A paper published in the Journal of Virology on January 2nd reports that the nefarious activities of HIV’s Nef protein can influence the size of the persistent viral reservoir in people on ART. Nef is known to be able to shield HIV-infected cells from recognition by the immune system, and Fredrick Omondi and colleagues found that this capacity correlated with measures of the HIV reservoir in a group of early-treated individuals assessed after 48 weeks of ART. The researchers also uncovered evidence that HIV reservoir size differed depending on viral subtype, likely partly due to between-subtype variation in the Nef protein.
The study involved 30 men with HIV in Canada who initiated ART within six months of infection. Of these participants, 25 had HIV subtype B while five had non-B subtypes (two CRF01_AE and three subtype G). The researchers investigated two different possible effects of the HIV Nef protein to assess if they influenced HIV reservoir size: downregulation of the CD4 molecule on CD4 T cells, and downregulation of class I HLA molecules.
As background, class I HLA molecules act somewhat like trash collectors, picking up protein fragments from within cells and shuttling them to the cell surface so that passing CD8 T cells can inspect them. Most of the time, the protein fragments represent normal debris from human proteins and the cell goes unmolested by CD8 T cells. But if a class I HLA molecule picks up a protein fragment from a foreign infecting virus like HIV, this can trigger a cytotoxic reaction by CD8 T cells that leads to the cell’s destruction (videos of CD8 T cells destroying other cells can be found online). Downregulation of class I HLA molecules by Nef can act to shield HIV-infected cells from this type of immune surveillance.
Laboratory assays were used to measure the capacity of the Nef protein from HIV sampled from each study participant to downregulate CD4 or class I HLA molecules. While CD4 downregulation showed no effect, the efficiency with which Nef downregulated class I HLA strongly correlated with HIV reservoir size as measured by viral DNA levels (Spearman's R=0.61, p=0.0004). A correlation was also observed when the reservoir was assessed using a virus outgrowth assay, which measures replication-competent HIV rather than viral DNA.
An analysis that compared participants with HIV subtype B to those with non-B subtypes found that the former group had significantly larger reservoirs (median 2.45 versus 1.72 log10 copies HIV DNA per million CD4 T-cells), with the evidence indicating that the difference was at least partly due to variation in Nef-mediated class I HLA downregulation between the subtypes. The authors note that this phenomenon may be relevant to a prior report of lower HIV reservoirs in a Ugandan cohort, in which the prevalent HIV consisted of subtype D or A/D recombinant viral strains.
The researchers suggest that the effect of Nef on HIV reservoir size is primarily due to shielding infected cells from destruction prior to ART initiation. They note that establishing whether Nef also impedes clearance of infected cells during ART is technically challenging, and would require larger numbers of study participants. Larger studies, involving more diverse participants, will also be needed to better understand the role of HIV subtype in governing HIV reservoir size, and the extent to which Nef contributes.
The results imply that efforts to induce killing of latently infected cells by CD8 T cells could be stymied by Nef. However, laboratory studies have been published demonstrating that—should it turn out to be a problem—there are compounds capable of inhibiting Nef function which can enhance CD8 T cell-mediated destruction of latently infected cells.
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