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HIV replication enhances production of free fatty acids, low density lipoproteins and many key proteins involved in lipid metabolism: a proteomics study.

Rasheed S, Yan JS, Lau A, Chan AS - PLoS ONE (2008)

Bottom Line: Since many genetic, epigenetic, dietary and other factors influence lipid metabolism in vivo, we have chosen to study genome-wide changes in the proteomes of a human T-cell line before and after HIV infection in order to circumvent computational problems associated with multiple variables.We conclude that HIV replication alone (i.e. without any influence of antiviral drugs, or other human genetic factors), can induce novel cellular enzymes and proteins that are significantly associated with biologically relevant processes involved in lipid synthesis, transport and metabolism (p = <0.0002-0.01).This is the first direct evidence that HIV-modulates production of proteins that are significantly involved in disrupting the normal lipid-metabolic pathways.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Viral Oncology, AIDS and Proteomics Research, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America. srasheed@usc.edu <srasheed@usc.edu>

ABSTRACT

Background: HIV-infected patients develop multiple metabolic abnormalities including insulin resistance, lipodystrophy and dyslipidemia. Although progression of these disorders has been associated with the use of various protease inhibitors and other antiretroviral drugs, HIV-infected individuals who have not received these treatments also develop lipid abnormalities albeit to a lesser extent. How HIV alters lipid metabolism in an infected cell and what molecular changes are affected through protein interaction pathways are not well-understood.

Results: Since many genetic, epigenetic, dietary and other factors influence lipid metabolism in vivo, we have chosen to study genome-wide changes in the proteomes of a human T-cell line before and after HIV infection in order to circumvent computational problems associated with multiple variables. Four separate experiments were conducted including one that compared 14 different time points over a period of >3 months. By subtractive analyses of protein profiles overtime, several hundred differentially expressed proteins were identified in HIV-infected cells by mass spectrometry and each protein was scrutinized for its biological functions by using various bioinformatics programs. Herein, we report 18 HIV-modulated proteins and their interaction pathways that enhance fatty acid synthesis, increase low density lipoproteins (triglycerides), dysregulate lipid transport, oxidize lipids, and alter cellular lipid metabolism.

Conclusions: We conclude that HIV replication alone (i.e. without any influence of antiviral drugs, or other human genetic factors), can induce novel cellular enzymes and proteins that are significantly associated with biologically relevant processes involved in lipid synthesis, transport and metabolism (p = <0.0002-0.01). Translational and clinical studies on the newly discovered proteins may now shed light on how some of these proteins may be useful for early diagnosis of individuals who might be at high risk for developing lipid-related disorders. The target proteins could then be used for future studies in the development of inhibitors for preventing lipid-metabolic anomalies. This is the first direct evidence that HIV-modulates production of proteins that are significantly involved in disrupting the normal lipid-metabolic pathways.

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Proteins modulated by HIV post-infection.Up-regulated proteins are APOB and LRP1 and downregulated proteins are ACBP, STIP1, LRP2, and PDIA3. X-axis = protein names (abbreviations according to SwissPROT). Each protein was detected in multiple gels. Y-Axis = average of normalized quantities and standard deviations for each protein detected in multiple gels. The line limits are +/− one standard deviation for the range of data points for each protein. Full protein names and Accession #s of each protein are provided in Tables 1 & 2.
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pone-0003003-g003: Proteins modulated by HIV post-infection.Up-regulated proteins are APOB and LRP1 and downregulated proteins are ACBP, STIP1, LRP2, and PDIA3. X-axis = protein names (abbreviations according to SwissPROT). Each protein was detected in multiple gels. Y-Axis = average of normalized quantities and standard deviations for each protein detected in multiple gels. The line limits are +/− one standard deviation for the range of data points for each protein. Full protein names and Accession #s of each protein are provided in Tables 1 & 2.

Mentions: Each circle represents proteins associated with the respective function/s. Proteins in red were downregulated post-HIV infection (Figure 3). All other proteins were either expressed exclusively in HIV infected cells (Figure 2) or upregulated after virus infection (Figure 3). Full names, abbreviations and accession numbers of each protein are listed in Tables 1&2.


