The HIV-1/AIDS epidemic continues to spread at an alarming rate world-wide, despite considerable efforts to control it. Central nervous system (CNS) infection by HIV-1 is common and occurs early after systemic infection. Sequence analysis has indicated that the virus may evolve independently in the CNS, probably resulting in adaptation to replication in microglia and macrophages within the brain. However, the potential mechanisms and phenotypic consequences of such adaptation are not well understood. HIV-1 enters cells through the sequential interactions of the viral envelope surface glycoprotein subunit gp120 with the main host cell receptor CD4, and a co-receptor (mainly CCR5 and/or CXCR4). It was previously reported that a primary, peripheral HIV-1 isolate adapted in vitro to replicate in microglial cells acquired increased fusion capacity concurrently with lower CD4 dependence and altered envelope conformation and sensitivity to antibodies and entry inhibitors. Due to the low levels of CD4 in microglial cells and macrophages, and the relative immunological isolation of the CNS, it is hypothesized that viruses containing envelope glycoproteins with similar phenotypes (low CD4 dependence, high fusogenicity and altered sensitivity to entry inhibitors) will arise in vivo as a consequence of viral adaptation to replication in microglial cells and brain macrophages. Preliminary studies have shown that envelope genes amplified from brain tissue feature the above phenotype (including significantly increased sensitivity to a novel allosteric inhibitor of gp120, HNG-105), while those from peripheral tissues do not. However, it is not clear whether viral isolates recovered from brain tissue have this phenotype, as well as the potential role of these phenotypic features in neurotoxicity and neurovirulence. Therefore, the goals of this application are: (i) to determine the phenotypes (CD4 dependence, fusogenicity, cell tropism) of viral isolates recovered from brain and spleen, and of authentic envelopes generated by single genome amplification, from HIV patients with various degrees of neurocognitive impairment;(ii) to define the relationship between these phenotypes and altered sensitivity to two selected, prototypic entry inhibitors (BMS- 378806 and HNG-105) and to identify viral determinants for the phenotypic differences;and (iii) to determine neurotoxicity of viral isolates and envelopes and to define the potential role of these entry inhibitors in decreasing neurotoxicity. Altogether, these studies will provide a functional analysis of the in vivo evolution of HIV-1 in the CNS, complementing previous genetic studies, and will help define a critical correlation between low CD4 dependence, fusogenicity and macrophage tropism, with in vitro neurotoxicity and neurovirulence in vivo, and with an altered sensitivity to specific entry inhibitors, which will potentially allow more targeted approaches for the particular inhibition of replication o viruses present in the CNS of HIV-1-infected patients.

Public Health Relevance

ese studies will extend our understanding of the mechanisms involved in the neurotropism and neurovirulence of HIV-1. They can also potentially lead to more appropriate approaches for the specific inhibition of infection by viruses that replicate in the brain of HIV-1-infected patients and, subsequently, result in a reduction of HIV-1-associated neurological complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS065727-01A1
Application #
7755476
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
1
Fiscal Year
2009
Total Cost
$397,304
Indirect Cost
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chen, Natalie C; Partridge, Andrea T; Sell, Christian et al. (2017) Fate of microglia during HIV-1 infection: From activation to senescence? Glia 65:431-446
Swaminathan, Gokul; Navas-Martín, Sonia; Martín-García, Julio (2014) Interplay between microRNAs, Toll-like receptors, and HIV-1: potential implications in HIV-1 replication and chronic immune activation. Discov Med 18:15-27
Swaminathan, Gokul; Navas-Martín, Sonia; Martín-García, Julio (2014) MicroRNAs and HIV-1 infection: antiviral activities and beyond. J Mol Biol 426:1178-97
Swaminathan, Gokul; Pascual, Daniel; Rival, Germaine et al. (2014) Hepatitis C virus core protein enhances HIV-1 replication in human macrophages through TLR2, JNK, and MEK1/2-dependent upregulation of TNF-? and IL-6. FEBS Lett 588:3501-10
Zentner, Isaac; Sierra, Luz-Jeannette; Maciunas, Lina et al. (2013) Discovery of a small-molecule antiviral targeting the HIV-1 matrix protein. Bioorg Med Chem Lett 23:1132-5
Zentner, Isaac; Sierra, Luz-Jeannette; Fraser, Ayesha K et al. (2013) Identification of a small-molecule inhibitor of HIV-1 assembly that targets the phosphatidylinositol (4,5)-bisphosphate binding site of the HIV-1 matrix protein. ChemMedChem 8:426-32
Swaminathan, Gokul; Martin-Garcia, Julio; Navas-Martin, Sonia (2013) RNA viruses and microRNAs: challenging discoveries for the 21st century. Physiol Genomics 45:1035-48
Mazaleuskaya, Liudmila; Veltrop, Rogier; Ikpeze, Nneka et al. (2012) Protective role of Toll-like Receptor 3-induced type I interferon in murine coronavirus infection of macrophages. Viruses 4:901-23
Gupta, Archana; Swaminathan, Gokul; Martin-Garcia, Julio et al. (2012) MicroRNAs, hepatitis C virus, and HCV/HIV-1 co-infection: new insights in pathogenesis and therapy. Viruses 4:2485-513
Kortagere, Sandhya; Madani, Navid; Mankowski, Marie K et al. (2012) Inhibiting early-stage events in HIV-1 replication by small-molecule targeting of the HIV-1 capsid. J Virol 86:8472-81

Showing the most recent 10 out of 13 publications