine function. Production of Th1 cytokines was compromised while IL-4 production was augmented in a highly differentiated (CD150low) subpopulation of TFH cells that was also characterized by decreased survival, cycling, and trafficking capacity. Compared to non-TFH cells, TFH cells exhibited a distinct gene profile that was significantly altered by SIV infection. TFH cells were found to be infected by SIV yet, in some animals, these cells actually accumulated during chronic SIV infection. Generalized immune activation and increased IL-6 production helped drive TFH differentiation during SIV infection. Accumulation of TFH was associated with increased frequency of activated germinal center B cells and SIV-specific antibodies. These processes contribute to B cell and immunoglobulin abnormalities in SIV, and by extension HIV, infection.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIAAI005015-12
• Application #: 8745610
• Support Year: 12
• Fiscal Year: 2013
• Total Cost: $1,273,880

Institution

• Name: National Institute of Allergy and Infectious Diseases

Publications

Paris, Robert M; Milagres, Lucimar G; Moysi, Eirini et al. (2017) Lower Baseline Germinal Center Activity and Preserved Th1 Immunity Are Associated With Hepatitis B Vaccine Response in Treated HIV Infection. Pathog Immun 2:66-88

Ferrando-Martinez, Sara; De Pablo-Bernal, Rebeca S; De Luna-Romero, Marta et al. (2017) Thymic Function Failure Is Associated With Human Immunodeficiency Virus Disease Progression. Clin Infect Dis 64:1191-1197

Coates, Emily E; Costner, Pamela J; Nason, Martha C et al. (2017) Lymph Node Activation by PET/CT Following Vaccination With Licensed Vaccines for Human Papillomaviruses. Clin Nucl Med 42:329-334

Francica, Joseph R; Sheng, Zizhang; Zhang, Zhenhai et al. (2015) Analysis of immunoglobulin transcripts and hypermutation following SHIV(AD8) infection and protein-plus-adjuvant immunization. Nat Commun 6:6565

Yamamoto, Takuya; Lynch, Rebecca M; Gautam, Rajeev et al. (2015) Quality and quantity of TFH cells are critical for broad antibody development in SHIVAD8 infection. Sci Transl Med 7:298ra120

Wheatley, Adam K; Whittle, James R R; Lingwood, Daniel et al. (2015) H5N1 Vaccine-Elicited Memory B Cells Are Genetically Constrained by the IGHV Locus in the Recognition of a Neutralizing Epitope in the Hemagglutinin Stem. J Immunol 195:602-10

Prentice, Heather A; Tomaras, Georgia D; Geraghty, Daniel E et al. (2015) HLA class II genes modulate vaccine-induced antibody responses to affect HIV-1 acquisition. Sci Transl Med 7:296ra112

Liang, Frank; Ploquin, Aurélie; Hernández, José DelaO et al. (2015) Dissociation of skeletal muscle for flow cytometric characterization of immune cells in macaques. J Immunol Methods 425:69-78

Petrovas, Constantinos; Koup, Richard A (2014) T follicular helper cells and HIV/SIV-specific antibody responses. Curr Opin HIV AIDS 9:235-41

Boswell, Kristin L; Paris, Robert; Boritz, Eli et al. (2014) Loss of circulating CD4 T cells with B cell helper function during chronic HIV infection. PLoS Pathog 10:e1003853