HIV-1 DNA Enrichment in β7high Cells
To determine whether β7high cells are preferentially targeted by HIV-1 during early acute infection, we measured integrated HIV-1 DNA in sorted β7high memory CD4+ T cells and their β7negative counterparts in peripheral blood (Figure 1A). During Fiebig I, integrated HIV-1 DNA burden was low in β7high cells (median, 87 copies per million [CPM] cells) and was similar between β7high and β7negative cells (Figure 2A). At Fiebig II/III, integrated HIV-1 DNA burden was considerably greater, with a median value of 760 CPM β7high cells. β7negative cells harbored less DNA; the median reduction relative to β7high cells was approximately 4-fold (P = .003). In chronic infection, β7high cells contained approximately 2500 integrated HIV-1 DNA CPM cells, which was approximately 2-fold greater than β7negative cells (P = .03). Comparing the ratio of integrated HIV-1 DNA in β7high and β7negative cells at each infection stage, the enrichment in β7high cells was greatest in Fiebig II/III (ie around peak viremia) (Figure 2B). Plasma viral load and absolute CD4 count did not correlate with this ratio.
To validate results from the integrated HIV-1 DNA assay, total HIV-1 DNA was assessed in the same cells from the Fiebig II/III donors. Additional controls included measurement in naive (CD45RA+) cells expressing intermediate surface β7 (β7int; Figure 1A) [9]. Similar to integrated HIV-1 DNA, total HIV-1 DNA was greatest in β7high cells (median, 6200 CPM cells; Supplementary Figure 2A), whereas β7negative and β7int cells contained approximately 2- and 60-fold fewer copies (P = .03 and P = .0005, respectively). Since HIV-1 infection downregulates CD4 surface expression [21], β7high and β7negative T cells double-negative for CD4 and CD8 were also analyzed (Supplementary Figure 2B). Median total HIV-1 DNA in β7high double-negative T cells was approximately 40-fold less than that of the β7high CD4+ T cells (160 CPM cells), and was similar between the β7high and β7negative subsets (Supplementary Figure 2C). Thus, both total and integrated HIV-1 DNA are enriched in β7high vs β7negative memory CD4+ T cells, while infection is less frequent in T cells lacking surface CD4.
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To determine whether viral transcription is also more common among β7high cells, we determined the frequency of cells expressing spliced viral RNA by qPCR for HIV-1 env in 7 of the Fiebig II/III donors [16]. The proportion of HIV-1 transcriptionally active β7high cells was approximately 400 per million cells and was 5-fold greater than that of β7negative CD4+ T cells (P = .03; Figure 2C). Therefore, β7high cells more commonly transcribe HIV-1 during acute infection.
To assess the maintenance of β7high cell preferential infection following viral suppression, we measured integrated HIV-1 DNA longitudinally in individuals who initiated cART during acute infection Fiebig stage II/III and remained on treatment for 8 months (n = 10). As expected [22], integrated HIV-1 DNA declined after treatment in both β7high and β7negative cells (Figure 2D). The median decrease was 49-fold in β7high cells (P = .002) and 6-fold in β7negative cells (P = .002). The decline in integrated DNA was significantly greater in β7high cells (P = .004), indicating potentially greater decay of infected β7high than β7negative cells during therapy. Integrated HIV-1 DNA burden was approximately 20 CPM β7high cells and did not differ between β7high and β7negative cells following treatment (Figure 2E). There was a strong correlation between integrated HIV-1 DNA before and after treatment, in both β7high and β7negative subsets, consistent with previous analyses of total CD4+ T cells [23] (Figure 2F).
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