X4-Tropic Latent HIV-1 Is Enriched in Peripheral Follicular Helper T Cells and Is Correlated with Disease Progression

Abstract

Follicular helper T (TFH) cells have been shown to support productive human immunodeficiency virus type 1 (HIV-1) replication and to serve as a key component of the latent viral reservoir. However, the viral characteristics of this latent reservoir and the clinical relevance of this reservoir remain unclear. In this study, we assessed the tropic composition of latent viruses from peripheral TFH (pTFH), non-TFH memory, and naive CD4+ T cells from individuals with HIV-1 infections on suppressive combined antiretroviral therapy (cART). X4-tropic latent HIV-1 was preferentially enriched in pTFH cells compared to levels in the other two subsets. Interestingly, the ratio of X4-tropic latent HIV-1 in pTFH cells not only was robustly and inversely correlated with blood CD4+ T cell counts across patients but also was prognostic of CD4+ 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 coinfections. 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 is a valuable indicator for disease progression and cART efficacy. IMPORTANCE TFH cells have been shown to harbor a significant amount of latent HIV-1; however, the viral characteristics of this reservoir and its clinical relevance remain largely unknown. In this study, we demonstrate that X4-tropic latent HIV-1 is preferentially enriched in pTFH cells, which also accurately reflects the viral tropism shift. The ratio of X4-tropic proviruses in pTFH cells but not in other memory CD4+ T cell subsets is inversely and closely correlated with blood CD4+ T cell counts and CD4+ T cell recovery rates with cART. Our data suggest that the ratio of X4-tropic provirus in peripheral TFH cells can be easily measured and reflects disease progression and treatment outcomes during cART.

Abnormal Shift in B Memory Cell Profile Is Associated With the Expansion of Circulating T Follicular Helper Cells via ICOS Signaling During Acute HIV-1 Infection

“…Some studies observed that the frequency of cTfh cells were high in HIV-1 infected individuals ( 52 , 53 ), which was consistent with our findings ( Figure 1D ). cTfh cells are highly permissive to HIV-1 ( 54 , 55 ), where viral replication or antigen stimulation may drive the proliferation and accumulation of cTfh cells. Cytokine storm in AHI, such as elevated IL-6 and IFN-γ during HIV/SIV infection, could be potential mechanisms for the expansion of cTfh cells ( 56 , 57 ).…”

Identification of CD98 as a Novel Biomarker for HIV-1 Permissiveness and Latent Infection

“…Previous studies revealed that peripheral follicular T helper cells are more susceptible to HIV-1 infection and are responsible for the persistence of the HIV-1 reservoir in HIV-1-infected individuals receiving cART ( 34 – 37 ). Therefore, using PD-1 and CXCR5 to characterize the pTFH cells in CD98 high CD4 + T cells or CD98 low CD4 + T cells, we found that the expression of CXCR5 and the proportion of pTFH cells were significantly higher in CD98 high CD4 + T cells than those in CD98 low CD4 + T cells from PBMCs of HIV-1-infected individuals receiving cART ( Fig.…”

Clinical Association of Viral Tropism and Serum Cytokines in Untreated HIV-1 Infection Patients

“…The env gene was ampli ed by two rounds of nested PCR. The sequences of primers are F:5'-GAGAAAGAGCAGAAGACAGTGGCAATGAGAG-3', R:5'-CTTGTAAGTCATTGGTCTTAAAGGTACCTGAGGTCTG-3' [13]. After obtaining the gene sequencing product, the data sets were subsequently evaluated with the coreceptor tropism prediction algorithm Geno2pheno (https://coreceptor.geno2pheno.org), which predicts HIV-1 coreceptor usage based on a database [14].…”