Our studies have now demonstrated the presence of strong NK cell responses in acute HIV-1 infection, and that HIV-1 infection induces a significant redistribution of NK cell subsets resulting in the accumulation of functionally anergic NK cells in chronic viremic HIV-1 infection. New data now suggest that NK cells are directly involved in the control of HIV-1 replication possibly via a peptide-specific manner during the interaction of KIR3DS1 and HLA-Bw4 alleles expressing and isoleucine at position 80. These data demonstrate that NK cells may play a critical role in the early immune response to HIV-1 infection, and that clonal populations of NK cells may respond “specifically” in order to contain the viral infection prior to the induction of strong adaptive immune responses.

We employ novel methodologies to understand the role of NK cells and their receptors in both the control of chronic viral infections as well as their contribution to immunopathology. The labs research interests are focused around 4 research questions:

a) Characterizing the underlying mechanism of NK cell mediated recognition of HIV-1 infected CD4+ T cells focusing on KIR3DS1 and KIR3DL1 interactions with HLA-Bw480I.

b) Understanding the mechanisms by which NK cell receptor induction on CD8+ T cells may lead to the disruption of the immunological synapse and therefore T cell activation;
NK cell receptor expression increases dramatically on the surface of virus-specific CD8+ T cells during chronic viral infections. NK cell receptor+ virus-specific CD8+ T cells respond poorly to antigenic stimulation, suggesting that they are anergic. Thus we aim to understand how NK cell receptor expression on HIV-1 specific CD8+ T cells may induce CD8+ T cell anergy via the inhibition of TCR signaling within the immunological synapse.

c) Determining the role of NK cell mediated ADCC in the control of HIV-1 disease progression;
NK cells are also involved in the elimination of virally infected cells or malignant cells via Antibody-Dependent-Cellular-Cytotoxicity (ADCC). ADCC function, but not neutralizing antibody function, are elevated in subjects with slow HIV-1 disease progression. Furthermore recent evidence from Hessell et al. have shown that ADCC is critical in the protection of macaques from infection. Thus it is conceivable that NK cells may also play a critical role in the control of chronic viral infections through non-neutralizing cytolytic antibodies. Thus defining the role of ADCC in HIV-1 disease progression will provide critical insights into possible new immunological approaches that may elicited through vaccines to improve control over viral replication.

d) Defining the fundamental role of NK cells in shaping the antigen presenting DC pool;
Increasing evidence suggests that NK cells play a critical role in shaping the early adaptive immune response by deleting immature or improperly matured dendritic cells. Given the profound impact of this potential interaction, it is critical to begin to understand how NK cells may affect the accumulation of antigen-presenting DCs in HIV-infection in order to better establish what impact this interaction may have on the HIV-1 immunopathogenesis and the emergence of dysregulated CD8+ and CD4+ T cell responses.

Selected Publications of Interest:

1. Alter G, Malenfant J, Delabre R, Burgett N, Yu X, Lichterfeld M, Zaunders J, and Altfeld M. Increased Natural Killer Cell Activity in Viremic HIV1 Infection. Journal of Immunol. 2004 Oct 15;173(8):5305-11.
2. Alter G, Malenfant JM, Altfeld M. CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods. 2004 Nov;294(1-2):15-22.
3. Alter G, Teigen N, Davis BT, Addo MM, Suscovich TJ, Waring MT, Streeck H, Johnston MN, Staller KD, Zaman MT, Yu XG, Lichterfeld M, Basgoz N, Rosenberg ES, Altfeld M.Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection. Blood. 2005 Jul 14
4. Galit Alter, Todd J Suscovich, Marianna Kleyman, Nickolas Teigen, Hendrik Streeck, M. Tauheed Zaman, Angela Meier, and Marcus Altfeld Low perforin and elevated SHIP-1 expression is associated with functional anergy of NK cells in chronic viremic HIV-1 infection. AIDS 2006 Jul 13;20(11):1549-51.
5. Galit Alter, Nickolas Teigen, Angela Meier, Mathias Lichterfeld, Eric S. Rosenberg, and Marcus Altfeld. Dynamic evolution of innate and adaptive immunity in acute HIV-1 infection. J. Infect Dis. 2007 May 15;195(10):1452-60.
6. Galit Alter, Todd Suscovich, Nickolas Teigen, Angela Meier, Hendrik Streeck, and Marcus Altfeld. Single-Stranded RNA Derived from HIV-1 Serves as a Potent Activator of NK Cells. J Immunol. 2007 Jun 15;178(12):7658-66.
7. Galit Alter, Angela Meier, Nickolas Teigen, Hendrick Streeck, Marcus Altfeld. MyD88-dependent Immune Activation mediated by HIV-1-encoded TLR Ligands. J Virol. 2007 May 16.
8. Galit Alter, Maureen Martin, Nickolas Teigen, William Carr, Todd Suscovich, Arne Schneidewind, Hendrik Streeck, Michael T. Waring, Angela Meier, Christian Brander, Jeffrey Lifson, Todd Allen, Mary Carrington, and Marcus Altfeld. Differential Natural Killer cell mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J Exp Med. 2007 Nov 26;204(12):3027-36.
   

For additional information contact:
Galit Alter
Instructor
Partners AIDS Research Center
Massachusetts General Hospital
Bldg. 149, 13th Street
Charlestown, MA 02129
Phone (617) 724-0546
galter@partners.org

Currently there is a post-doctoral position open in the Alter Lab. Please contact Dr. Alter directly for more information.