Abstract:Background: Identifying biomarkers for cells harboring replication-competent HIV is a major research priority. Recently, there have been mixed reports addressing the possibility that CD32-expressing T-cells are enriched for HIV. There is growing evidence that CD32 expression increases with cellular activation that may be related to, but not necessarily specific for, infection with HIV. However, the relationship of CD32 expression to HIV-infection in subtypes of tissue-resident leukocytes is unclear. Methods:… Show more
“…These RNA in situ hybridization (ISH) experiments showing the co-expression of CD32a RNA and HIV RNA in lymphoid tissue support the notion that CD32a is associated with transcriptionally active tissue reservoirs. Similar results were recently obtained by Vásquez et al in the gut tissue (114). By using ISH-based methods, they demonstrated co-expression of HIV and CD32a mRNA, with most of the CD3 + CD32 + cells in the gut co-expressing HIV RNA.…”
Combination antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) replication and improves immune function, but is unable to eradicate the virus. Therefore, development of an HIV cure has become one of the main priorities of the HIV research field. The main obstacle for an HIV cure is the formation of latent viral reservoirs, where the virus is able to “hide” despite decades of therapy, just to reignite active replication once therapy is stopped. Revealing HIV hiding places is thus central to HIV cure research, but the absence of markers of these reservoir cells greatly complicates the search for a cure. Identification of one or several marker(s) of latently infected cells would represent a significant step forward toward a better description of the cell types involved and improved understanding of HIV latency. Moreover, it could provide a “handle” for selective therapeutic targeting of the reservoirs. A number of cellular markers of HIV reservoir have recently been proposed, including immune checkpoint molecules, CD2, and CD30. CD32a is perhaps the most promising of HIV reservoir markers as it is reported to be associated with a very prominent enrichment in HIV DNA, although this finding has been challenged. In this review, we provide an update on the current knowledge about HIV reservoir markers. We specifically highlight studies that characterized markers of persistently infected cells in the lymphoid tissues.
“…These RNA in situ hybridization (ISH) experiments showing the co-expression of CD32a RNA and HIV RNA in lymphoid tissue support the notion that CD32a is associated with transcriptionally active tissue reservoirs. Similar results were recently obtained by Vásquez et al in the gut tissue (114). By using ISH-based methods, they demonstrated co-expression of HIV and CD32a mRNA, with most of the CD3 + CD32 + cells in the gut co-expressing HIV RNA.…”
Combination antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) replication and improves immune function, but is unable to eradicate the virus. Therefore, development of an HIV cure has become one of the main priorities of the HIV research field. The main obstacle for an HIV cure is the formation of latent viral reservoirs, where the virus is able to “hide” despite decades of therapy, just to reignite active replication once therapy is stopped. Revealing HIV hiding places is thus central to HIV cure research, but the absence of markers of these reservoir cells greatly complicates the search for a cure. Identification of one or several marker(s) of latently infected cells would represent a significant step forward toward a better description of the cell types involved and improved understanding of HIV latency. Moreover, it could provide a “handle” for selective therapeutic targeting of the reservoirs. A number of cellular markers of HIV reservoir have recently been proposed, including immune checkpoint molecules, CD2, and CD30. CD32a is perhaps the most promising of HIV reservoir markers as it is reported to be associated with a very prominent enrichment in HIV DNA, although this finding has been challenged. In this review, we provide an update on the current knowledge about HIV reservoir markers. We specifically highlight studies that characterized markers of persistently infected cells in the lymphoid tissues.
“…1b and 1c). These data together with recent publications demonstrating that CD32–RNA correlates with HIV transcriptional activity in T cells from the gut 13 , and from lymph nodes 10 , not only confirms their existence in human tissues, but also raises interest on defining their nature.Fig. 2CCR5 + CD4 + T RM protein expression signature in cervix.…”
Section: Resultssupporting
confidence: 75%
“…Interestingly, we detected a small subset of cervical CD4 + CCR5 + T RM that readily expressed CD32, a marker originally associated to HIV-latently infected cells 9 , which was later linked to transcriptionally active infected cells 10–13 . We observed that the fraction of T RM expressing CD32 was enriched for most of the molecules investigated, many of them associated to HIV susceptibility.…”
Section: Discussionmentioning
confidence: 94%
“…Considering that HIV-1 isolates from newly infected individuals predominantly use CCR5 as a co-receptor, we performed a detailed analysis of the phenotype of cervical CD4 + CCR5 + CD69 + (T RM ) and CD69 − (non-T RM ) cells from HIV uninfected tissues. Moreover, since we observed that a fraction of cervical CD4 + T RM consistently expressed low levels of CD32 in uninfected tissues, a molecule which expression has been associated with the identification of transcriptionally active infected cells during HIV infection 10,11,13 , we analyzed this fraction separately to determine phenotypic characteristics that could render these cells more vulnerable to HIV infection. Figure 2a shows the general gating strategy established for these analyses (which follows the gating already established in Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Further, CD4 + T cells with high expression of CD2 have been postulated as potentially associated with latently infected cells 8 . More recently, CD32 expression in a subset of CD4 + T cells was also associated to HIV-latently infected cells 9 , but soon after it was demonstrated to be linked to transcriptionally active infected cells 10–13 . Similarly, the effector memory phenotype and the expression of CD30 have also been associated to transcriptionally active infected cells 14,15 .…”
HIV viral reservoirs are established very early during infection. Resident memory T cells (TRM) are present in tissues such as the lower female genital tract, but the contribution of this subset of cells to the pathogenesis and persistence of HIV remains unclear. Here, we show that cervical CD4+TRM display a unique repertoire of clusters of differentiation, with enrichment of several molecules associated with HIV infection susceptibility, longevity and self-renewing capacities. These protein profiles are enriched in a fraction of CD4+TRM expressing CD32. Cervical explant models show that CD4+TRM preferentially support HIV infection and harbor more viral DNA and protein than non-TRM. Importantly, cervical tissue from ART-suppressed HIV+ women contain high levels of viral DNA and RNA, being the TRM fraction the principal contributor. These results recognize the lower female genital tract as an HIV sanctuary and identify CD4+TRM as primary targets of HIV infection and viral persistence. Thus, strategies towards an HIV cure will need to consider TRM phenotypes, which are widely distributed in tissues.
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