2006 - 2007 Publications > Molecular Genetics of Host Response to HIV and HCV

Molecular Genetics of Host Response to HIV and HCV

Chan et al (2007) examined changes in expression levels of approximately 3200 proteins in the CD4(+) CEMx174 cell line after infection with human immunodeficiency virus type 1 (HIV-1). At peak virus production (36h post-infection), 687 (21%) proteins were found to have altered levels of expression. Changes in protein levels were selectively associated with certain pathways such as ubiquitination, nucleocytoplasmic transport, cell cycle progression, and the citrate cycle. In addition, altered expression levels were seen in proteins that are known to interact with HIV-1 viral proteins.  Virol. 2007 Jul;81(14):7571-83.

Li et al. (2007) compared the response of pigtail macaque (Macaca nemestrina) peripheral blood mononuclear cells (mPBMCs) to infection with either human immunodeficiency virus type 1 (HIV-1) or simian immunodeficiency virus (SIV). HIV-1 displayed a markedly lower rate of replication within mPBMCs than that of SIV. In addition, microarray gene expression profiling demonstrated differential gene expression patterns in HIV-1-infected mPBMCs as compared to SIV-infected cells. Specifically, genes involving antigen presentation, T cell receptor, ERK/MAPK signaling, Wnt/beta-catenin signaling, and natural killer cell signaling pathways showed altered regulation patterns between HIV-1 and SIV infected cells. Furthermore, although HIV-1 replicated at lower levels than SIV, the former activated a stronger regulation of immune response genes early after infection as compared to SIV. Virology. 2007 Sep 15;366(1):137-49.

Opioid abuse worsens human immunodeficiency virus (HIV)-induced pathogenesis via the direct effects of opioid compounds in immature glia or glial precursors. Buch et al. (2007) evaluated the direct toxicity of HIV and opioids, both separately and in combination, in spinal cord-derived glial-restricted precursors (GRPs). Exposure to both Tat and morphine alone or in combination with each other resulted in considerable increases in GRP cell death at 96 hours, but not at 24 hours. In addition, morphine or Tat caused increased caspase-3 activity; however, this did not correlate with increased GRP cell death.  Extended exposure of GRPs to Tat or morphine in vitro is inherently toxic and may be associated with a particular stage of GRP maturation and development. Neuroscience. 2007 Jun 8;146(4):1546-54.

Exposure to human immunodeficiency virus (HIV) Tat protein induces toxicity in striatal neurons by increased activation of multiple parallel cell death pathways. Zhao et al. (2007) demonstrated complete protection of striatal neurons from Tat-induced toxicity via RNAi suppression of the phosphatase and tensin homolog (PTEN) gene. PTEN is a negative regulator of Akt/Protein Kinase B, which, in turn, mediates the activity of several downstream pathways which promote cell proliferation and survival. The authors identify Akt regulation as a potential therapeutic target for reducing Tat-initiated neurotoxicity in HIV encephalitis. J Neurovirol. 2007 Apr;13(2):97-106.

Hadas et al. (2007) evaluated the efficacy of the anti-retroviral drugs dideoxycytidine (ddC) and avacavir via a chimeric HIV-1 infection model in immunocompetent mice. The chimeric virus, EcoHIV, establishes spreading infection in conventional mice, in which viral DNA is measureable within 3 to 12 weeks after infection. Mice that were infected with EcoHIV and subsequently administered ddC displayed markedly lower viral DNA and RNA levels in the spleen. In addition, administration of abacavir resulted in a near complete inhibition of viral DNA synthesis in both the spleen and macrophages. EcoHIV infection of mice may provide a suitable model for testing the efficacy of antiviral therapeutics in vivo. AIDS. 2007 May 11;21(8):905-9

Brumme et al. (2007) employed a viral lineage-corrected analytical model to examine HLA class-I related sequence imprinting in a number of HIV-1 proteins, including viral protease, reverse transcriptase, Vpr and Nef. A number of cytotoxic T lymphocyte epitope escape maps were organized and characterized according to 478 unique HLA associated polymorphisms. Nef demonstrated the greatest support for HLA class-I mediated selection in comparison with other genes investigated. The results indicate an inverse correlation between HLA-associated polymorphisms and stage of HIV infection based on CD4+ T cell count. The above provides evidence for the link between viral escape of CTL immune response, as influenced by HLA-associated polymorphisms, and HIV disease stage. PLoS Pathog. 2007 Jul;3(7):e94

