Early Antiretroviral Therapy Preserves Functional Follicular Helper T and HIV-Specific B Cells in the Gut Mucosa of HIV-1–Infected Individuals

Abstract

HIV-1 infection is associated with B cell dysregulation and dysfunction. In HIV-1-infected patients, we previously reported preservation of intestinal lymphoid structures and dendritic cell maturation pathways after early combination antiretroviral therapy (e-ART), started during the acute phase of the infection, compared with late combination antiretroviral therapy started during the chronic phase. In this study, we investigated whether the timing of combination antiretroviral therapy initiation was associated with the development of the HIV-1-specific humoral response in the gut. The results showed that e-ART was associated with higher frequencies of functional resting memory B cells in the gut. These frequencies correlated strongly with those of follicular Th cells in the gut. Importantly, frequencies of HIV-1 Env gp140-reactive B cells were higher in patients given e-ART, in whom gp140-reactive IgG production by mucosal B cells increased after stimulation. Moreover, IL-21 release by PBMCs stimulated with HIV-1 peptide pools was greater with e-ART than with late combination antiretroviral therapy. Thus, early treatment initiation helps to maintain HIV-1-reactive memory B cells in the gut as well as follicular Th cells, whose role is crucial in the development of potent affinity-matured and broadly neutralizing Abs.

The Early Bird Gets the Worm: Benefits and Future Directions With Early Antiretroviral Therapy Initiation in Primary Hiv Infection

“…T-follicular helper cells (T FH ) and B cells are crucial in the development of antibodies against a wide variety of infections. T FH -mediated B-cell responses are significantly altered after PHI in the absence of ART [20,21]. This coincides with increased inflammation and a reduction in memory and effector B-cell functions.…”

The Architecture of Circulating Immune Cells Is Dysregulated in People Living With HIV on Long Term Antiretroviral Treatment and Relates With Markers of the HIV-1 Reservoir, Cytomegalovirus, and Microbial Translocation

“…B/T cell interactions take place in the germinal centers in lymph nodes and are orchestrated by follicular Th cells (Tfh) (64). As these cells are known to be highly permissive to HIV infection and serve as reservoirs during chronic infection, they could potentially explain these disrupted B/T cell interactions (64)(65)(66). Clinically, compromised B/T cells interactions may contribute to impaired immune responses to vaccination as well as increased risks for infections, such as invasive pneumococcal disease (5,67).…”

HIV-1 Envelope Recognition by Polyreactive and Cross-Reactive Intestinal B Cells

“…Ileum-resident plasmablasts and memory B cells in HIV-1-infected individuals have been shown to contain very few HIV-1-specific cells ( Trama et al., 2014 ). ART regimen early during the acute phase may be beneficial in preserving B cell immunity at mucosal sites ( Planchais et al., 2018 ). Interestingly, we found high-affinity gp140 antibodies more frequently in the eART donor, but studies on more donors are needed to confirm that observation.…”

“…Nonetheless, early antiretroviral therapy (eART) partially prevents HIV-1-induced mucosal damages and immune dysregulation ( Costiniuk and Angel, 2012 , Kök et al., 2015 , Ponte et al., 2016 ). eART allows preserving functional gut TFH and resting memory B cells specific to glycoprotein (gp)140 trimers ( Planchais et al., 2018 ). Mucosal transmission of HIV-1 induces a local production of immunoglobulin (Ig)G and IgA antibodies that predominantly target the gp41 subunit of the viral envelope glycoprotein gp160 ( Trama et al., 2014 , Yates et al., 2013 ).…”