The AIDS pandemic continues unchecked, and the prospect of an effective vaccine provides the best hope for HIV prevention. Our efforts to develop a protective vaccine have been hampered by the fact that we still do not understand correlates of immunity to HIV-1. Ongoing vaccine trials promise to provide insight into whether the immune responses that are involved in controlling HIV-1 replication during chronic infection can also play a role in mediating protection from new infection with HIV-1. Recent reports of HIV-1 superinfection (also called re-infection, defined as infection by a second virus after the first virus is already established in the individual), suggest that the immune responses generated during natural infection do not necessarily induce protective immunity. Thus, identifying potential immune deficits in superinfected individuals will be important for vaccine design. Our lab has recently identified several cases of HIV-1 superinfection among a cohort of high-risk women in Mombasa, Kenya. We hypothesize that deficits in both humoral and cellular immunity to HIV-1 contribute to the ability of a second viral strain to establish infection.
The aims of this proposal are to characterize the humoral and cellular immune responses to HIV-1 in superinfected individuals, and to compare these responses to those of women who have not become superinfected. To analyze the humoral immune responses, we will first generate a panel of full length, functional envelope clones from initially infecting and superinfecting strains. We will use these envelopes to develop a panel of viruses with which we can assess the potency and the breadth of the neutralizing antibody responses in superinfected women and in women who do not show evidence of superinfection.
We aim to identify correlates of cellular immunity using multiparameter flow cytometry and multiplex cytokine assessment following stimulation of peripheral blood mononuclear cells with HIV-1 and non-HIV-1 antigens. We will assess whether there are deficits or changes in cytokine production, cytolysis, and proliferative capacity among CD4+ and CD8+ T cells in superinfected women. Analyses of the humoral and cellular immune responses of women who have become superinfected will aid in defining correlates of both protective and failed immunity to HIV;such advances will provide key insights to incorporate into future vaccine design.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Investigator Award (CIA) (K08)
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Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
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Embry, Alan C
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Fred Hutchinson Cancer Research Center
United States
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Blish, Catherine A; Dogan, Ozge C; Jaoko, Walter et al. (2014) Association between cellular immune activation, target cell frequency, and risk of human immunodeficiency virus type 1 superinfection. J Virol 88:5894-9
Blish, Catherine A; Dogan, Ozge C; Jaoko, Walter et al. (2012) Cellular immune responses and susceptibility to HIV-1 superinfection: a case-control study. AIDS 26:643-6
Blish, Catherine A; McClelland, R Scott; Richardson, Barbra A et al. (2012) Genital Inflammation Predicts HIV-1 Shedding Independent of Plasma Viral Load and Systemic Inflammation. J Acquir Immune Defic Syndr 61:436-40
Blish, Catherine A; Baeten, Jared M (2011) Hormonal contraception and HIV-1 transmission. Am J Reprod Immunol 65:302-7
Blish, Catherine A; Sangaré, Laura; Herrin, Bradley R et al. (2010) Changes in plasma cytokines after treatment of ascaris lumbricoides infection in individuals with HIV-1 infection. J Infect Dis 201:1816-21
Blish, Catherine A; Sather, D Noah; Sellhorn, George et al. (2010) Comparative immunogenicity of subtype a Human Immunodeficiency Virus type 1 envelope exhibiting differential exposure of conserved neutralization epitopes. J Virol 84:2573-84
Blish, Catherine A; Jalalian-Lechak, Zahra; Rainwater, Stephanie et al. (2009) Cross-subtype neutralization sensitivity despite monoclonal antibody resistance among early subtype A, C, and D envelope variants of human immunodeficiency virus type 1. J Virol 83:7783-8
Blish, Catherine A; Dogan, Ozge C; Derby, Nina R et al. (2008) Human immunodeficiency virus type 1 superinfection occurs despite relatively robust neutralizing antibody responses. J Virol 82:12094-103
Blish, Catherine A; Nguyen, Minh-An; Overbaugh, Julie (2008) Enhancing exposure of HIV-1 neutralization epitopes through mutations in gp41. PLoS Med 5:e9
Blish, Catherine A; Blay, Wendy M; Haigwood, Nancy L et al. (2007) Transmission of HIV-1 in the face of neutralizing antibodies. Curr HIV Res 5:578-87