Highly active antiretroviral therapy (HAART) can consistently reduce HIV viremia to below the limit of detection of clinical assays. However, virus persists in a latent form in resting memory CD4* T cells. Low levels of free virus particles are detected in plasma of patients on HAART;this residual viremia (RV) may represent ongoing cycles of viral replication not completely blocked by HAART or release of virus from latently infected cells that are activated. Release of virus from other stable reservoirs probably contributes to RV. We have shown in our SIV HAART Model that SIV persists in the central nervous system (CNS). Eradication of the infection will likely require HAART regimens that completely block new infection of susceptible cells. In addition, it will be necessary to identify all of the stable reservoirs where non-replicating forms of the virus persist in order to eliminate all reservoirs. Novel approaches for reducing or purging latent reservoirs have the potential for adverse effects so that testing of therapeutic approaches should initially be done in an animal model that recapitulates the latent viral reservoirs in HIV. Our SIV HAART Model mirrors the virologic state of patients on HAART, establishes latent infection in resting macaque CDA^ T cells, with frequencies of latently infected cells in blood, lymphoid organs and tissues of infected macaques very similar to HIV-1-infected humans. Despite the control of HIV replication and the decreased incidence of AIDS due to HAART, studies report that mild/moderate cognitive impairment occurs in up to 50 % of those on long term HAART. Further, it is not clear whether early versus delayed initiation of HAART impacts the CNS or development of cognitive impairment, the level of viral latency, residual viremia, or preservation of innate and adaptive immune responses. Our SIV HAART model provides a rigorous model to examine these issues as well as to test novel therapy to reduce or purge latent reservoirs in the CNS and other tissues. In the proposed studies, we will carry out critical experiments to characterize all viral reservoirs, particularly in CNS, PNS and progenitor cells in bone marrow. In addition, we will use this model to explore anatomical and cellular reservoirs in which virus reactivates during antiretroviral therapy, including those that cannot be readily studied in humans. We will also test eradication strategies designed to eliminate these reservoirs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH070306-09
Application #
8387773
Study Section
Special Emphasis Panel (ZMH1-ERB-F (05))
Program Officer
Colosi, Deborah
Project Start
2003-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
9
Fiscal Year
2013
Total Cost
$1,509,354
Indirect Cost
$582,189
Name
Johns Hopkins University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Meulendyke, Kelly A; Croteau, Joshua D; Zink, M Christine (2014) HIV life cycle, innate immunity and autophagy in the central nervous system. Curr Opin HIV AIDS 9:565-71
Meulendyke, Kelly A; Ubaida-Mohien, Ceereena; Drewes, Julia L et al. (2014) Elevated brain monoamine oxidase activity in SIV- and HIV-associated neurological disease. J Infect Dis 210:904-12
Abreu, Celina M; Price, Sarah L; Shirk, Erin N et al. (2014) Dual role of novel ingenol derivatives from Euphorbia tirucalli in HIV replication: inhibition of de novo infection and activation of viral LTR. PLoS One 9:e97257
Mangus, Lisa M; Dorsey, Jamie L; Laast, Victoria A et al. (2014) Unraveling the pathogenesis of HIV peripheral neuropathy: insights from a simian immunodeficiency virus macaque model. ILAR J 54:296-303
Meulendyke, Kelly A; Queen, Suzanne E; Engle, Elizabeth L et al. (2014) Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease. J Neurovirol 20:591-602
Akay, Cagla; Cooper, Michael; Odeleye, Akinleye et al. (2014) Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neurovirol 20:39-53
Dorsey, Jamie L; Mangus, Lisa M; Oakley, Jonathan D et al. (2014) Loss of corneal sensory nerve fibers in SIV-infected macaques: an alternate approach to investigate HIV-induced PNS damage. Am J Pathol 184:1652-9
Witwer, Kenneth W; McAlexander, Melissa A; Queen, Suzanne E et al. (2013) Real-time quantitative PCR and droplet digital PCR for plant miRNAs in mammalian blood provide little evidence for general uptake of dietary miRNAs: limited evidence for general uptake of dietary plant xenomiRs. RNA Biol 10:1080-6
Russell, Julia N; Clements, Janice E; Gama, Lucio (2013) Quantitation of gene expression in formaldehyde-fixed and fluorescence-activated sorted cells. PLoS One 8:e73849
Metcalf Pate, Kelly A; Lyons, Claire E; Dorsey, Jamie L et al. (2013) Platelet activation and platelet-monocyte aggregate formation contribute to decreased platelet count during acute simian immunodeficiency virus infection in pig-tailed macaques. J Infect Dis 208:874-83

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