HIV/SIV infection is a two-phase viral replication process with primary infection resulting in high peak plasma viral load set points, extensive depletion of CCR5+ CD4+ effector memory cells residing in extra-lymphoid tissues (e.g., lung, gut, liver) and the onset of chronic immune activation. A decline from peak plasma viral load and a maintenance of a stable level of viral replication characterizes the chronic viral replication phase which can last several years and takes a huge toll on the immune system leading to its inability to combat opportunistic infections and ultimately death. The onset of this immune deficiency in HIV/SIV infection is intimately linked with the patterns of CD4+ memory T cell dynamics, and reflects a complex interplay of direct viral cytopathogenicity and the indirect effects of persistent immune activation on CD4+ T cell homeostasis. We have shown that the collapse of CD4+ effector memory T cell populations in effector sites is a strong, primary correlate of overt disease in SIVmac239-infected, AIDS-susceptible rhesus macaques and have traced the pathogenesis of this collapse back to the failure of CD4+ central memory T cell homeostasis.Our current work is aimed at understanding the physiologic and molecular mechanisms responsible for the instability of the CD4+ central memory population in progressive SIV infection.
Natural Killer Cells
Broadly neutralizing antibodies are the “holy grail” of HIV/AIDS vaccine development, based on the concept that such antibodies would bind directly to infectious viral particles, preventing their entry into susceptible target cells. However, recent work suggests that antibody-mediated effector activity in vivo might involve more than simple neutralization, that the ability of antibodies to mediate anti-HIV activity might rely on or be facilitated by Fc-receptor bearing cells that mediate antibody-dependent, cell-mediated cytotoxicity (ADCC). In line with this, studies have shown that passive administration of HIV neutralizing antibodies produces significant protection to rhesus macaques challenged with SHIV (HIV/SIV chimera) by intravenous, vaginal and rectal routes. In fact, the protection resulting from the passive infusion of the human monoclonal antibody b12 was shown to be associated with its Fc receptor binding activity, suggesting the involvement of Fc-mediated effector functions such as ADCC and highlighting the importance of understanding the role of innate immune mechanisms in antibody-mediated protection and AIDS vaccine development. We are working to assess the function of natural cells in mediating the protection associated with broadly neutralizing antibodies against HIV.
Afam Okoye is a staff scientist at the Vaccine and Gene Therapy Institute, OHSU. He received his bachelor's degree in Microbiology from the University of Nigeria in 1998. He went on to receive a Master's degree in Biotechnology from Nottingham Trent University, UK. He moved to Glasgow, Scotland, in 2000 to perform his doctoral degree at the Institute of Comparative Medicine, University of Glasgow, studying the interaction between the human papillomavirus E2 (trans activator) and the minor capsid protein L2. His postdoctoral training was in Dr. Louis J. Picker’s lab at the Vaccine and Gene Therapy Institute studying nonhuman primate models of SIV pathogenesis, T cell biology and therapeutic approaches to immune reconsitution.
Leone A, Rohankhedkar M, Okoye A, Legasse A, Axthelm M, Villinger F, Piatak M Jr, Lifson J, Assouline B, Morre M, Picker L, and Sodora D. 2010. Increased CD4+ T cell levels during IL-7 administration of antiretroviral therapy-treated simian immunodeficiency virus-positive macaques are not dependent on strong proliferative responses. J Immunol. 185(3):1650-1659.
Okoye A, Park HM, Walker JM, Rohankhedkar M, Lum R, Planer SL, Legasse A, Sylwester AW, Piatak M Jr, Lifson JD, Sodora DL, Villinger F, Axthelm MK, Schmitz J, and Picker LJ. 2009. Profound CD4+/CCR5+T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis. J Exp Med. 206(7):1575-1588.
Okoye A, Meier-Schellersheim M, Brenchley JM, Hagen SI, Walker JM, Rohankhedkar M, Lum R, Edgar JB, Planer SL, Legasse A, Sylwester AW, Piatak M Jr, Lifson JD, Maino VC, Sodora DL, Douek DC, Axthelm MK, Grossman Z, and Picker LJ. 2007. Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection. J Exp Med. 204(9):2171-2185.
Okoye A, Cordano P, Taylor ER, Morgan IM, Everett R, and Campo MS. 2005. Human papillomavirus 16 L2 inhibits the transcriptional activation function, but not DNA replication function of HPV-16 E2. Virus Res. 108(1-2):1-14.