Abstract
A recent study conducted in blood has proposed CD32 as the marker identifying the "elusive" HIV reservoir. We have investigated the distribution of CD32+ CD4 T cells in blood and lymph nodes (LNs) of HIV-1-uninfected subjects and viremic untreated and long-term-treated HIV-1-infected individuals and their relationship with PD-1+ CD4 T cells. The frequency of CD32+ CD4 T cells was increased in viremic compared to treated individuals in LNs, and a large proportion (up to 50%) of CD32+ cells coexpressed PD-1 and were enriched within T follicular helper (Tfh) cells. We next investigated the role of LN CD32+ CD4 T cells in the HIV reservoir. Total HIV DNA was enriched in CD32+ and PD-1+ CD4 T cells compared to CD32- and PD-1- cells in both viremic and treated individuals, but there was no difference between CD32+ and PD-1+ cells. There was no enrichment of latently infected cells with inducible HIV-1 in CD32+ versus PD-1+ cells in antiretroviral therapy (ART)-treated individuals. HIV-1 transcription was then analyzed in LN memory CD4 T cell populations sorted on the basis of CD32 and PD-1 expression. CD32+ PD-1+ CD4 T cells were significantly enriched in cell-associated HIV RNA compared to CD32- PD-1- (averages of 5.2-fold in treated individuals and 86.6-fold in viremics), CD32+ PD-1- (2.2-fold in treated individuals and 4.3-fold in viremics), and CD32- PD-1+ (2.2-fold in ART-treated individuals and 4.6-fold in viremics) cell populations. Similar levels of HIV-1 transcription were found in CD32+ PD-1- and CD32- PD-1+ CD4 T cells. Interestingly, the proportion of CD32+ and PD-1+ CD4 T cells negatively correlated with CD4 T cell counts and length of therapy. Therefore, the expression of CD32 identifies, independently of PD-1, a CD4 T cell population with persistent HIV-1 transcription and coexpression of CD32 and PD-1, the CD4 T cell population with the highest levels of HIV-1 transcription in both viremic and treated individuals.IMPORTANCE The existence of long-lived latently infected resting memory CD4 T cells represents a major obstacle to the eradication of HIV infection. Identifying cell markers defining latently infected cells containing replication-competent virus is important in order to determine the mechanisms of HIV persistence and to develop novel therapeutic strategies to cure HIV infection. We provide evidence that PD-1 and CD32 may have a complementary role in better defining CD4 T cell populations infected with HIV-1. Furthermore, CD4 T cells coexpressing CD32 and PD-1 identify a CD4 T cell population with high levels of persistent HIV-1 transcription.
Highlights
A recent study conducted in blood has proposed CD32 as the marker identifying the “elusive” HIV reservoir
Studies performed in memory CD4 T cell populations isolated from lymph nodes (LNs) of viremic and long-term-treated HIV-1-infected individuals have demonstrated that PD-1-positive and T follicular helper (Tfh) CD4 T cells are the major reservoir for replication-competent and infectious virus in both viremic and long-term-treated individuals [12, 13]
The percentage of LN CD32ϩ CD4 T cells was significantly higher in viremics than in long-term antiretroviral therapy (ART)-treated individuals (Fig. 1A and B) (P ϭ 0.0007) but not HIV-uninfected individuals (Fig. 1A and B)
Summary
A recent study conducted in blood has proposed CD32 as the marker identifying the “elusive” HIV reservoir. Studies performed in memory CD4 T cell populations isolated from lymph nodes (LNs) of viremic and long-term-treated HIV-1-infected individuals have demonstrated that PD-1-positive and T follicular helper (Tfh) CD4 T cells are the major reservoir for replication-competent and infectious virus in both viremic and long-term-treated individuals [12, 13]. A recent study performed in blood has proposed that the low-affinity receptor for the immunoglobulin G Fc fragment, CD32a, defines a small population of HIV-1-infected resting CD4 T cells and that CD32aϩ CD4 T cells represent the elusive HIV reservoir [14]. On the basis of the CD32a study and our previous observations on the role of PD-1ϩ/Tfh cells in the HIV reservoir [12,13,14], we have addressed the following issues: (i) the differences in the percentages of CD32ϩ CD4 T cells in HIV-uninfected versus HIV-infected individuals; (ii) the distribution of CD32 in blood versus lymphoid tissue, i.e., LNs; (iii) the distribution of CD32 in different populations of memory CD4 T cells; and (iv) the relationship between CD32ϩ and PD-1ϩ CD4 T cell populations and their role in defining the HIV reservoir
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