HIV infection is characterized by an extensive loss of CD4 T cells very early during infection. This coupled with the demonstration that HIV specific CD4 T cell are preferentially infected and destroyed during the course of HIV infection suggests that the ability of the immune system to generate anti-viral immune responses to control HIV is severely compromised very early during HIV infection. Recent studies in small animal modes and HIV infected subjects treated with anti-retroviral therapy (ART) during primary infection indicate that early loss of CD4 T cells may have significant implications for the generation and maintenance of anti-viral CDS T cell responses. The exact role of CD4 T cells in CDS mediated control of HIV infection has not been completely delineated. The long term objectives of this study are to delineate the role of CD4 T cell help in the generation of anti-viral immune responses, and to determine how these responses correlate with durable control of infection and long term outcome.
The Specific Aims of this proposal are (1) to determine if early initiation of ART can preserve CD4 T cells in peripheral and mucosal tissues, and if this preservation correlates with qualitative changes in the nature of anti-viral CDS T cell responses (2) to examine if the qualitative differences in the nature of CDS T cell responses correlate with durable viral control and favorable long term outcome after cessation of ART. We hypothesize that early ART will preserve CD4 T cells that in turn will lead to generation of stronger and more effective poly functional CDS T cell responses that will aid in better control of viral infection. Rhesus macaques infected with SIVmac239 and treated with PMPA and FTC will be used in this study. The degree of CD4 T cell preservation in both peripheral and mucosal tissues after ART will be determined using multi-color flow cytometry and molecular techniques. SIV specific CDS T cell responses will be evaluated by measuring multiple functional markers simultaneously using intracellular staining and multi-color flow cytometry. These studies will provide extremely valuable insights into the role of CD4 T cells in CDS mediated control of HIV infection, and will help develop better therapeutic approaches for durable control of HIV infection. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
5K22AI071812-02
Application #
7344795
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Voulgaropoulou, Frosso
Project Start
2007-02-01
Project End
2011-01-31
Budget Start
2008-02-01
Budget End
2011-01-31
Support Year
2
Fiscal Year
2008
Total Cost
$108,000
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
George, Jeffy; Cofano, Egidio Brocca; Lybarger, Elizabeth et al. (2011) Early short-term antiretroviral therapy is associated with a reduced prevalence of CD8(+)FoxP3(+) T cells in simian immunodeficiency virus-infected controller rhesus macaques. AIDS Res Hum Retroviruses 27:763-75
Teran, Rommy; Mitre, Edward; Vaca, Maritza et al. (2011) Immune system development during early childhood in tropical Latin America: evidence for the age-dependent down regulation of the innate immune response. Clin Immunol 138:299-310
Geisbert, Thomas W; Daddario-DiCaprio, Kathleen M; Hickey, Andrew C et al. (2010) Development of an acute and highly pathogenic nonhuman primate model of Nipah virus infection. PLoS One 5:e10690
Kader, M; Wang, X; Piatak, M et al. (2009) Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection. Mucosal Immunol 2:439-49
Kader, M; Bixler, S; Roederer, M et al. (2009) CD4 T cell subsets in the mucosa are CD28+Ki-67-HLA-DR-CD69+ but show differential infection based on alpha4beta7 receptor expression during acute SIV infection. J Med Primatol 38 Suppl 1:24-31
Eberly, Matthew D; Kader, Muhamuda; Hassan, Wail et al. (2009) Increased IL-15 production is associated with higher susceptibility of memory CD4 T cells to simian immunodeficiency virus during acute infection. J Immunol 182:1439-48
Mueller, Yvonne M; Do, Duc H; Boyer, Jean D et al. (2009) CD8+ cell depletion of SHIV89.6P-infected macaques induces CD4+ T cell proliferation that contributes to increased viral loads. J Immunol 183:5006-12
Kader, M; Bixler, S; Piatak, M et al. (2009) Anti-retroviral therapy fails to restore the severe Th-17: Tc-17 imbalance observed in peripheral blood during simian immunodeficiency virus infection. J Med Primatol 38 Suppl 1:32-8
Kader, Muhamuda; Hassan, Wail M; Eberly, Matthew et al. (2008) Antiretroviral therapy prior to acute viral replication preserves CD4 T cells in the periphery but not in rectal mucosa during acute simian immunodeficiency virus infection. J Virol 82:11467-71
Mattapallil, Joseph J; Roederer, Mario (2008) Mucosa and vaccine-induced immune protection in nonhuman primates. Curr Opin HIV AIDS 3:387-92