The current need for routine measurement CD4+ cell counts of HIV-infected individual's is immense. Currently, the cost of CD4+ counting is a major issue (especially) in resource-poor environments, where the infection rates are highest. Cost of obtaining an accurate CD4+ count is not the only barrier to routine CD4+ monitoring in resource poor settings. Personnel need to be trained to use relatively complex equipment (cytometers, cell sorters, plate readers) and such equipment needs a controlled environment (machine maintenance in high humidity and non-standard temperature environments is problematic). This proposal is aimed at development of a rapid CD4+ count assay that addresses these concerns. The assay will combine current point-of-care (POC) methodologies ("lateral flow") with a proprietary and inexpensive means of creating anti-CD4+ "avidity" capture reagents. This assay will be capable of being performed in resource-poor environments, requires no expensive equipment, is robust with respect to environmental variables, and can be executed and interpreted by unskilled personnel. We suggest that an accurate CD4+ counting assay with these attributes could be manufactured that would cost the end-user less than US $1.00 per test. This assay cost estimate is partially based on two assumptions: 1) all reagents for the assay will be developed in-house to circumvent reagent license fees built in to pricing, and 2) use of a combination of public domain procedures for assay construction (e.g. ink-jet deposition of reagents and available nitrocellulose assay membranes) to avoid the necessity for technology in-licensing. From a technical perspective we need to demonstrate that our "avidity" anti-CD4+ capture reagent displays a dissociation constant for CD4+ expressing T cells approaching zero and is thereby capable of CD4+ cell capture. The total HIV positive patient population worldwide is in excess 40 million. The vast majority of individuals living with this disease are in resource poor environments where conventional CD4 enumeration is both too expensive to perform and technically challenging, due to a paucity of trained personnel. Treatment efforts currently underway, such as the World Health Organizations "3 by 5" Initiative, will be providing access to HAART (e.g. highly active anti-retroviral therapy) to millions of patients in these areas of the world over the next several years. It is in such resource poor environments where CD4 counts are arguably the most important to perform. Current costs and assay complexities limit this. An accurate CD4 count can be employed: to facilitate AIDS surveillance; to monitor the rate of progression to AIDS, to define when therapy is required to prevent opportunistic infections, to place drug-naive patients into cohorts prior to therapy, and to monitor the effects of anti-retroviral therapy. It is currently recommended that a CD4 assay is performed on every HIV infected individual every 3-6 months and more frequently depending on circumstance. The assay described here is intended to answer this need, both from the standpoint of addressing the technical difficulties and the cost requirements. It is currently believed that lack of such an assay leads to unneeded death due to opportunistic infections. The type of rapid assay being developed under this phase I proposal, if successful, could have a dramatic impact on the ability to detect (and thereby enable appropriate treatment) opportunistic infections in the developing world for HIV infected individuals on anti-retroviral therapy.
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