Early Preservation of CXCR5 ⁺ PD-1 ⁺ Helper T Cells and B Cell Activation Predict the Breadth of Neutralizing Antibody Responses in Chronic HIV-1 Infection

Abstract

Much is known about the characteristics of broadly neutralizing antibodies (bNAbs) generated during HIV-1 infection, but little is known about immunological mechanisms responsible for their development in only a minority of those infected by HIV-1. By monitoring longitudinally a cohort of HIV-1-infected subjects, we observed that the preservation of CXCR5 IMPORTANCEBroadly neutralizing antibodies are developed by HIV-1-infected subjects, but so far (and despite intensive efforts over the past 3 decades) they have not been elicited by immunization. Understanding how bNAbs are generated during natural HIV-1 infection and why only some HIV-1-infected subjects generate such antibodies will assist our efforts to elicit bNAbs by immunization. CXCR5؉ PD-1 ؉ CD4 ؉ T cells are critical for the development of high-affinity antigen-specific antibody responses. In our study, we found that the HIV-1-infected subjects who develop bNAbs have a higher frequency of peripheral CXCR5 ؉ PD-1 ؉ CD4 ؉ T cells in early infection and also that this frequency mirrored what was observed in uninfected subjects and correlated with the level of B cell activation across subjects. Our study highlights the critical role helper T cell function has in the elicitation of broadly neutralizing antibody responses in the context of HIV infection.

CXCL13 is a plasma biomarker of germinal center activity

“…A positive correlation between Ab breadth and CXCL13 was also observed in an independent cohort containing a small number (five) of individuals with neutralizing breadth (24). The generation of HIV neutralizing Abs is also positively correlated with HIV viral load (23,25), and viral load could affect plasma CXCL13 levels (24,26). We, therefore, asked whether viral load and CXCL13 were independent variables.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…Subjects developing bnAbs also have higher plasma levels of CXCL13, a biomarker of GC activity, at both early and chronic infection timepoints, than subjects who develop little/no antibody neutralization breadth 200, 201. Furthermore, in in vitro B‐cell co‐culture assays CXCR5 +  CD4 + Tfh cells isolated during acute infection from subjects who subsequently developed good neutralization breadth showed induction of similar levels of antibody secretion, but higher levels of class‐switch antibodies than Tfh cells from subjects developing little/no neutralization breadth, suggesting that Tfh cell function may potentially be superior in those who make bnAbs 200. Although these studies only addressed total circulating Tfh frequencies and function, in macaques infected with a simian‐human immunodeficiency virus (SHIV) expressing the HIV‐1 AD8 Env (SHIV AD8 ), the frequency of Env‐specific CD154 + or IL‐4 + (but not IFNγ + ) Tfh cells (LN PD1 +  CXCR5 +  CD4 + cells) at 44‐47 weeks post‐infection was shown to correlate positively with the concurrent frequency of IgG + GC B cells and with antibody neutralization breadth at both this and later timepoints during infection 188.…”

“…Analysis of the relationship between Tfh cell responses and bnAb induction during HIV‐1 infection is hampered by the limited availability of longitudinal samples from individuals who eventually develop bnAbs and the difficulty in studying LN Tfh cell responses in humans. Nonetheless individuals developing bnAbs have been shown to have a higher frequency of circulating memory Tfh cells (defined as PD1 +  CXCR3 − cells within CXCR5 +  CD4 + T cells47, 160 or PD1 +  CXCR5 + cells within CD4 + T cells200) both early (approximately 6 months) after infection and during chronic infection than individuals developing antibodies with little or no cross‐neutralizing breadth, an observation independent of the higher viral loads in subjects developing bnAbs 47, 160. Subjects developing bnAbs also have higher plasma levels of CXCL13, a biomarker of GC activity, at both early and chronic infection timepoints, than subjects who develop little/no antibody neutralization breadth 200, 201.…”

“…Nonetheless individuals developing bnAbs have been shown to have a higher frequency of circulating memory Tfh cells (defined as PD1 +  CXCR3 − cells within CXCR5 +  CD4 + T cells47, 160 or PD1 +  CXCR5 + cells within CD4 + T cells200) both early (approximately 6 months) after infection and during chronic infection than individuals developing antibodies with little or no cross‐neutralizing breadth, an observation independent of the higher viral loads in subjects developing bnAbs 47, 160. Subjects developing bnAbs also have higher plasma levels of CXCL13, a biomarker of GC activity, at both early and chronic infection timepoints, than subjects who develop little/no antibody neutralization breadth 200, 201. Furthermore, in in vitro B‐cell co‐culture assays CXCR5 +  CD4 + Tfh cells isolated during acute infection from subjects who subsequently developed good neutralization breadth showed induction of similar levels of antibody secretion, but higher levels of class‐switch antibodies than Tfh cells from subjects developing little/no neutralization breadth, suggesting that Tfh cell function may potentially be superior in those who make bnAbs 200.…”

HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4 + T Cell Responses

“…In nonhuman primates infected with simian-human immunodeficiency virus (SHIV), the quality and quantity of germinal center Env-specific CD4 ϩ T-follicular helper (Tfh) cells have been associated with the expansion of Envspecific B cells and broader antibody neutralization activity (6). In HIV-infected humans, studies have investigated the association between the frequencies of peripheral Tfh (pTfh) cells and the development of neutralizing antibodies (7)(8)(9). However, these and other studies in HIV-infected humans have examined only bulk CD4…”