Helper T cell and B cell responses during the natural course of HIV infection

The acute phase of HIV-1 infection is characterized by a swift increase of viremia, resulting in a significant reduction of CD4+ T cell counts. Moreover, during this period seeding of the latent reservoir takes place. It has been previously shown that different memory subsets of CD4+ T cells play distinct roles in the establishment of the latent reservoir and are differently susceptible to infection. However, the dynamics and infection status of these subsets during the acute phase of the disease have not been sufficiently described. In the first part of our study we, therefore, investigated changes in the frequency of CD4+ T cells along the course of acute HIV-1 infection. Our data revealed a profound expansion of stem-cell-like memory CD4+ T cells (SCM) as a consequence of pro-apoptotic Fas receptor (CD95) up-regulation on the surface of naïve cells. We also demonstrated that the HIV-1 integration and replication preferentially take place in CD4+ T cells belonging to highly differentiated subsets, while naïve cells and SCM prove to be more resistant. Despite the relatively low frequency of infected SCM, we suggest that their quiescent phenotype and extensive expansion make them one of the key players in the establishment and persistence of the HIV-1 reservoir. Moreover, the magnitude of SCM expansion was positively associated with the set point viral load and frequency of productively infected CD4+ T cells. Thus, our data demonstrate an expansion of SCM during the acute phase of HIV1 infection and its association with the disease progression. Humoral response to HIV-infection shows a poor neutralizing capacity and only a fraction of individuals develop protective broadly neutralizing antibodies at the late stages of infection. In contrast antibodies with functional Fc portions, that are also proven to limit viral replication, develop soon after the onset of disease and can be detected in the majority of cases. The conditions under which these antibodies are generated however remain largely unknown. In the second part of this work, we report that the production of HIV-1 Env-specific antibodies triggering innate immune functions including ADCD, ADCP, ADNP, and NK cell activation depends on help from cognate CD4+ T and pTfh cells. The crucial signaling molecule sustaining functional antibody response was IL-21 while CD40L, IFNγ, and IL-4/13 played minor roles. Interestingly, the abundance of antigen did not increase the magnitude of antibody-dependent innate responses. As a potential source of these antibodies, we identified Env-specific memory B cells that are known to get activated in chronic HIV-1 infection. In particular,112 the TLM subset was strongly associated with antibody-dependent innate responses. The frequency and level of Blimp-1 expression in Env-specific memory B cells and TLM correlated with the same functional T cell subsets as antibody response. Thus, our data suggest a mechanism responsible for the generation of functional antibodies in chronically HIV-infected individuals that is based on CD4+ T cell-induced activation of memory B cells.


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