Credit: Macmillan Publishers Limited

Antiretroviral therapy has greatly reduced mortality from HIV-1 infection, but the virus can persist in a small proportion of infected CD4+ T cells, forming a latent HIV reservoir. The eradication of this reservoir has proved difficult as markers for these cells have been lacking. Now, Descours, Petitjean et al. show that CD32a is specifically expressed on the surface of dormant CD4+ T cells that harbour HIV-1.

To investigate the HIV reservoir the authors developed an in vitro model of HIV latency in which dormant CD4+ T cells were generated by inducing degradation of SAMHDI — a protein previously shown to be responsible for HIV-1 restriction in resting CD4+ T cells. Peripheral blood mononuclear cells (PBMCs) from HIV-negative controls were subjected to SAMHDI degradation and then infected with an HIV-1-derived vector expressing green fluorescent protein. RNA sequencing revealed 103 differentially expressed genes — 16 of which encode cell surface transmembrane proteins — in infected quiescent CD4+ T cells compared with uninfected cells. The most highly expressed gene was FCGR2A, which encodes CD32a — a low-affinity receptor for the IgG Fc fragment.

CD32a is a specific marker of HIV-1-infected resting CD4+ T cells

The expression of CD32a was examined in the HIV latency in vitro system using PBMCs from HIV-negative individuals. CD32a expression was selectively induced on HIV-1-infected resting CD4+ T cells. Of note, infection of T cells stimulated with phytohaemagglutinin and interleukin-2 was not associated with induction of CD32a expression compared with infection of resting CD4+ T cells. Thus, CD32a is a specific marker of HIV-1-infected resting CD4+ T cells in vitro.

Finally, the authors tested whether CD32a could be used as a marker to separate HIV-infected dormant CD4+ T cells from other PBMCs isolated from individuals treated with antiretroviral therapy. CD32a immunostaining showed a continuum of expression that correlated with HIV infection frequency, and CD32a+ CD4+ T cells constituted approximately 50% of the total CD4+ T cell reservoir. Further experiments showed that CD32a+ CD4+ T cells contain inducible replication-competent provirus and depletion of these T cells led to delay in virus production and spreading, indicating that CD32a+ CD4+ T cells contribute to the inducible viral reservoir in CD4+ T cells.

To conclude, the identification of CD32a as a cell surface marker of the CD4+ T cell HIV reservoir will facilitate the study and, hopefully, therapeutic targeting of HIV latency.