Cross-reactivity to gut microbiota could explain failure of HIV vaccine

More than 30 years since its discovery and there is still no FDA licensed HIV vaccine. It is not even entirely clear if the failure to develop effective HIV vaccine has really anything to do with frequent HIV antigenic shift. Flu virus, for example, also undergo quite frequent antigenic shift and still there is Flu vaccines with 60-90% efficacy.   

New study published this week in journal Science suggested new explanation for frequent failure with HIV vaccine(s). It appears that cross-reactivity between gp41 component of HIV vaccine and endogenous microbiota antigen (component of E. coli RNA polymerase) prevented development of neutralizing gp120-specific antibody titre.

The authors have analysed Ab repertoire to HIV-1 DNA prime, recombinant Adenovirus Type 5 (rAd5) boost vaccine. They found that 93% of Env specific antibodies derived from sorted memory B cells were directed against non-neutralizing gp41 antigen. 

Interestingly, majority of those gp41-specific antibodies utilized polyreactive, innate-like IGHV1-69 variable segment. VH1-69 locus is involved in Ab repertoire directed to Flu stem region. But unlike Flu specific VH1-69 Abs, gp41-specific VH1-69 Abs were made of allele variants with Leucine substitution at position 54 in HCDR2.

Finally, analysis of antigen specificity of individual gp41 mAbs revealed high level of polyreactivity towards commensal and self antigens.

In summary, these results points to the most important aspect of immune system, namely that strength and specificity of immune response is controlled by environmental antigens, including microflora antigens. It is my opinion that future vaccine testing would require incorporation of cross-reactivity tests against wide range of environmental antigens to select the most effective immunogens.  

David Usharauli

    

   

Exposure to premature inflammatory milieu inhibits antigen receptor signaling in CD4 T cells

It is believed that proper T cell activation require sequential signaling through Signal 1 (e.g. CD3), Signal 2 (e.g. CD28), Signal 3 (e.g. IL-12 or type I IFN induced inflammation). However, occasionally, for example during autoimmune inflammation or immunotherapy, T cells could be exposed to "out-of-order" Signal 3 without Signal 1. So what are the consequences for such exposure for T cells?

New paper in Immunity has provided some answers. Using human T cells derived from patients treated with high dose of IL-2, the authors found that CD4 T cells, but not CD8 T cells, displayed diminished antigen-specific proliferation in mixed MLR or ConA stimulation assays.

Similar results were obtained with human CD4 T cells pre-incubated in vitro with IL-2 prior to MLR assay (that tests Signal 1 activity). One caveat is that the authors have used linear scale to "highlight" the difference in proliferation of treated T cells. However, the proliferation is a geometrical function and ordinarily should be depicted in logarithmic scale.

Next, the authors found that inhibition of Signal 1 by inflammatory milieu was short-lived and quickly recovered if inflammatory milieu was removed.

Similar quick recovery was seen in vivo with mouse OVA-specific OT-II CD4 T cells treated anti-CD40 antibody and IL-2 to mimic inflammatory milieu and later harvested at different time points post treatment.

Mechanistically, the authors showed that Socs3 was selectively up-regulated in CD4 T cells upon exposure to Signal 3 and inhibited STAT5 signaling in CD4 T cells.

In summary, this very simple paper raises very interesting points regarding how T cells computes external signals. As the authors noted Signal 3 could exist in conditions such as systemic autoimmune inflammation and sepsis, or during immunotherapy. How would these conditions affect activation of CD4 T cells?

David Usharauli


  

Memory T cells can eliminate virus from the brain without tissue damage

Dealing with viral infection in the brain (CNS) is a big challenge to immune system. Unlike other tissues, even minor local inflammation in CNS could make the host unfit to survive. So what immune system can do?

New paper in Journal of Experimental Medicine (JEM) suggested that T cells are using non-cytopathic, non-inflammatory effector signalling to clear the brain from the persisting virus.

Using neonatal brain infection model (carrier mice), the authors showed that adoptive transfer of donor memory T cells into carrier mice did not induce brain tissue damage.

The authors found that memory T cell immunotherapy of carrier mice was associated with limited inflammatory cytokine release and minimal brain tissue damage.

Examination of brain tissue in carrier mice showed that adoptive anti-viral T cell therapy induced brain-wide modification of virus-infected microglia population (CD11c up-regulation).  

Further experiments showed that memory T cells activated IFN-γ mediated STAT1 signaling in the brain.
 

Finally, the authors found that memory T cells cleared virus from infected microglia using non-cytopathic IFN-γ / STAT1 pathway.

In summary, these results suggest that immune system can employ tissue-specific defense mechanisms, as proposed by Matzinger and Kamala.

David Usharauli