HIV Infections and the Safety of the Blood Supply

Principal Investigator: Andrew I. Dayton, MD, PhD
Office / Division / Lab: OBRR / DETTD / LMV

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Overview

Public Health Issue: HIV is a continually evolving threat to the safety of the blood supply. HIV can rapidly evolve naturally (and artificially) to novel, dangerous forms that may be more difficult to detect by current assays used to screen blood donors and monitor the progress of HIV infection. HIV evolves with altered rates and mechanisms of clinical progression resulting in changes in the duration of the crucial "window period" between when an infected person's blood can transmit the infection and when the infection can be detected by screening assays. Faced with an ever increasing list of emerging transfusion transmissible infectious agents and a finite volume of blood available from each unit for screening, industry is moving towards screening tests using multiplex formats, further compounding the complexity of detection. In diagnostic and treatment settings, not only are these sensitivity issues of concern, but also an increasing reliance on complicated algorithms to predict clinical outcome and optimize treatment regimens requires an increasing understanding of host and viral predictors of clinical progression and drug efficacy. Furthermore, the dependence on steroid hormones of antiretroviral agents is unknown.

Regulatory Contribution: CBER is responsible for evaluating the safety of the entire blood supply and for regulating diagnostics for all human retroviruses, including HIV. CBER advises industry on and evaluates the efficacy of blood donor screening tests (such as nucleic acid tests for the presence of infectious agents and antibody tests for indirect evidence of infection) used to prevent HIV from entering the blood supply. The screening tests all critically depend on three factors: 1.The specific genetic make up of the infecting HIV; 2.The blood concentrations of the infecting HIV or anti-HIV antibodies detected by the test's chemistry; and 3. diagnostic and screening assay detection technologies. To knowledgeably evaluate tests for the nucleic acids of infectious agents and for the antibodies that indicate their presence indirectly, it is essential to understand what viral and cellular determinants are crucial for transmission, replication and pathogenesis, how pathogens may elude detection and thereby enter the blood supply and how host cellular immune response mechanisms can succeed and fail in mitigating HIV infection. It is also important to know more about new nucleic acid detection technologies to establish policy and guidance for industry. Finally, understanding both human and viral factors that contribute to antiretroviral drug efficacy is important to understanding the likely sources of emerging drug resistant variants. In addition, understanding the factors influencing the efficacy of complicated algorithms and assays used to predict the outcomes of particular antiretroviral drug regimens, is critical to regulating the burgeoning number of assays that are used to select optimal treatment regimens based on viral and host parameters.

Research Approach: HIV pathogenesis and transmission involves complex interactions between the invading pathogen (HIV) and the human host. HIV appears to replicate early in macrophages during transmission. Later on, during clinical progression, HIV spreads throughout other cellular compartments, most notably the T-cells, whose HIV-induced demise is most closely associated with the clinical progression of AIDS. Because of the close correlation between HIV-induced T-cell death and AIDS, the vast preponderance of HIV research focuses on HIV infection of (and effects on) T cells. The close correlation between macrophage infection and HIV transmission, however, underscores a need for in depth understanding of HIV infection of macrophages. In addition, host natural killer (NK) cells play a role in protecting against HIV infection. We are studying the biology of HIV in macrophages and in NK cells to understand what virus and cellular functions are critical to macrophage infection and thus to transmission and pathogenesis. One outcome from these studies may be the identification of cellular functions that may be harnessed to effectively combat HIV replication and pathogenesis. By understanding this biology, we will also understand what factors contribute to the initial rise of virus levels in the blood post infection and it's subsequent diminution. The rate of the initial rise determines how quickly after infection there is enough virus in the blood to detect by screening assays and is a factor of major continuing concern in blood safety: the longer the rise to detectability, the greater the risk an infected unit will slip through the screening tests and contaminate the blood supply. The eventual set point of virus levels can influence the sensitivity of Nucleic Acid Tests (NAT) for viral load at longer times after infection. We are also studying the sensitivity of new testing technologies and are determining the effects of sex steroid hormones on antiretroviral drug efficacy in vitro. These studies will provide knowledge critical for evaluating safety and efficacy of diagnostic tests of AIDS patients and potential blood donors for accurate detection of HIV and other blood born pathogens and will develop knowledge to help us formulate policy and advise industry on expectations for regulatory submissions.

Mission Relevance & Outcomes: These studies will provide knowledge critical for evaluating safety and efficacy of diagnostic tests of AIDS patients and potential blood donors for accurate detection of HIV and other blood born pathogens and will develop knowledge to help us formulate policy and advise industry on expectations for regulatory submissions.

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Publications

J Infect Dis 2008 Nov 1;198(9):1300-1308
In Vitro Evaluation of the Protective Role of Human Antibodies to West Nile Virus (WNV) Produced during Natural WNV Infection.
Rios M, Daniel S, Dayton AI, Wood O, Hewlett IK, Epstein JS, Caglioti S, Stramer SL

Retrovirology 2008 Sep 22;5(1):82
Beta-estradiol attenuates the anti-HIV-1 efficacy of Stavudine (D4T) in primary PBL.
Zhang M, Huang Q, Huang Y, Wood O, Yuan W, Chancey C, Daniel S, Rios M, Hewlett I, Clouse KA, Dayton AI

Retrovirology 2008 Feb 1;5:15
Hitting HIV where it hides.
Dayton AI

Retrovirology 2006 Aug 30;3:55
Beyond open access: open discourse, the next great equalizer.
Dayton AI

J Leukoc Biol 2006 Jun;79(6):1328-38
HIV regulation of the IL-7R: a viral mechanism for enhancing HIV-1 replication in human macrophages in vitro.
Zhang M, Drenkow J, Lankford CS, Frucht DM, Rabin RL, Gingeras TR, Venkateshan C, Schwartzkopff F, Clouse KA, Dayton AI

Transfusion 2006 Apr;46(4):659-667
Monocytes-macrophages are a potential target in human infection with West Nile virus through blood transfusion.
Rios M, Zhang MJ, Grinev A, Srinivasan K, Daniel S, Wood O, Hewlett IK, Dayton AI

J Virol 2005 Nov;79(21):13735-46
Human immunodeficiency virus type 1 Vpr interacts with antiapoptotic mitochondrial protein HAX-1.
Yedavalli VS, Shih HM, Chiang YP, Lu CY, Chang LY, Chen MY, Chuang CY, Dayton AI, Jeang KT, Huang LM

J Biol Chem 2004 Nov 19;279(47):49055-63
Polyarginine inhibits gp160 processing by furin and suppresses productive human immunodeficiency virus type 1 infection.
Kibler KV, Miyazato A, Yedavalli VS, Dayton AI, Jacobs BL, Dapolito G, Kim SJ, Jeang KT

Retrovirology 2004 Oct 29;1(1):35
Within you, without you: HIV-1 Rev and RNA export.
Dayton AI