HIV-associated neurocognitive disorders (HAND) have persisted at a high prevalence in the era of combined antiretroviral therapy (ART) in spite of increased HIV suppression and immune reconstitution. The majority of HAND studies have been performed in developed countries on patients infected with HIV-1 subtype B. However, two-thirds of the 33.4 million people living with HIV/AIDS are in sub-Saharan Africa (SSA) and are infected with non-B HIV subtypes, including recombinant viruses. The HIV epidemic in Cameroon and nearby areas of West and Central Africa is characterized by both a broad diversity of HIV-1 clades and the emergence of a circulating recombinant form that combines clades A and G (CRF02_AG). The HIV-1 CRF02_AG strain constitutes the predominant (52 to 84%) viral genotype in Central and West Africa, a region that includes 26 countries with over 456 million inhabitants. Furthermore, this mosaic virus is spreading to other parts of the world and is now present in Europe, Asia, and America, but nothing is known of its CNS effects and neuropathogenesis. Considering the AIDS pandemic and global geographic distribution of HIV subtypes, it is possible that viral genetic diversity influences its spread and neuropathogenesis;however, the effects of HIV genotypes and recombinant HIV strains on viral transmission, infectivity, and neuroAIDS are not known. Our proposal fills this important knowledge gap. Our preliminary studies showed increased in vitro replication capacity of HIV-1 CRF02_AG in human macrophages and peripheral blood mononuclear cells, compared to its parental subtypes A and G and Western HIV-1 subtype B. Because the primary role of Tat is to transactivate viral gene promoter and induce transcription, it is likely that Tat play a major role in this increased replication of CRF02_AG isolates. We further show that HIV-1 CRF02_AG Tat amino acid (AA) sequences form a monophyletic cluster and are different from Tat sequences of other HIV-1 subtypes. Thus, we hypothesize that CRF02_AG has increased fitness compared to subtype B virus, and this increases its cytopathicity, neuroinflammation and blood-brain barrier (BBB) injury. We further hypothesize that HIV genotypes influence the host's susceptibility to HAND and disease progression. We propose to test these hypotheses in three specific aims.
Aim 1 : Use a battery of neuropsychological (NP) tests in HIV- and HIV+ Cameroonians to develop norms.
Aim 2 : Investigate the effects of HIV genotypes on viral fitness and the host's susceptibility to HAND.
Aim 3 : To test our hypothesis that differences between CRF02_AG and subtype B Tat AA influence Tat transactivation and toxicity. These novel studies are significant and will help determine the effect of HIV genetic variation on viral fitness, Tat transactivation and neuropathogenesis. Data generated will provide insights into the link between HIV genetics, epidemiology, and HAND.

Public Health Relevance

Over 70% of the 33.4 million people currently living with HIV/AIDS are in sub-Saharan Africa and are infected with non-B HIV subtypes, including the recombinant HIV-1 CRF02_AG, which is spreading to other parts of the world, including America and Europe. This proposal investigates whether infection with HIV strains that have particular genetic characteristics, such as recombinant CRF02_AG, increases viral replication, cellular toxicity, and neurocognitive impairment. These novel studies will help unravel the role genetic variation plays in infection, transmission, and viral neuropathogenesis, and is relevant in tracking HIV/AIDS epidemiology and designing HAND therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH094160-01A1
Application #
8257050
Study Section
Special Emphasis Panel (ZRG1-BDCN-Z (50))
Program Officer
Joseph, Jeymohan
Project Start
2012-02-14
Project End
2016-12-31
Budget Start
2012-02-14
Budget End
2012-12-31
Support Year
1
Fiscal Year
2012
Total Cost
$696,560
Indirect Cost
$191,172
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Woollard, Shawna M; Li, Hong; Singh, Sangya et al. (2014) HIV-1 induces cytoskeletal alterations and Rac1 activation during monocyte-blood-brain barrier interactions: modulatory role of CCR5. Retrovirology 11:20
Woollard, Shawna M; Bhargavan, Biju; Yu, Fang et al. (2014) Differential effects of Tat proteins derived from HIV-1 subtypes B and recombinant CRF02_AG on human brain microvascular endothelial cells: implications for blood-brain barrier dysfunction. J Cereb Blood Flow Metab 34:1047-59
Joseph, Jeymohan; Achim, Cristian L; Boivin, Michael J et al. (2013) Global NeuroAIDS roundtable. J Neurovirol 19:1-9
Teto, Georges; Kanmogne, Georgette D; Torimiro, Judith N et al. (2013) Lipid peroxidation and total cholesterol in HAART-naive patients infected with circulating recombinant forms of human immunodeficiency virus type-1 in Cameroon. PLoS One 8:e65126