Tuesday, November 27, 2012

A Rival for HIV

Hello

   In my previous blog post, I hosted 3 relatively new terminologies of interest. Today, I want to chat about a GB virus that has raised its interest in Clinical Virology, not because it causes a disease, but probably it is a virophage against HIV!!!

    GB virus (or more preferentially known as GBV-C or Hepatitis G virus) is a Flaviviridae member. The virus name comes from G. Barker, a surgeon, who fell ill in 1966 with a non-A non-B hepatitis which at the time was thought to have been caused by a new, infectious hepatic virus. The virus was first reported isolated in 1955 (Reference). It is not currently assigned to any particular genus, but proposed to be put under the Pegivirus. GBV-C has 7 genotypes in it. (Reference). GB virus is a lymphotrophic, non pathogenic virus found in a small set of human populations. The Fig 1 shows the distribution of GBV-C distribution.

Fig 1: Distribution of GB virus C/hepatitis G virus genotypes. Source
   The term "non pathogenic virus", that i have come across in literature is questionable in this context. If there is a virus that can be seen in humans and can infect lymphocytes do you call it non pathogenic. I do agree that healthy individuals, clear the virus from their system and cause no observable effects in many. Evidence of infection has been demonstrated by HGV RNA detection and serum anti-HGV-E2 antibody among children with histories of transfusions. So that means they have been in and out of cell. And to call a virus non pathogenic, is not easily digestible to me. The virus is transmitted efficiently through sexual contact, mother to infant, and blood products.

    If the GBV-C virus is such a non interesting case where the infection is blown below the carpet, then why is medical virology taking such a large interest in this virus? The answer comes from a remarkable concept, "Retro positive patients co-infected with GBVC tend to show a slower disease progression". That is something science can bank upon.

Photo 1: Press conference with Jack T. Stapleton, MD, University of Iowa.
   In a press conference in 49th Annual meeting of infectious disease society of America, JT Stapleton posed a question "Every study that shows persistent [GBV-C] infection over time has shown a survival benefit to HIV co-infected patients. How does this work? Why does this virus improve survival among people with HIV? Can we use it therapeutically?” “If we put this peptide on top of cells it does not inhibit, but if we introduce it inside the cell it does inhibit HIV". I read over it again and again. Are we dealing with concept of virophage here?. For source of Photo 1 and information go here.
   
   There are several theories as to what is the mechanism. But most of theory revolves around 4 important players- RANTES, MIP-1α, MIP-1β, and SDF-1.
Every study that shows persistent [GBV-C] infection over time has shown a survival benefit to HIV co-infected patients. How does this work? Why does this virus improve survival among people with HIV? Can we use it therapeutically?”

Read more: http://sciencespeaksblog.org/2011/10/21/gb-virus-c-hiv%e2%80%99s-viral-enemy/#ixzz2DPdNs8Fu
49th Annual Meeting of the Infectious Diseases Society of America in Boston

Read more: http://sciencespeaksblog.org/2011/10/21/gb-virus-c-hiv%e2%80%99s-viral-enemy/#ixzz2DPd2UbX6
Fig 2: In vivo effects of GB virus C (GBV-C) infection that can potentially interfere with HIV replication. Source
    
     RANTES or CCL5, stands for "Regulated on Activation, Normal T Cell Expressed and Secreted". RANTES is known to compete with HIV envelope for co-receptor binding, which alters activation of the HIV fusogenic machinery. RANTES is also known to produce a steric hindrance in HIV binding.  MIP-1α (CCL3) and MIP-1β (CCL4) represents Macrophage Inflammatory Protein are known to be involved in suppression of HIV infection in a dose dependent pattern.

     SDF-1 (Stromal cell derived factor-1; CXCL12) can bind to CXCR4 and inhibit viral entry, but also increased susceptibility to CCR5. This provides an interesting case where effects of SDF-1 on the HIV-1 life cycle is multiple and often a paradox, with inhibition of viral entry and a stimulation of proviral gene expression (Reference). That to some extent does explain why X4 strains are predominant in early infection and later an increase is seen in CCR5 tropic strains.

    With the Co-infection of GBV-C, it is speculated that the interfering virus causes an increased expression of RANTES, MIP-1α, MIP-1β, and SDF-1 which by said mechanisms above can inhibit the HIV to a observable extent. This brings me a question. Can I achieve the same with any other virus? The most obvious answer is "Yes". For example human herpesvirus type 6 inhibits R5 strains of HIV-1 in vitro by inducing RANTES (Reference) and Influenza virus can inhibit HIV through a type 1 interferon action (Reference). T. cruzi produces a substance called as cruzipain (Secreted by trypomastigote form) has also been shown to inhibit HIV-1 replication (Reference). But then its known that, clinically significant HIV suppression doesn't occur with HHV 6 or Influenza. Its plausible that the apropos factors are not the only and deeper mechanism should exist.

Fig 3: In vitro effects of GB virus C (GBV-C) proteins E2 and NS5A on CD4+ T cells. Source
    
      So when I had a detailed look at the above figure (from a review by JT Stapleton), it made sense. The protein E2 and NS5A (Nonstructural Phosphoprotein 5A) had a direct impact on the HIV replication system rather than just the entry system. The exact mechanism of action is not known but then there is a impact. Possibly the GBV-C is a competitor of HIV. And how does that make sense, in evolutionary terms? As I can see it, GBV-C and HIV, both can be sexually transmitted, passed through blood products etc. Possibly, their co infection induced rivalry. I have no paper to cite this or support my saying but i don't see why not!!!

    Take home message is simple.GBV-C and HIV are antagonistic with significant effects. Probably we can think of probiotic with this virus.

ResearchBlogging.orgBhattarai N, & Stapleton JT (2012). GB virus C: the good boy virus? Trends in microbiology, 20 (3), 124-30 PMID: 22325031

Further Reading:

1. Mohr EL, Murthy KK, McLinden JH, Xiang J, Stapleton JT. The natural history of non-human GB virus C in captive chimpanzees. J Gen Virol. 2011 Jan;92(Pt 1):91-100. Link

2. Sánchez-Martín MJ, Urbán P, Pujol M, Haro I, Alsina MA, Busquets MA. Biophysical investigations of GBV-C E1 peptides as potential inhibitors of HIV-1 fusion peptide. Chemphyschem. 2011 Oct 24;12(15):2816-22. Link

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