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Host - Pathogen interactions in Human Immunodeficiency Virus-1 (HIV-1) Infection
Dr. Tomaras' overall research program is to understand the cellular and humoral immune response to HIV-1 infection and vaccination that are involved in protection from HIV-1. The research in the Tomaras laboratory centers around three main projects involving 1) antiviral CD8+ T cell responses in HIV-1 infection and post vaccination, 2) mucosal and systemic antibody responses to infection and vaccination in both non-human primates and humans and 3) the ontogeny of neutralizing antibodies in HIV-1 infection.
Antiviral CD8+ T Cell Responses
Our laboratory studies CD8+ T cell immune responses to HIV involving noncytolytic CD8 T cells that mediate suppression of HIV replication. During human acute HIV-1 infection and acute SIV infection in non-human primates, CD8+ T cell responses have been associated with the initial control of viremia. A detailed understanding of the properties of CD8+ T cells that correlate with virologic control will inform vaccine development by focusing on strategies that elicit functional cellular responses. In this regard, it is critical to determine the phenotypic and functional properties of CD8+ T cells that can mediate viral suppression. We have developed a robust and high throughput multi-clade virus inhibition assay for the measurement of functional CD8 T cell activity to decipher the mechanisms of virus inhibition that include both lytic and nonlytic mechanism. We identified that CD8+ T cell mediated virus inhibition, like other memory CD8+ T cells, can use epigenetics to control expression of inhibitory molecules so that they can control molecules released to target infected CD4+ T cells. Studying the role of epigenetics in CD8+ T cell mediated virus inhibition is an innovative concept that will likely uncover pathways for induction of highly functional CD8+ T cells. Insights into the induction of these CD8+ T cell responses are central to understanding how to precisely target this population of cells by vaccination. We found that CD8+ T cell antiviral activity from vaccinees and virus controllers were defined by CD107a and MIP-1β expression and that CD8+ T cell from all memory stages of differentiation exhibit antiviral activity, including transitional memory CD8+ T cells. Our data define attributes of an antiviral CD8+ T cell response that may be optimized in the search for an efficacious HIV-1 vaccine. Current work aims to probe the specific CD8 T cell populations that are responsible for mediating HIV-1 inhibition and the contribution of soluble factors during acute infection, in natural virus controllers, and post vaccination.
Mucosal and Systemic Antibodies
A window of opportunity for immune responses to extinguish HIV-1 exists from the moment of transmission through establishment of the latent pool of HIV-1-infected cells. A critical time to study the initial immune responses to the transmitted/founder virus is the eclipse phase of HIV-1 infection. We have shown that the first detectable antibody response is in the form of HIV-1 virion-Ab complexes and the initial free antibody response is targeted only to the gp41 portion of the HIV-1 envelope. This body of work provided a deeper understanding of the initial B cell response to HIV infection that has allowed subsequent work to focus on why the humoral response is targeted initially to gp41 and not other potentially protective epitopes. Moreover, this work is leading to more detailed analyses of the ontogeny of the initial B cell response and whether this pathway to an ineffectual antibody response impedes the elicitation of more protective responses. This is critical for defining what a vaccine must do differently from natural infection in stimulating the B cell response. We are currently working to understand the functional significance of systemic and mucosal HIV-1 specific IgM, IgG subclasses and IgA. As part of our analysis of candidate HIV-1 vaccine trials, the RV144 efficacy trial, and non-human primate studies we are working to define the potential humoral correlates of protection and define the contributions of different types of non-neutralizing (HIV-1 inhibitory) antibodies.
Heterologous Neutralizing Antibodies
Identification of broadly neutralizing antibody specificities in HIV-1 infection will allow an understanding of what antibody specificities the human immune system is capable of making that can neutralize or eliminate diverse strains of HIV-1. We identified that 2F5-like antibodies can develop in chronic HIV-1 infection and can mediate neutralization breadth. As a result of this work, we continued to investigate the nature of the HIV-1 viruses that were most sensitive to HIV-1 gp41 MPER mediated neutralization. We identified a single amino acid substitution in gp41 that leads to prolonged MPER exposure with implications for vaccine design. For potential envelope based vaccine strategies, a greater understanding of the evolution of the HIV envelope under selective pressure is critical in understanding and predicting vaccine efficacy.
Vaccine-Induced Env V1-V2 IgG3 Correlates with Lower HIV-1 Infection Risk and Declines Soon After Vaccination.
Yates NL, Liao HX, Fong Y, Decamp A, Vandergrift NA, Williams WT, Alam SM, Ferrari G, Yang ZY, Seaton KE, Berman PW, Alpert MD, Evans DT, O'Connell RJ, Francis D, Sinangil F, Lee C, Nitayaphan S, Rerks-Ngarm S, Kaewkungwal J, Pitisuttithum P, Tartaglia J, Pinter A, Zolla-Pazner S, Gilbert PB, Nabel GJ, Michael NL, Kim JH, Montefiori DC, Haynes BF, Tomaras GD.
Sci Transl Med. 2014 Mar 19; 6(228): 228ra39. Abstract l Full Text l Reprint