Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, Cavrois M, Huang Y, Mahley RW, Dolan MJ, McCune JM, Ahuja SK. Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8718-23. PubMed.
Recommends
Please login to recommend the paper.
Comments
Universities of Manchester and Oxford
It’s good to see yet another study showing that a genetic factor determines outcome of infection by a microbe—a concept all too rarely understood though indicating simply that infected might not mean affected, so that an infected individual might suffer severe or mild disease (or even, in some cases be asymptomatic, and therefore seemingly a “control”). Burt et al. (1) investigated APOE in HIV-infected and uninfected Americans of “European,” “Hispanic,” and of African descent. They found that risk of infection was independent of APOE, but that disease progression and progression to death were slower in APOE-ε3 hetero- or homozygotes than in those with no APOE-ε3 allele, the effect being greater in the African Americans (who have a particularly high APOE ε4 allele frequency). Also, both APOE ε4 and APOE-ε2 homozygosity, but not heterozygosity, were associated with a faster course of disease and progression to death for each of the groups. (As APOE-ε2 homozygosity is very rare, they subsequently analyzed only ε3 and ε4 alleles.) Surprisingly, in view of the findings of Corder et al. (2), HIV-associated dementia was not associated with APOE ε4; this was perhaps because, as suggested in a Commentary in Science (3), new antiviral drugs have reduced greatly this condition.
The APOE ε4 effect on progression held after adjustment for several parameters that affect disease progression, such as baseline CD4 T cell count, but disappeared after adjusting for viral load. However, viral load itself, indicating the extent of viral replication, was significantly greater among the African Americans in APOE4 heterozygotes and even more so in APOE4 homozygotes. Consistently, viral load in HIV-infected cell cultures was greater in the presence of added ApoE4 compared to added ApoE3 isoform. Among the possible explanations for this effect, the authors suggested a mechanism involving blockage of HIV attachment to cells, on the basis that ApoE4 might block better than ApoE3. In fact we proposed this mechanism for the APOE ε4 effect on HIV dementia (4), after suggesting that it might explain the risk of Alzheimer disease conferred by this allele together with herpes simplex virus type 1 (HSV1) in brain (and might explain, too, the risk of cold sores, a PNS disorder caused by HSV1) (5,6).
Incidentally, ApoE4 is not always the villain: we have found that possession of an APOE ε4 allele is strongly protective against severe liver disease caused by the hepatitis C virus (7) and that it is protective also against post-herpetic neuralgia, a consequence of shingles, which is caused by varicella zoster virus (8).
See also:
Lin, W. Alzheimer’s Reports; 1998; 1: 173-178.
References:
Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, Cavrois M, Huang Y, Mahley RW, Dolan MJ, McCune JM, Ahuja SK. Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8718-23. PubMed.
Corder EH, Robertson K, Lannfelt L, Bogdanovic N, Eggertsen G, Wilkins J, Hall C. HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat Med. 1998 Oct;4(10):1182-4. PubMed.
Youngsteadt E. Virology. Alzheimer's risk factor also aids HIV. Science. 2008 Jun 20;320(5883):1577. PubMed.
Itzhaki RF, Wozniak M, Dobson C, Lin WR. ApoE-viral interactions. Nat Med. 1998 Dec;4(12):1344. PubMed.
Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet. 1997 Jan 25;349(9047):241-4. PubMed.
Wozniak MA, Itzhaki RF, Faragher EB, James MW, Ryder SD, Irving WL, . Apolipoprotein E-epsilon 4 protects against severe liver disease caused by hepatitis C virus. Hepatology. 2002 Aug;36(2):456-63. PubMed.
Wozniak MA, Shipley SJ, Dobson CB, Parker SP, Scott FT, Leedham-Green M, Breuer J, Itzhaki RF. Does apolipoprotein E determine outcome of infection by varicella zoster virus and by Epstein Barr virus?. Eur J Hum Genet. 2007 Jun;15(6):672-8. Epub 2007 Mar 14 PubMed.
Make a Comment
To make a comment you must login or register.