Cytotoxic T lymphocyte homing to HIV infected lymphoid tissue is presumed to be disrupted in advanced stage HIV infection. Brainard et al. (2007) report differential expression of the chemokine receptor CXCR3 in CD8+ T cells of individuals with stable, chronic infection as compared to those with advanced stage infection. In persons with chronic infection, had a larger number of CXCR3+ CD8 T cells in blood and lymph nodes in relation to individuals with advanced stage disease. These results suggest that this receptor may play a significant role in CTL homing to infected lymphoid tissue. J Virol. 2007 Aug;81(16):8439-50.

Sabado et al (2007) examined the antigen presenting activity of dendritic cells in response to aldrithiol-2-treated and infectious HIV-1. Results demonstrate that HIV-associated antigen presentation was independent of DC-SIGN, DEC-205, macrophage mannose receptor, and C-type lectins expressed.. In addition, antigen presentation in MHC class I dendritic cells was dependent on CD4/coreceptor associated viral fusion at the cell surface, whereas MHC class II presentation was associated with active endocytosis and subsequent degradation of the virus in acidified endosomes.  Eur J Immunol. 2007 Jul;37(7):1752-63.

Crawford et al (2007) characterized an escape mutation associated with the HLA-B*5703-restricted epitope in chronic HIV-1 infection. The mutation was found to decrease viral replication rates. J Virol. 2007 Aug;81(15):8346-51.

Streeck et al (2007) compared HIV-1 specific T cell response between subjects who possess the allele HLA-B27 or –B57 in a cohort of 290 persons. A 32 amino acid (240 to 272) region within the HIV-1 p24 Gag protein serves as a specific target for initial CD8(+) T cells in individuals expressing the above protective alleles; however, within persons expressing alleles associated with faster disease progression or non-B57/B27 alleles, this sequence was infrequently recognized. These results provide a basis for the development of vaccines that stimulate increased recognition of this highly conserved region by CD8(+) T cell responses within individuals expressing non-protective HLA alleles. J Virol. 2007 Jul;81(14):7725-31.

Timm et al (2007) describe the full genomes of several HCV genotype 4, including seven type 4a genomes and one type 4d.  Most notably, all genotype 4 sequences possessed a unique deletion of four amino acids within the ISDR region of the viral protein NS5A. Such a mutation has been associated with sensitivity to interferon treatment, and the above results may provide a rationale for the design of vaccines and novel therapies. J Viral Hepat. 2007 May;14(5):330-7.

Addo et al. (2007) compared HIV-1 specific CD8 (+) T cell responses in individuals with progressive and non-progressive HIV-1 infection. Individuals with stable infections possessed a greater number of terminally differentiated CD45RA-/CCR7- HIV-1 specific CD8(+) T cells. However, the strength and extent of HIV-1 specific CD8(+) T cell responses did not appreciably differ between the two patient populations. These results demonstrate that the maturation of epitope-specific responses is quite variable within and in between populations of individuals with stable or progressing HIV-1 infection. PLoS ONE. 2007 Mar 28;2(3):e321

Yu et al (2007) investigated HIV-1 specific CD8 (+) T cell responses associated with the HLA class I alleles B*5701 and B57*03, both of which are linked to a dominant response to the HIV-1 Gag epitope KF11. Upon presentation by HLAB*5701, KF11 initiates a highly conserved T cell repertoire that is not associated with viral escape mutations. However, HLA B*57-03, triggers a more variable response that is unable to recognize KF11 escape variants. J Virol. 2007 Feb;81(4):1619-31.

Copolymer-1 (COP-1) induces neuroprotection in various neurodegenerative disorders via adaptive immune regulated control of microglial inflammatory activity. Gorantha et al developed an animal model which reproduces HIV-1 encephalitis in rodents that express innate and adaptive immune responses. Immunization with COP-1 resulted in decreased astrogliosis and microgliosis with a concomitant reduction in neurodegeneration. J Immunol. 2007 Oct 1;179(7):4345-56.

