Latent X4-Tropic HIV-1 Preferentially Accumulates in Peripheral Follicular Helper T Cells and Serve as a Biomarker for Disease Progression

Abstract

Background: Follicular helper T (TFH) cells play a prominent role in immune responses to human immunodeficiency virus type 1 (HIV-1), but these cells are quantitatively and functionally altered in chronic HIV-1 infection and harbor a significant amount of replication-competent latent viruses. We aimed to identify the viral characteristics of this latent reservoir and its clinical relevance. Methods: We enrolled 41 HIV-1 infected individuals (including 25 AE strain, 12 C strain and 4 B strain infected subjects) on suppressive combined antiretroviral therapy (ranging from 1.7 to 10 years). The viral tropism of proviral DNA in and replication-competent virus from peripheral follicular helper T cells (TFH), non-TFH memory CD4+ T (mCD4) and non-TFH naive CD4+ T cells were assessed by deep-sequencing. Furthermore, the relationship between the ratio of X4-tropic latent HIV-1 and blood CD4+ T cell counts at least 6 months before and 12 months after the reference point was analyzed. Findings: We found that X4-tropic latent HIV-1 preferentially enriched in pTFH cells, comparing to other blood CD4+ T cell subsets (19.68% ± 4.54%, 13.06% ± 3.17% and in pTFH and mCD4, respectively; mean and SEM; P < 0.05). In addition, pTFH harbored a two-fold larger replication-competent of X4-tropic HIV-1 compared to mCD4 (0.50 ± 0.18 and 0.24 ± 0.08 IUPM in pTFH and mCD4, respectively; mean and SEM; P < 0.05). In cART-suppressed individuals, the ratio of X4-tropic latent HIV-1 in pTFH cells was precisely and inversely correlated with CD4+ T cell count in the peripheral blood (R = -0.80; P < 0.0001) and predicted its recovery after long-term cART treatment. The individuals with higher ratios of X4-tropic latent HIV-1 in pTFH cells were more likely to develop opportunistic co-infections. Interpretation: Given that few methods are currently available to quantify HIV-1 latent infection and it is difficult to analyze the virion-associated RNA in the presence of suppressive cART, we propose that the ratio of X4-tropic latent HIV-1 in pTFH cells could be an easily-measured indicator for the character of viral reservoir and disease progression. Funding Statement: National Special Research Program of China. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All human samples were anonymously coded in accordance with the local ethical guidelines (as stipulated by the Declaration of Helsinki). Written informed consents were provided by all study participants, and the protocol was approved by the IRB of Guangzhou Eighth People's Hospital (Guangzhou, China).