HIV replication enhances production of free fatty acids, low density lipoproteins and many key proteins involved in lipid metabolism: a proteomics study.

Rasheed S, Yan JS, Lau A, Chan AS - PLoS ONE (2008)

Proteins modulated by HIV post-infection.Up-regulated proteins are APOB and LRP1 and downregulated proteins are ACBP, STIP1, LRP2, and PDIA3. X-axis = protein names (abbreviations according to SwissPROT). Each protein was detected in multiple gels. Y-Axis = average of normalized quantities and standard deviations for each protein detected in multiple gels. The line limits are +/− one standard deviation for the range of data points for each protein. Full protein names and Accession #s of each protein are provided in Tables 1 & 2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2500163&req=5

pone-0003003-g003: Proteins modulated by HIV post-infection.Up-regulated proteins are APOB and LRP1 and downregulated proteins are ACBP, STIP1, LRP2, and PDIA3. X-axis = protein names (abbreviations according to SwissPROT). Each protein was detected in multiple gels. Y-Axis = average of normalized quantities and standard deviations for each protein detected in multiple gels. The line limits are +/− one standard deviation for the range of data points for each protein. Full protein names and Accession #s of each protein are provided in Tables 1 & 2.
Mentions: Each circle represents proteins associated with the respective function/s. Proteins in red were downregulated post-HIV infection (Figure 3). All other proteins were either expressed exclusively in HIV infected cells (Figure 2) or upregulated after virus infection (Figure 3). Full names, abbreviations and accession numbers of each protein are listed in Tables 1&2.

Bottom Line: Since many genetic, epigenetic, dietary and other factors influence lipid metabolism in vivo, we have chosen to study genome-wide changes in the proteomes of a human T-cell line before and after HIV infection in order to circumvent computational problems associated with multiple variables.We conclude that HIV replication alone (i.e. without any influence of antiviral drugs, or other human genetic factors), can induce novel cellular enzymes and proteins that are significantly associated with biologically relevant processes involved in lipid synthesis, transport and metabolism (p = <0.0002-0.01).This is the first direct evidence that HIV-modulates production of proteins that are significantly involved in disrupting the normal lipid-metabolic pathways.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Viral Oncology, AIDS and Proteomics Research, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America. srasheed@usc.edu <srasheed@usc.edu>

ABSTRACT

Background: HIV-infected patients develop multiple metabolic abnormalities including insulin resistance, lipodystrophy and dyslipidemia. Although progression of these disorders has been associated with the use of various protease inhibitors and other antiretroviral drugs, HIV-infected individuals who have not received these treatments also develop lipid abnormalities albeit to a lesser extent. How HIV alters lipid metabolism in an infected cell and what molecular changes are affected through protein interaction pathways are not well-understood.

Results: Since many genetic, epigenetic, dietary and other factors influence lipid metabolism in vivo, we have chosen to study genome-wide changes in the proteomes of a human T-cell line before and after HIV infection in order to circumvent computational problems associated with multiple variables. Four separate experiments were conducted including one that compared 14 different time points over a period of >3 months. By subtractive analyses of protein profiles overtime, several hundred differentially expressed proteins were identified in HIV-infected cells by mass spectrometry and each protein was scrutinized for its biological functions by using various bioinformatics programs. Herein, we report 18 HIV-modulated proteins and their interaction pathways that enhance fatty acid synthesis, increase low density lipoproteins (triglycerides), dysregulate lipid transport, oxidize lipids, and alter cellular lipid metabolism.

Conclusions: We conclude that HIV replication alone (i.e. without any influence of antiviral drugs, or other human genetic factors), can induce novel cellular enzymes and proteins that are significantly associated with biologically relevant processes involved in lipid synthesis, transport and metabolism (p = <0.0002-0.01). Translational and clinical studies on the newly discovered proteins may now shed light on how some of these proteins may be useful for early diagnosis of individuals who might be at high risk for developing lipid-related disorders. The target proteins could then be used for future studies in the development of inhibitors for preventing lipid-metabolic anomalies. This is the first direct evidence that HIV-modulates production of proteins that are significantly involved in disrupting the normal lipid-metabolic pathways.

Show MeSH
Related in: MedlinePlus