Li et al (2007) examined the relative capacity of HIV-1 to bind and infect human fetal astrocytes (HFA). HIV-1 tagged with green fluorescence protein-Vpr fusion proteins (GFP-Vpr) was used to identify virus binding, while HIV-1 expressing Rev and Nef served to measure productive infection. HFA universally bound HIV-GFP independent of CCR5 or CXCR4 expression; however, despite the high binding efficiency, only 1% of cells displayed productive infection. Binding of HIV-1 to HFA resulted in increased synthesis of IL-6 and IL-8. These results suggest that HFA limit HIV-1 entry and may play a role in HIV-1 neuropathogenesis. BMC Neurosci. 2007 May 12;8:31

Sulkowski et al (2007) examined the incidence of fibrosis progression in a cohort of 184 hepatitis C (HCV)/HIV co-infected adults in order to investigate whether HCV or HIV treatment reduces the risk of progression and to evaluate the efficacy of liver biopsy in predicting future disease. Approximately 77% of patients displayed little to no fibrosis upon initial biopsy and, of those, 24% progressed to severe fibrosis. HIV disease stage and treatment measures did not appreciably differ between progressors and non-progressors. In addition, HCV treatment did not significantly influence fibrosis progression. AIDS. 2007 Oct 18;21(16):2209-16.

Smith et al, have identified a gene expression profile from liver biopsies that predicts rapid progression to cirrhosis in liver transplant patients.  Gastroenterology. 2006 Jan;130(1):179-87 

Walters et al (2006) compared the gene expression profiles of hepatocytes obtained from liver biopsies of patients infected with HCV or HCV/HIV.  The gene expression patterns did not differ significantly between HCV and HCV/HIV co-infected individuals.  A subset of patients show enhanced gene expression profile that is associated with FAS-apoptosis pathway and increased expression of lymphocyte adhesion molecules and lymphocyte-specific genes.  A partially impaired interferon type I and II response is also observed in the EGE positive patients that is required to prevent fibrogenic responses.   The EGE positive gene expression profile is very similar to the profile of transplant patients that develop fibrosis within a year of receiving a liver transplant.  Virology. 2006 Jul 5;350(2):453-64. 

Lederer et al (2006) identified distinct gene expression profiles between HCV and ethanol induced liver cirrhosis.  HCV induce more changes in gene expression than ethanol.  The changes in gene expression produced by HCV are characterized by innate immune reponses.  In contrast, the expression profiles of ethanol induced cirrhosis were characterized by the induction of genes involved in the inflammatory response, oxidative stress, and deposition of extracellular matrix components by macrophages  The stages of ethanol induced liver injury but not HCV induced liver injury could be predicted by gene expression profiles.  Virol J. 2006 Nov 22;3:98 

Thio et al (2006) report that risk of developing persistant HBV infection in individuals with a non-functional CCR5(Delta)32 receptor is reduced by half.  Thio suggests that the CCR5 receptor contributes to viral persistence by dampening the adaptive immune response J Virol. 2007 Jan 81(2): 441-4 

Sterling et al (2006) reports the development of a simple non-invasive index (FIB-4)to predict significant fibrosis in patients with HIV/HCV coinfection.  This index is based on age, and measuring aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet (PLT) count.  This non-invasive index could lead to a significant reduction of liver biopsies.   Hepatology. 2006 Jun;43(6):1317-25

The virion infectivity factor (Vif) accessory protein of HIV-1 forms a complex with the cellular cytidine deaminase APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) to block its antiviral activity. The ability of Vif to block this activity is species-specific.  Landau et al (Salk) reports that A single amino acid of APOBEC3G controls its species-specific interaction with virion infectivity factor (Vif).Schrofelbauer et al Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3927-32  

Schröfelbauer et al (2006) has now identified a four amino acid sequence in the N-terminus region of Vif in HIV and SIV that confer species specific interaction with ABOBEC3G.  This work lays the foundation for the development of a primate model for HIV because the species specificity can be overcome by modifying the four amino in Vif  protein in HIV to permit infection in non-human primates by HIV. J Virol. 2006 Jun;80(12):5984-91