Immune control of HIV-1 is dependent on the migration of HIV-1 specific CTLs towards and colocalization with infected cells. This process is orchestrated by the action of chemokines serving as chemoattractants at sites of infection. We recently demonstrated that leukocytes could also be repelled from specific agents including chemokines and viral proteins including SDF-1 and the HIV-1 envelope protein, gp120 via a chemokine receptor mediated mechanism termed fugetaxis or chemorepulsion (Nature Medicine.2000.6.543;J Virol. 2004: 2004: 78.5184;Reviewed in J.Mol.Med..2005.83:752). We propose that T cell and in particular CTL chemorepulsion in response to CXCR4 or CCR5 binding gp120 generated from retrovirally infected cells plays a role in a novel mechanism by which HIV-1 evades the immune system. First we developed novel fully quantitative assays for measuring leukocyte migration to SDF-1 or HIV-1gp120 and demonstrated that chemorepulsion was mediated via a signaling pathway which was distinct from that for chemoattraction (Nature Med., J. Virol op cit;J. Leuk. Biol. 2005. in press.). In order to determine whether T cell chemorepulsion to SDF-1 or HIV-1gp120 was demonstrable in vivo, we established novel assays for quantitating leukocyte chemorepulsion and subsequently demonstrated its role in physiological and pathological processes including thymic emigration and immune evasion by cancer (J. Clin. Invest. 2002.109:1101;J. Immunol. 2005.175:5115)( J. Immunol. Accepted Dec.2005). We also showed that antigen specific CTLs and monocytes move away from X4 or R5 binding HIV-1 gp120 in vitro and in vivo and that this response was critically dependent on the presence of the V3 loop of the envelope protein (./ Virol. op cit.}. We have demonstrated in pilot that cells engineered to express gp120 repel and thereby dysregulate CTL migration and function in vitro and their subsequent localization in vivo and that chemorepellent concentrations of gp120 are detectable within the lymph nodes of acutely SHIV-1 infected monkeys. We now plan to explore the mechanism and pathophysiological relevance of these findings to HIV/AIDS.
The aims of this proposal are 1: Definition of mechanistic elements of HIV-1gp120 induced CTL chemorepulsion and the effect of chemorepellent concentrations of the retroviral protein on CTL function. 2. Quantitation of the effects of X4gp120 on CTL migration, localization and function in murine models using multiphoton intravital microscopy and MRI for imaging dye or nanomagnetically labeled CTLs in vivo. 3. Quantitation and modeling of gp120 gradients in tissues and correlation with the localization and function of CTLs in acutely SHIV-1 infected monkeys. This focused and innovative exploration of the pathophysiological relevance of HIV-1 gp120 induced CTL chemorepulsion to HIV/AIDS is supported by synergistic and ongoing collaborations between retrovirologists, immunologists and bioengineers and access to recently developed fully quantitative technologies for examining T cell migration and localization in vitro and in vivo. We hope, in this way, to delineate both a novel mechanism by which HIV-1 evades the immune system and a new immunotherapeutic target for HIV-1 infected individuals.
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