Table 1.

Pathogenesis of HIV/HCV-associated diseases and complications

Affected organ/system	Complication	Proposed mechanism of action	References
Immune	↑ HIV disease progression	↑ CD4 and CD8 T-cell activation, leading to ↑ immune dysfunction and cytokine production, enhanced HIV and HCV production, and ↓ T-cell counts	[24••, 25, 26]
		HCV-induced ↑ CD4 T-cell apoptosis, leading to severe immunodeficiency	[27]
		HCV-induced ↓ CD4 recovery post-HAART	[28]
	↑Cryoglobulinemia	↑ Cryoglobulin production by activated B cells	[53]
	↓ CRP production in liver	Unknown	[54]
Liver	↑ Steatosis	HIV-related mitochondrial translocation (↑LPS)-induced immune activation	[16, 18, 26, 42]
	↑ Fibrosis	↑ Activation of CD4 and CD8 T cells	[26]
	↑ Cirrhosis	↑ Levels of cytokines (eg, IL-4, IL-5, IL-13, TGF-β, IFN-γ and TNF-α ) and chemokines (eg, IP-10 and IL-8)	[17, 18]
	↑ ESLD	HIV-induced ↓ HCV-specific CD4 and CD8 T-cell responses	[16, 17]
	↑ HCC	↑ Levels of cytotoxic CD8 T cells in liver	[39, 40]
		↑ Activation of HSC	[18, 19, 43]
		↑ Apoptosis of hepatocytes and HSC, mediated by TRAIL	[16–19, 44]
		↑ Collagen synthesis by HIV-infected HSC	[43]
		↑ HSC production of collagen by HIV-infected Kupffer cells	[16]
		Insulin resistance–associated hyperinsulinemia and hyperglycemia stimulate HSC to ↑ connective tissue growth factor and extracellular matrix	[45, 46]
Liver/metabolic	Diabetes mellitus	Unknown	[68]
	Insulin resistance	Unknown	[46]
Cardiovascular		HIV- and HCV-associated chronic inflammation leads to endothelial dysfunction, causing ↑ sCAMS	[59, 60]
Hematologic	Thrombocytopenia	Sequestration of platelets in cirrhosis and portal hypertension	[55]
		↓ Production of thrombopoietin in advanced liver disease	[55]
Kidney	Proteinuria	Unknown	[56]
	Acute interstitial nephritis	Unknown	[58]
	Acute tubular necrosis
	MPGN	Stimulation of B cells to ↑cryoglobulin production and deposits in renal vessels	[53, 56–58]
	Acute renal failure
	Chronic kidney disease
Gastrointestinal	Mitochondrial translocation	HIV-inducted ↑gut permeability and depletion of CD4 cells from gut-associated lymphoid tissue	[16]
Central/peripheral nervous	Neurocognitive syndromes	HIV and HCV replication in brain	[61]
	Peripheral neuropathy syndromes	HCV core protein activates glia and ↑HIV-associated neurotoxicity	[62]
		LPS-induced monocyte activation and ↑HIV-associated dementia	[65]
Bone	Osteoporosis	↓ Bone mass in chronic liver disease	[70]
	Osteonecrosis

CRP C-reactive protein; ESLD end-stage liver disease; HCC hepatocellular carcinoma; HSC hepatic stellate cells; LEE liver enzyme elevations; LPS lipopolysaccharides; MPGN membranoproliferative glomerulonephritis; sCAMS, soluble cellular adhesion molecules; TRAIL, tumor necrosis factor–related apoptosis-inducing ligand