Enhanced Replication of R5 HIV-1 Over X4 HIV-1 in CD4+CCR5+CXCR4+ T Cells

Abstract

To enter human cells, HIV-1 usually uses CD4 and 1 of 2 coreceptors: CCR5 and CXCR4. Interestingly, even though CCR5 is expressed on far fewer T cells than is CXCR4, many patients in early- and late-stage HIV disease maintain high levels of CCR5-tropic (R5) viruses. We hypothesized that such high R5 viral loads may be sustained because, relative to CXCR4-tropic (X4) HIV-1 infection, R5 HIV-1 infection of permissive CD4(+)CCR5(+)CXCR4(+) T cells results in the production of significantly more infectious virus particles per target cell. To investigate this possibility, we compared the levels of virus production per target cell after isogenic R5 and X4 HIV-1 infection of 2 in vitro primary human lymphocyte culture systems: T-cell receptor-stimulated blood-derived CD4(+) T cells and tonsil histoculture (which requires no exogenous stimulation for ex vivo infection). We provide evidence that R5 HIV-1 does indeed compensate for a small target cell population by producing, on average, 5 to 10 times more infectious virus per CCR5(+) target cell than X4 HIV-1. This replicative advantage may contribute to the predominance of R5 HIV-1 in vivo.

HIV-1 gp120/V3-derived epitopes promote activation-induced cell death to superantigen-stimulated CD4+/CD45RO+ T cells

“…It is accepted that CXCR4 is mainly expressed on naïve CD4 T cells and CCR5 on effector/memory T cells [37,38]. The presence of double positive CCR5 + /CXCR4 + CD4 T cells has been previously reported with the remark that the majority of CCR5 + T cells co-express CXCR4 [39]. Indeed, it has been postulated that the co-existence of CXCR4 and CCR5 on T cells may represent a transient state from naïve to activated T cells.…”

Dissecting How CD4 T Cells Are Lost During HIV Infection

“…Indeed, pseudotyping HIV-1 with an amphotropic MLV envelope does not lead to productive infection of nonpermissive lymphoid-derived CD4 T cells (Doitsh et al, 2010). Although CCR5-expressing CD4 T cells in tonsillar tissues are more permissive to HIV infection (possibly effector memory T cells) (Roy et al, 2005; Schweighardt et al, 2004), a significant fraction of this cell population (possibly central memory T cells) becomes abortively infected by HIV-1 and dies via caspase-1-mediated pyroptosis (Doitsh et al, 2014). Of note, in situ immunostaining of fresh lymph nodes obtained from untreated subjects infected with R5-tropic HIV-1 revealed abundant caspase-1 activity in the paracortical zone comprised primarily of resting CD4 T cells (Doitsh et al, 2014).…”

Humanized mice dually challenged with R5 and X4 HIV-1 show preferential R5 viremia and restricted X4 infection of CCR5+CD4+ T cells

“…Here, we found that both R5 and X4 HIV-1 were cytopathic, and that the cytopathic effects of X4 HIV-1 may be higher than those of R5 HIV-1 in vivo (as evidenced by the effects in dually challenged mice). It is possible that the potential replicative advantage that R5 HIV-1 holds over X4 HIV-1 [34,35] is due to the lower cytopathic effect of R5 HIV-1, such that R5 HIV-1 is able to propagate more readily than X4 HIV-1 in vivo. However, cytopathic effects alone do not fully explain the restricted infection of CCR5 þ CD4 þ T cells by X4 HIV-1 because this cell type was not selectively targeted and damaged by X4 HIV-1.…”

“…In humans, CCR5 is expressed predominantly on memory CD4 þ T cells [30,31], and we previously demonstrated that the CCR5 þ CD4 þ T cell population in humanized mice comprises a high proportion of cells with an activated memory phenotype [18]. During the early stage of a primary HIV-1 infection, the virus preferentially targets activated CCR5 þ CD4 þ T cells rather than other CD4 þ T cell populations (such as resting naïve CD4 þ T cells) [32,33], thereby promoting efficient virus production [34]. Therefore, it is likely that restricted X4 HIV-1 infection of CCR5 þ CD4 þ T cells in the presence of R5 HIV-1 resulted in the diminished replication/ dissemination of X4 HIV-1 in our humanized mouse model.…”