HIV and FIV glycoproteins increase cellular tau pathology via cGMP-dependent kinase II activation

As the development of combination antiretroviral therapy (cART) against human immunodeficiency virus (HIV) drastically improves the lifespan of individuals with HIV, many are now entering the prime age when Alzheimer's disease (AD)-like symptoms begin to manifest. Hyperphosphorylated tau, a known AD pathological characteristic, has been prematurely increased in the brains of HIV-infected patients as early as in their 30s and is increased with age. This thus suggests that HIV infection may lead to accelerated AD phenotypes. However, whether HIV infection causes AD to develop more quickly in the brain is not yet fully determined. Interestingly, we have previously revealed that viral glycoproteins, HIV gp120 and feline immunodeficiency virus (FIV) gp95, induce neuronal hyperexcitation via cGMP-dependent kinase II (cGKII) activation in cultured hippocampal neurons. Here, we use cultured mouse cortical neurons to demonstrate that HIV gp120 and FIV gp95 are sufficient to increase cellular tau pathology, including intracellular tau hyperphosphorylation and tau release to the extracellular space. We further reveal that viral glycoprotein-induced cellular tau pathology requires cGKII activation. Together, HIV infection likely accelerates AD-related tau pathology via cGKII activation.

Differential V2-directed Antibody Responses in Non-human Primates Infected with SHIVs or Immunized with Diverse HIV Vaccines

V2p and V2i antibodies (Abs) that are specific for epitopes in the V1V2 region of the HIV gp120 envelope (Env) do not effectively neutralize HIV but mediate Fc-dependent anti-viral activities that have been correlated with protection from, or control of HIV, SIV and SHIV infection. Here, we describe a novel molecular toolbox that allows the discrimination of antigenically and functionally distinct polyclonal V2 Ab responses. We identified different patterns of V2 Ab induction by SHIV infection and three separate vaccine regimens that will aid in fine tuning an optimized immunization protocol for inducing V2p and V2i Abs. We observed no, or weak and sporadic V2p and V2i Abs in non-vaccinated Tier 1 and Tier 2 SHIV-infected NHPs, but in contrast, strong V2p and/or V2i Ab responses after immunization with a V2-targeting vaccine protocol using a prime/boost regimen with gp120 DNA and a V1V2-scaffold protein. The V2-targeting vaccine protocol is superior to both natural infection and to immunization with whole Env constructs for inducing functional V2p- and V2i-specific responses. Strikingly, levels of V2-directed Abs correlated inversely with Abs specific for gp120 and peptides of V3 and C5. These data demonstrate that a V1V2-targeting vaccine have advantages over the imprecise targeting of SIV/SHIV infections and of whole Env-based immunization regimens for inducing a more focused functional V2p- and V2i-specific Ab response.

Mixed Origins: HIV gp120-specific memory develops from pre-existing memory and naive B cells following vaccination in humans

The most potent and broad HIV envelope (Env)-specific antibodies often when reverted to their inferred germline versions representing the naive B cell receptor, fail to bind Env suggesting that the initial responding B cell population is not exclusively comprised of a naive population, but also a pre-existing cross-reactive antigen-experienced B cell pool that expands following Env exposure. Previously we isolated gp120-reactive monoclonal antibodies (mAbs) from participants in HVTN 105, an HIV vaccine trial. Using deep sequencing VH-lineage tracking we identified several of these mAb lineages in pre-immune peripheral blood. Several of these pre-immune lineages also persisted in the bone marrow, including CD138+ long-lived plasma cell compartment, ~7 months after the final vaccination. The majority of the pre-immune lineage members included IgM, however IgG and IgA members were also prevalent and exhibited somatic hypermutation. These results suggest that vaccine-induced gp120-specific antibody lineages originate from both naive and cross-reactive memory B cells.

Differential recognition of oligomannose isomers by glycan-binding proteins involved in innate and adaptive immunity

The recognition of oligomannose-type glycans in innate and adaptive immunity is elusive due to multiple closely related isomeric glycan structures. To explore the functions of oligomannoses, we developed a multifaceted approach combining mass spectrometry assignments of oligomannose substructures and the development of a comprehensive oligomannose microarray. This defined microarray encompasses both linear and branched glycans, varying in linkages, branching patterns, and phosphorylation status. With this resource, we identified unique recognition of oligomannose motifs by innate immune receptors, including DC-SIGN, L-SIGN, Dectin-2, and Langerin, broadly neutralizing antibodies against HIV gp120, N-acetylglucosamine-1-phosphotransferase, and the bacterial adhesin FimH. The results demonstrate that each protein exhibits a unique specificity to oligomannose motifs and suggest the potential to rationally design inhibitors to selectively block these protein-glycan interactions.