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

Abstract

Background: Follicular helper T (TFH) cells are quantitatively and functionally altered in chronic human immunodeficiency virus type 1 (HIV-1) infection and harbor a significant amount of replication-competent latent viruses. However, the viral characteristics of this latent reservoir and its clinical relevance remain unclear. Methods: The viral tropism of proviral DNA in and replication-competent virus from peripheral TFH, non-TFH memory CD4+ T and non-TFH naive CD4+ T cells from 47 HIV-1 infected individuals on suppressive combined antiretroviral therapy (cART) were assessed by deep-sequencing. 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: X4-tropic latent HIV-1 were preferentially enriched in pTFH cells compared 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). Interestingly, the ratio of X4-tropic latent HIV-1 in pTFH cells was not only robustly and inversely correlated with blood CD4+ T cell count across patients (R = -0.80; P < 0.0001) but prognostic of the T cell recovery in individuals on long-term cART. Moreover, patients with higher X4-tropic latent HIV-1 ratios in pTFH cells showed greater risks of opportunistic co-infections. Interpretation: These findings reveal the characteristics of latent HIV-1 in TFH cells and suggest that the ratio of X4-tropic latent HIV-1 in pTFH cells can serve as a valuable biomarker for disease progression and efficacy of cART. Funding Statement: This work was supported by the National Special Research Program of China for Important Infectious Diseases (2018ZX10302103 and 2017ZX10202102), the Important Key Program of Natural Science Foundation of China (81730060), the Joint-innovation Program in Healthcare for Special Scientific Research Projects of Guangzhou (201803040002) to H.Z; supported by National Natural Science Foundation of China (81672024), Natural Science Foundation of Guangdong Province of China (2017A030306005, 2016A030313325), Pearl River Scholar Program of Guangdong, Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S638) to K.D; supported by the Natural Science Foundation of Guangdong (2016A030313826) to HH.L. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The Guangzhou Eighth People's Hospital Review Board approved all protocols for human study. All subjects gave informed consent.