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Posted: 11 Jun 2012
Journal Club: Review of recent publications - 11 June 2012

Latest research highlights: Transmitter viruses are not functionally different from chronic, early antibodies drive HIV evolution, neutralization does not correlate with protection in clinical trials, new and improved SHIV, review of interplay between NK and HIV

Isolation of transmitter/founder (T/F) viruses promised to provide insight into the specific properties of viral envelopes required for effective transmission.  Indeed, envelopes were found to have shorter variable loops, contain less glycosylation sites, be more sensitive to CD4BS antibodies and have higher affinity to alpha4beta7 integrin on average.  However, a recent paper by Parrish, Doms et al. (PLoS Path, direct link) found no differences between T/F and chronic viruses with regards to CD4 and CCR5 usage,  sensitivity to CD4BS antibodies or in CD4+ T cell subset tropism.  Moreover, neither T/F nor chronic variants were sensitive to saturating concentrations of alpha4beta7-binding antibodies.

Last week, we highlighted a paper showing impact of early cellular responses on the virus.  This week, Bar, Shaw et al. (PLoS Path, direct link) present data showing that low-titer neutralizing antibodies appear as early as two weeks after infection and apparently have an impact on virus replication, because the virus is escaping these antibodies by mutations in the targeted regions.  Using deep sequencing approaches they show that escape variants appear very quickly, even before any neutralization activity can be measured in the TZM-bl assay.  These findings suggest that even low titers of neutralizing antibodies may provide protection if present before viral transmission.

Montefiori, Kim et al. (JID, PMID 22634875) compared neutralization titers in serum samples from RV144 and VAX003 trials.  Despite showing no protection, the protein-only vaccine used in VAX003 elicited stronger antibody responses than the pox-prime/protein boost regimen of the RV144 trial, where a modest protection was observed.  It remains unclear whether the protection in RV144 was due to the lower risk of exposure of trial participants or if the vaccine elicited qualitatively different protective immune responses than VAX003.

Chimeric SIV viruses carrying HIV envelope (SHIVs) could prove useful for developing antibody-based HIV vaccines in non-human primates.  Unfortunately, SHIVs available to date have been either non-pathogenic, easy to neutralize, or had the less relevant CD4+ T cell subset tropism (CXCR4).  Three new stocks of SHIV-AD8 are described by Gautam, Martin et al (J Virol, PMID 22647691).  They are derived from passaging original SHIV-AD8 in three macaques, which came down with AIDS-like symptoms.  These swarms maintained fairly high viral loads (103-106) and caused depletion of both naïve and memory CD4+ T cells when introduced into naïve macaques.  They exhibit Tier 2 neutralization profiles and can be transmitted via mucosal challenge.

Jost and Altfeld (Microbes Infect, PMID 22626930) review the mechanisms of NK cell-mediated immune responses to HIV and how the virus escapes them.  Besides general dysregulation of the immune system and direct virus killing of some NK cell subsets, HIV also downregulates NKG2D ligand expression on the surface of infected cells and evolves to reduce binding of KIR3DL to its HLA I class ligand carrying HIV peptides.