About 30% of AIDS patients suffer from HIV-associated dementia (HAD). Whether neurotropic or neurovirulent HIV-1 variants are involved in HAD is not known. In the current grant period we described HIV-1 R5 envelopes from brain tissue of individuals with neuropathology that are highly fusogenic and tropic for macrophages. These envelopes exploit low amounts of CD4 and CCR5 for infection and may confer a broader tropism for T-cells as well as macrophages. Such envelopes may represent neurotropic or neurovirulent variants. Our hypothesis is that highly macrophage-tropic HIV-1 variants replicating in brain tissue are associated with neurotropism, neurovirulence and increased viral fitness. The brain may also act as a sanctuary site where persistent replication of highly macrophage-tropic viruses during HAART results in the evolution of drug resistant variants. If highly macrophage-tropic variants have increased fitness for CD4+ T-cells, they may then recolonize immune tissue, contributing to CD4+ T-cell depletion and disseminating drug resistance mutations. Here, we propose four aims that will to investigate whether highly macrophage-tropic envelopes are (1) limited to individuals with neuropathology, (2) present at different sites inside and outside the brain and (3) associated with drug resistance mutations in brain tissue of HAART treated patients. We will also evaluate whether highly macrophage-tropic brain envelopes confer increased fitness for CD4+ T-cells and thus carry the potential to re-colonize immune tissue. This application fits well with PA-04-154, which particularly requested applications proposing to study """"""""molecular diversity (of HIV) and functional consequences"""""""" as well as """"""""emergence of drug resistance in CMS"""""""". The proposed experiments will greatly extend our knowledge of highly macrophage-tropic variants in brain and other tissues, as well as providing important insights into their neurotropism and their association with neuropathogenesis and drug resistance. Results obtained may lead to the design of novel strategies to treat or prevent HIV dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH064408-08
Application #
7646240
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
2001-09-15
Project End
2012-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
8
Fiscal Year
2009
Total Cost
$365,625
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Peters, Paul J; Richards, Kathryn; Clapham, Paul (2013) Human immunodeficiency viruses: propagation, quantification, and storage. Curr Protoc Microbiol Chapter 15:Unit 15J.1
Gonzalez-Perez, Maria Paz; O'Connell, Olivia; Lin, Rongheng et al. (2012) Independent evolution of macrophage-tropism and increased charge between HIV-1 R5 envelopes present in brain and immune tissue. Retrovirology 9:20
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Musich, Thomas; Peters, Paul J; Duenas-Decamp, Maria José et al. (2011) A conserved determinant in the V1 loop of HIV-1 modulates the V3 loop to prime low CD4 use and macrophage infection. J Virol 85:2397-405
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Vaine, Michael; Duenas-Decamp, Maria; Peters, Paul et al. (2011) Two closely related Env antigens from the same patient elicited different spectra of neutralizing antibodies against heterologous HIV-1 isolates. J Virol 85:4927-36
Richards, Kathryn H; Aasa-Chapman, Marlén Mi; McKnight, Aine et al. (2010) Modulation of HIV-1 macrophage-tropism among R5 envelopes occurs before detection of neutralizing antibodies. Retrovirology 7:48
Zhang, Sharon; Alexander, Louis; Wang, Tao et al. (2010) Protection against HIV-envelope-induced neuronal cell destruction by HIV attachment inhibitors. Arch Virol 155:777-81

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