Background
Antiretroviral therapy (ART) is not a cure for HIV-1 infection due to the formation of latent reservoirs. Most long-lived viral reservoir cells are infected by the virus near the time of therapy initiation. A better understanding of the early events in viral reservoir seeding may help prevent latent reservoir formation. Unlike quiescent reservoir cells, CD4+CCR5+ T cells as the primary targets in HIV-1 infection present an activated Th1 and Th17 effector phenotype. This discrepancy suggests phenotypic and functional changes occur in CCR5+effector cells after HIV-1 entry, necessitating further elucidation.
Methods
We profiled CD4+CCR5+ T cells and evaluated in-vitro re-differentiation of activated CCR5+ cells to explore how terminal effectors reprogram into quiescent memory cells. We revealed that BACH2 is a key transcription factor in memory-precursor (MP) conversion of CCR5+cells which was validated through BACH2-knockout and overexpression assays. To investigate the impact of BACH2 on the HIV-1 latent reservoir, BACH2 knockout humanized mice were infected with R5-tropic virus and treated with ART. The measurement of HIV-1 DNA frequency in tissues and viral rebound analysis were performed.
Results
Upon TCR stimulation, CCR5 was upregulated predominantly in cells committed to terminal differentiation. Furthermore, the majority of CCR5+ cells became functionally impaired, characterized by elevated activation or exhaustion markers and increased apoptosis susceptibility. However, a small subset of these cells undergoes re-differentiation into memory precursor (MP) cells, a process regulated by BACH2. BACH2 deficiency prevents MP cell formation and reduces TCF1 expression, weakening recall response and cell proliferation. In humanized mice, BACH2 knockout did not affect plasma viral load or HIV-1 DNA frequency in tissues compared to controls. However, after ART, the knockout group had a lower frequency of HIV-1 DNA. Viral rebound occurred in 90% of control mice (9/10) but only in 29% of BACH2-knockout mice (4/14).
Conclusions
Our study shows that BACH2 reverses CCR5+cells from terminal differentiated cells to memory precursors. The absence of BACH2 abrogates the seeding of latent reservoirs, revealing the essential role of BACH2 in the seeding and establishment of long-lived HIV-1 reservoir in memory CD4+ T cells. Our finding identifies a potential avenue for targeted interventions.
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