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Richard Jeffreys, TAG
An important new study has just been published in Science Express, the advance online section of the widely read journal Science. Abraham Brass and colleagues report results obtained using a genome-wide screen for host proteins necessary for HIV replication. The researchers used an approach that involves blocking the activity of known human genes using small slices of RNA called small interfering RNAs (siRNAs). A staggering 21,121 pools of four siRNAs per gene were employed in the study, ultimately revealing 273 host proteins that appear necessary for efficient HIV replication (the researchers have dubbed them “HIV dependency factors” or HDFs). [1]
Thirty-six HDFs comprise previously reported factors such as the CD4 and CXCR4 proteins, but the others are novel, including proteins involved in transporting materials into a cell’s nucleus, glycosylation (addition of sugar molecules to proteins, [2]) and degradation of cellular proteins [3].
One identified protein, ZNRD1, was also implicated in a recent study of genomic associations with viral load set point in people with HIV (mutations in the gene for ZNRD1 were associated with slow progression). [4]
So much data was generated that much of it is not in the paper but in the supplemental online material that accompanies it. [5] The authors also offer a busy schematic that gives a sense of the complex theater of virus-host interactions that they have raised the curtain on.
In an accompanying news story by Jon Cohen, a number of leading HIV researchers praise the paper and note that it offers a dazzling array of potential new leads for scientists looking to better understand the HIV life cycle, and how to inhibit it. [6]
Source:
TAG Basic Science Blog (10 Jan 2008)
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2008/01/probing-hivs-de.html
References:
1. Brass A et al. Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen. DOI: 10.1126/science.1152725. Published Online January 10, 2008
.
http://www.sciencemag.org/cgi/content/abstract/1152725
2. http://en.wikipedia.org/wiki/Glycosylation
3. http://en.wikipedia.org/wiki/Autophagy
4. http://www.sciencemag.org/cgi/content/full/317/5840/944
5. http://www.sciencemag.org/cgi/content/full/sci;1152725/DC1
6. http://www.sciencemag.org/cgi/content/full/319/5860/143
The November issue of the Journal of Clinical Investigation (JCI) contains an excellent review of research which aims to elucidate the benign nature of SIV infection in natural hosts (sooty mangabeys and African green monkeys). Guido Silvestri and colleagues outline current knowledge about the differences between non-pathogenic and pathogenic immunodeficiency virus infections with an emphasis on the now well-accepted role of immune activation in determining disease outcome.
The authors also offer the intriguing suggestion that perhaps non-pathogenic SIV infections have less impact on the function of CD4 T cells because the CD4 T cells that are infected are at a later stage of differentiation and are destined to undergo activation-induced death anyway; in this model, important self-renewing central memory CD4 T cells are not as disrupted by SIV and thus immunodeficiency does not ensue. While speculative, this represents an important area for future research.
The authors conclude by stressing that studies of benign SIV infections have made a huge contribution to understanding the pathogenesis of HIV infection in humans, and emphasize that additional studies will provide more important insights as well as potentially revealing new therapeutic targets for the treatment of the HIV and AIDS.
As with all JCI content, access to the full text of the paper is free of charge.
Source:
TAG Basic Science Blog (20 Nov 2007)
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2007/11/an-eye-on-the-b.html
Ref: Silvestr G et al. Understanding the benign nature of SIV infection in natural hosts. J. Clin. Invest. 117:3148-3154 (2007). doi:10.1172/JCI33034.
http://www.jci.org/cgi/content/full/117/11/3148
Back in February the blog covered two conference presentations relating to interactions between HIV and endogenous retroviruses. [1]
The gist of the story is that cells infected with HIV appear to also produce fragments of ancient endogenous retroviruses; these remnants of past retroviral infections litter the human genome but cannot replicate or, under normal conditions, transcribe their genetic material into proteins. The HIV protein Vif seems to allow these retroviral zombies to awaken by facilitating the transcription of their genetic material.
The production of endogenous retrovirus proteins by HIV-infected cells may thus provide an additional means for the immune system to recognize and target these cells for elimination.
