Hann Low1, Lesley Cheng2, Maria-Silvana Di Yacovo3, Melissa J Churchill4, Peter Meikle5, Michael Bukrinsky6, Andrew F Hill2, Dmitri Sviridov7. 1. Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia. 2. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, 3010, Australia. 3. Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia; Institut de Resercha Biomedica Bellvitge, University of Barcelona, Gran Via de l'Hospitalet, 199, 08908 Hospitalet de Llobregat, Barcelona, Spain. 4. Macfarlane Burnett Institute for Medical Research and Public Health, 85 Commercial Rd, Melbourne, VIC, 3004, Australia. 5. Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, 3010, Australia. 6. Department of Microbiology, Immunology and Tropical Medicine, George Washington University, 2300 I St. NW, Ross Hall, Washington DC, 20037, USA. 7. Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia. Electronic address: Dmitri.Sviridov@Bakeridi.edu.au.
Abstract
BACKGROUND: HIV protein Nef plays a key role in impairing cholesterol metabolism in both HIV infected and bystander cells. The existence of a small cohort of patients infected with Nef-deficient strain of HIV presented a unique opportunity to test the effect of Nef on lipid metabolism in a clinical setting. METHODS: Here we report the results of a study comparing six patients infected with Nef-deficient strain of HIV (ΔNefHIV) with six treatment-naïve patients infected with wild-type HIV (WT HIV). Lipoprotein profile, size and functionality of high density lipoprotein (HDL) particles as well as lipidomic and microRNA profiles of patient plasma were analyzed. RESULTS: We found that patients infected with ΔNefHIV had lower proportion of subjects with plasma HDL-C levels <1 mmol/l compared to patients infected with WT HIV. Furthermore, compared to a reference group of HIV-negative subjects, there was higher abundance of smaller under-lipidated HDL particles in plasma of patients infected with WT HIV, but not in those infected with ΔNefHIV. Lipidomic analysis of plasma revealed differences in abundance of phosphatidylserine and sphingolipids between patients infected with ΔNefHIV and WT HIV. MicroRNA profiling revealed that plasma abundance of 24 miRNAs, many of those involved in regulation of lipid metabolism, was differentially regulated by WT HIV and ΔNefHIV. CONCLUSION: Our findings are consistent with HIV protein Nef playing a significant role in pathogenesis of lipid-related metabolic complications of HIV disease.
BACKGROUND: HIV protein Nef plays a key role in impairing cholesterol metabolism in both HIV infected and bystander cells. The existence of a small cohort of patients infected with Nef-deficient strain of HIV presented a unique opportunity to test the effect of Nef on lipid metabolism in a clinical setting. METHODS: Here we report the results of a study comparing six patients infected with Nef-deficient strain of HIV (ΔNefHIV) with six treatment-naïve patients infected with wild-type HIV (WT HIV). Lipoprotein profile, size and functionality of high density lipoprotein (HDL) particles as well as lipidomic and microRNA profiles of patient plasma were analyzed. RESULTS: We found that patients infected with ΔNefHIV had lower proportion of subjects with plasma HDL-C levels <1 mmol/l compared to patients infected with WT HIV. Furthermore, compared to a reference group of HIV-negative subjects, there was higher abundance of smaller under-lipidated HDL particles in plasma of patients infected with WT HIV, but not in those infected with ΔNefHIV. Lipidomic analysis of plasma revealed differences in abundance of phosphatidylserine and sphingolipids between patients infected with ΔNefHIV and WT HIV. MicroRNA profiling revealed that plasma abundance of 24 miRNAs, many of those involved in regulation of lipid metabolism, was differentially regulated by WT HIV and ΔNefHIV. CONCLUSION: Our findings are consistent with HIV protein Nef playing a significant role in pathogenesis of lipid-related metabolic complications of HIV disease.
