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HIVe Features | Journal Club: Review of latest publications - 11 May 2012
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Posted: 11 May 2012
Journal Club: Review of latest publications - 11 May 2012

Latest research highlights: Cytoplasmic tail of gp41 has a complex role in determining Env conformation, repeated immunizations fail to elicit bNAbs (but many opportunities remain), adding GM-CSF to an SIV vaccine abolishes protection, T-cell mapping studies post RV144. Reviews: HIV latency, host restriction factors.

Research articles

The cytoplasmic tail (CT) of gp41 has been known to affect neutralization sensitivity of cell-free HIV and SIV virions, as well as the ability of the envelope to mediate fusion, but now Durham et al. (PMID 22553332) show that it also affects the spread of the virus via the virological synapse (VS).  While wild-type virus was resistant to neutralization when spreading via the VS, delta-CT viruses were much more sensitive to antibodies.

Broadly-neutralizing antibodies (bNabs) are heavily-mutated, suggesting the need for prolonged affinity maturation, which requires prolonged presence of antigen in the body.  Moody et al. (PMID 22553329) attempted to stimulate affinity maturation by doing four sequential injections of gp120 protein over a 6 months period.  While robust immune responses were observed, the maturation level of the isolated antibodies was far from that of bNabs.  It’s not clear whether simply a longer antigen exposure would have helped (it takes approximately two years for bNAbs to develop in HIV-positive patients) or if a specific type of signaling (either by an adjuvant or through T-cell help) is needed to induce high levels of maturation. In their perspective article, Haynes et al. (PMID 22565972) lay out possible approaches to stimulate and guide antibody maturation toward a particular specificity.

While the HVTN 094 clinical trial is in the works to test a GM-CSF-coding plasmid as an adjuvant, Schell et al. (PMID 22537983) reported that adding GM-CSF-expressing VSV to a VSV-based SIV vaccine in macaques actually reduced the ability of the vaccine to protect against viral challenge.  The result suggests caution in using the cytokine as an adjuvant.  Interestingly, both humoral and cellular immune responses appeared to be unaffected by the addition of GM-CSF. This opens up an opportunity to identify a novel correlate of protection in this model.

The binding of IgG antibodies to the V1V2 loop of gp120 was one of the correlates of risk found in RV144, increasing interest on the highly variable V1V2 region.  De Souza et al. (PMID 22529301) performed T cell epitope mapping studies using IFN-gamma ELISPOT.  Although in general CD4+ T cell responses were modest, 60% were directed to the V2 region, including the binding site of alpha(4)beta(7) integrin.  These results are not unexpected and more studies will be needed to define the relevance of the V1V2 region in protection.

Reviews

Abbas and Herbein (PMID 22548060) review the mechanisms of HIV latency.
Malim and Bieniasz (PMID 22553496) provide an overview of antiviral restriction factors and how HIV escapes them.





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