Because endogenous retroviruses cannot replicate, they also cannot mutate. So while the rapidly-mutating HIV typically represents a moving target for the immune system, targeting proteins from endogenous retroviruses may offer an additional, easier means for immune responses to recognize HIV-infected cells.
Keith Garrison and colleagues have now published their data showing that T cell responses to human endogenous retroviruses (HERVs) can be detected in people with HIV and, furthermore, that these T cell responses show a correlation with control of HIV replication during acute HIV infection. [2]
The data were also mentioned by senior author Doug Nixon in a recently published interview with TAG. [3] The researchers suggest that the finding may lead to novel HIV vaccine strategies targeting HERVs. However, more study of the circumstances under which otherwise healthy cells might express HERV proteins is needed in order to ascertain the safety and practicality of this idea (so far, HERV expression has been primarily reported in people with HIV and people with certain cancers such as seminoma and breast cancer).
Source:TAG Basic Science Blog (26 Nov 2007)
References
1. Does HIV Unleash Endogenous Retroviral Elements?
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2007/02/does_hiv_unleas.html
2. Garrison K et al. T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection. PLoS Pathogens Vol. 3, No. 11, e165 doi:10.1371/journal.ppat.0030165.
http://pathogens.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.ppat.0030165
3. Interview with David Nixon.
http://www.aidsinfonyc.org/tag/science/interviews/dnixon.html
A new study just published online in the Journal of Infectious Diseases (authored by Peter Hunt from UCSF and colleagues) reports that levels of CD4 and CD8 T cell activation correlate with declines in peripheral blood CD4 T cell counts, even in individuals who consistently maintain viral loads below 75 copies/mL (dubbed “controllers”). [1]
It has been reported previously that maintenance of a low viral load does not confer absolute protection against disease progression; [2] for example, an individual in the Sydney Blood Bank Cohort who was infected with a partially attenuated HIV eventually developed immune deficiency despite a persistently low viral load. [3]
A prior study also found that CD4 T cell declines in HIV-2-infected individuals can occur despite very low or undetectable viremia; these declines correlated with immune activation levels, echoing the findings of Hunt et al.
The JID paper also notes that LPS levels - a potential indicator of the translocation of microbial products from the gut - were elevated compared to HIV-negative individuals and correlated with CD8 (but not CD4) T cell activation levels in the controllers. However, the authors do not state whether a similar correlation was seen in the HIV-infected individuals with detectable viral loads (as has been reported previously by Jason Brenchley, one of the co-authors of this paper). [4]
This study further highlights the critical role of immune activation in the pathogenesis of HIV/AIDS. Critical issues that remain to be addressed include the specificity of the activated T cells (a question that may be complicated by the fact that activated T cells can transiently downregulate their T cell-receptor), the phenotype of the T cells ‘at the time of activation’ (naive, central memory, effector memory), the factors driving immune activation (HIV antigens, non-HIV antigens such as translocated microbial products, cytokines, stimulation through toll-like receptors or some combination of these or other factors) and whether novel therapeutic approaches can beneficially ameliorate immune activation in HIV infection. Studies such as this one may also suggest that immune activation levels should be measured (in addition to viral loads and CD4 T cell counts) in trials of vaccines intended to prevent or slow progression of HIV infection in immunised individuals.
Source: TAG Basic Science Blog (05 Dec 2007)
References:
1. Hunt PW, Brenchley J, Sinclair E et al. Relationship between T Cell Activation and CD4+ T Cell Count in HIV-Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy. JID 2008;197:000–000. DOI: 10.1086/524143
http://www.journals.uchicago.edu/doi/abs/10.1086/524143
2. Greenough TC et al. Declining CD4 T-cell counts in a person infected with nef-deleted HIV-1. NEJM 1999 Jan 21;340(3):236-7.
http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&dopt=AbstractPlus&list_uids=9917232
3. Sousa A et al. CD4 T Cell Depletion Is Linked Directly to Immune Activation in the Pathogenesis of HIV-1 and HIV-2 but Only Indirectly to the Viral Load. Journal of Immunology, 2002, 169: 3400-3406.
http://www.jimmunol.org/cgi/content/full/169/6/3400
4. Leaking Bacteria & HIV Pathogenesis.
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2007/01/leaking_bacteri.html
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