Authors: J J Zaunders; A F Geczy; W B Dyer; L B McIntyre; M A Cooley; L J Ashton; C H Raynes-Greenow; J Learmont; D A Cooper; J S Sullivan Journal: AIDS Res Hum Retroviruses Date: 1999-11-20 Impact factor: 2.205
Authors: J C Learmont; A F Geczy; J Mills; L J Ashton; C H Raynes-Greenow; R J Garsia; W B Dyer; L McIntyre; R B Oelrichs; D I Rhodes; N J Deacon; J S Sullivan Journal: N Engl J Med Date: 1999-06-03 Impact factor: 91.245
Authors: Isabella Sudano; Lukas E Spieker; Georg Noll; Roberto Corti; Rainer Weber; Thomas F Lüscher Journal: Am Heart J Date: 2006-06 Impact factor: 4.749
Authors: Erin E Verity; Dimitra Zotos; Kim Wilson; Catherine Chatfield; Victoria A Lawson; Dominic E Dwyer; Anthony Cunningham; Jennifer Learmont; Wayne Dyer; John Sullivan; Melissa Churchill; Steven L Wesselingh; Dana Gabuzda; Paul R Gorry; Dale A McPhee Journal: J Virol Date: 2007-06-13 Impact factor: 5.103
Authors: Dmitri Sviridov; Jaye Chin-Dusting; Paul Nestel; Bronwyn Kingwell; Anh Hoang; Beata Olchawa; Jennifer Starr; Anthony Dart Journal: Transplantation Date: 2006-02-15 Impact factor: 4.939
Authors: Zahedi Mujawar; Honor Rose; Matthew P Morrow; Tatiana Pushkarsky; Larisa Dubrovsky; Nigora Mukhamedova; Ying Fu; Anthony Dart; Jan M Orenstein; Yuri V Bobryshev; Michael Bukrinsky; Dmitri Sviridov Journal: PLoS Biol Date: 2006-10 Impact factor: 8.029
Authors: Paul R Gorry; Dale A McPhee; Erin Verity; Wayne B Dyer; Steven L Wesselingh; Jennifer Learmont; John S Sullivan; Michael Roche; John J Zaunders; Dana Gabuzda; Suzanne M Crowe; John Mills; Sharon R Lewin; Bruce J Brew; Anthony L Cunningham; Melissa J Churchill Journal: Retrovirology Date: 2007-09-23 Impact factor: 4.602
Authors: Hui-Ling Yeoh; Allen C Cheng; Catherine L Cherry; Jacquelyn M Weir; Peter J Meikle; Jennifer F Hoy; Suzanne M Crowe; Clovis S Palmer Journal: EBioMedicine Date: 2017-07-18 Impact factor: 8.143
Authors: Hann Low; Anh Hoang; Tatiana Pushkarsky; Larisa Dubrovsky; Elizabeth Dewar; Maria-Silvana Di Yacovo; Nigora Mukhamedova; Lesley Cheng; Catherine Downs; Gary Simon; Maria Saumoy; Andrew F Hill; Michael L Fitzgerald; Paul Nestel; Anthony Dart; Jennifer Hoy; Michael Bukrinsky; Dmitri Sviridov Journal: PLoS One Date: 2019-04-18 Impact factor: 3.240
Authors: Jehad Alzahrani; Tabinda Hussain; David Simar; Riya Palchaudhuri; Mohamed Abdel-Mohsen; Suzanne M Crowe; George W Mbogo; Clovis S Palmer Journal: EBioMedicine Date: 2019-07-18 Impact factor: 8.143
Authors: Nigora Mukhamedova; Anh Hoang; Dragana Dragoljevic; Larisa Dubrovsky; Tatiana Pushkarsky; Hann Low; Michael Ditiatkovski; Ying Fu; Ryunosuke Ohkawa; Peter J Meikle; Anelia Horvath; Beda Brichacek; Yury I Miller; Andrew Murphy; Michael Bukrinsky; Dmitri Sviridov Journal: PLoS Pathog Date: 2019-07-25 Impact factor: 6.823
Authors: Dmitri Sviridov; Nigora Mukhamedova; Alexander A Makarov; Alexei Adzhubei; Michael Bukrinsky Journal: AIDS Date: 2020-01-01 Impact factor: 4.632