HIV‐1 infection of CD4 T cells impairs antigen‐specific B cell function

Abstract

Failures to produce neutralizing antibodies upon HIV‐1 infection result in part from B‐cell dysfunction due to unspecific B‐cell activation. How HIV‐1 affects antigen‐specific B‐cell functions remains elusive. Using an adoptive transfer mouse model and ex vivo HIV infection of human tonsil tissue, we found that expression of the HIV‐1 pathogenesis factor NEF in CD4 T cells undermines their helper function and impairs cognate B‐cell functions including mounting of efficient specific IgG responses. NEF interfered with T cell help via a specific protein interaction motif that prevents polarized cytokine secretion at the T‐cell–B‐cell immune synapse. This interference reduced B‐cell activation and proliferation and thus disrupted germinal center formation and affinity maturation. These results identify NEF as a key component for HIV‐mediated dysfunction of antigen‐specific B cells. Therapeutic targeting of the identified molecular surface in NEF will facilitate host control of HIV infection.

Nef dimerization defect abrogates HIV viremia and associated immune dysregulation in the Bone Marrow-Liver-Thymus-Spleen (BLTS) humanized mouse model

“…Mock inoculated BLTS-humanized mice (n=4) were used for controls, with those mice showing no detectable HIV genome (C; timepoints data not shown). Not significant (ns) = P>0.05, * = P≤ 0.05, ** = P≤ 0.01, *** = P≤ 0.001, **** = P≤ 0.0001. tissue culture studies demonstrate that Nef promotes B cell dysregulation via impairment of CD4+ T cell-B cell interactions (Kaw et al, 2020). We demonstrated that Nef homodimerization is crucial for Nef-mediated enhancement of HIV infectivity and replication as well as dysregulation of host defenses in tissue culture models (Li et al, 2020;Poe and Smithgall, 2009;Rosa et al, 2015;Ryan P. Staudt, 2020;Trible et al, 2006a).…”

“…Previous studies also show that HIV Nef dimers are required to activate non-receptor tyrosine kinases of the Src and Tec families to enhance viral replication (Staudt et al JBC 2020) and are also linked to downregulation of MHC-I and CD4 receptor on T cells (Poe and Smithgall, 2009; Shu et al, 2017). Additionally, Nef promotes B cell hyper-activation and dysregulation; this pathogenic effect has been associated with T cell interaction (Chirmule et al, 1994; Kaw et al, 2020). Dysregulated immune activation and signaling by Nef are presumed to drive chronic HIV infection and progression to AIDS (Lori, 2008).…”

“…Additionally, Nef promotes B cell hyper-activation and dysregulation; this pathogenic effect has been associated with T cell interaction (Chirmule et al, 1994;Kaw et al, 2020). Dysregulated immune Figure 7.…”

“…Tissue culture studies demonstrate that Nef downregulates major histocompatibility complex class I (MHC-I) molecules in HIV infected CD4+ T cells (Chang et al, 2001; Dirk et al, 2016; Hung et al, 2007; Roeth et al, 2004) to impair CD8+ cytotoxic T cell-mediated killing of HIV infected cells (Gorry et al, 2007). Additionally, tissue culture studies demonstrate that Nef promotes B cell dysregulation via impairment of CD4+ T cell-B cell interactions (Kaw et al, 2020). We demonstrated that Nef homodimerization is crucial for Nef-mediated enhancement of HIV infectivity and replication as well as dysregulation of host defenses in tissue culture models (Li et al, 2020; Poe and Smithgall, 2009; Rosa et al, 2015; Ryan P. Staudt, 2020; Staudt and Smithgall, 2020; Trible et al, 2006a).…”

Immune subversion by HIV: part B

“…Kaw et al (2020) discovered such a mechanism and describe it in an elegant new study published in this issue of the EMBO Journal. They found that the HIV‐1 pathogenesis factor NEF, a small virus‐encoded myristoylated protein of 27–36 kDa, which is expressed at high levels throughout the viral replication cycle, prevents proper T‐cell help to B cells, resulting in reduced GC formation, prevention of B‐cell expansion, and inhibition of somatic hypermutation.…”