Abstract
The signature for human immunodeficiency virus type 1 (HIV-1) neurovirulence remains a subject of intense debate. Macrophage viral tropism is one prerequisite but others, including virus-induced alterations in innate and adaptive immunity, remain under investigation. HIV-1–infected mononuclear phagocytes (MPs; perivascular macrophages and microglia) secrete toxins that affect neurons. The authors hypothesize that neurovirulent HIV-1 variants affect the MP proteome by inducing a signature of neurotoxic proteins and thus affect cognitive function. To test this hypothesis, HIV-1 isolates obtained from peripheral blood of women with normal cognition (NC) were compared to isolates obtained from women with cognitive impairment (CI) and to the laboratory adapted SF162, a spinal fluid R5 isolate from a patient with HIV-1–associated dementia. HIV-1 isolates were used to infect monocyte-derived macrophages (MDMs) and infection monitored by secreted HIV-1 p24 by enzyme-linked immunosorbent assay (ELISA). Cell lysates of uninfected and HIV-1–infected MDMs at 14 days post infection were fractionated by cationic exchange chromatography and analyzed by surface enhanced laser desorption ionization time of flight (SELDI-TOF) using generalized estimating equations statistics. Proteins were separated by one-dimensional sodium dodecyl sulfate–polyacrylamide gel electrophoresis (1D SDS-PAGE) and identified by tandem mass spectrometry. Levels of viral replication were similar amongst the HIV-1 isolates, although higher levels were obtained from one viral strain obtained from a patient with CI. Significant differences were found in protein profiles between virus-infected MDMs with NC, CI, and SF162 isolates (adjusted P value after multiple testing corrections, or q value <.10). The authors identified 6 unique proteins in NC, 7 in SF162, and 20 in CI. Three proteins were common to SF162 and CI strains. The MDM proteins linked to infection with CI strains were related to apoptosis, chemotaxis, inflammation, and redox metabolism. These findings support the hypothesis that the macrophage proteome differ when infected with viral isolates of women with and without CI.
Acknowledgements
The authors would like to thank their patients for supporting this research. Tania Ginebra and Tania de la Torre supported patient outreach, and Dr. Rosa Hechavarría performed neuropsychological testing. The authors thank Drs. Carmen Zorrilla and Hermes García (their clinic directors) for referring patients. The RCMI–Clinical Research Center is thanked for providing staff and supplies for laboratory sample collections. Thanks to Claribel Luciano for support on the gel processing. The authors thank and acknowledge Richard Skolasky for statistical support. They thank Dr. Joseph Bonanno for providing them with the AIF-L antibody. They acknowledge Drs. Howard Gendelman for his critical review of the manuscript, and Edmundo Kraiselburd for his continuous support of this work as part of the Puerto Rico Specialized Neuroscience Program in NeuroAIDS, and Idalí Martínez for her helpful suggestions. This work was supported by U54NS430, MBRS-SCORE-SO6GMO822, RCMI-CRC P20RR11126, RCMI-12-RR03051, and MBRS-RISE GM061838. The NIH AIDS Research and Reference Reagent Program is acknowledged for providing the HIV-1 SF162 viral isolate.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.