Immunity from reinfection: One of the many open questions about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is whether an individual who has cleared the virus can be infected a second time and get sick. Chandrashekar et al. and Deng et al. generated rhesus macaque models of SARS-CoV-2 infection and tested whether natural SARS-CoV-2 infection could result in immunity to viral rechallenge. They found that animals indeed developed immune responses that protected against a second infection. Although there are differences between SARS-CoV-2 infection in macaques and in humans, these findings have key implications for public health and economic initiatives if validated in human studies. Science , this issue p. 812 , p. 818

Despite the efficient suppression of HIV-1 replication that can be achieved with combined antiretroviral therapy (cART), low levels of type I interferon (IFN-I) signaling persist in some individuals. This sustained signaling may impede immune recovery and foster viral persistence. Here we report studies using a monoclonal antibody to block IFN-α/β receptor (IFNAR) signaling in humanized mice (hu-mice) that were persistently infected with HIV-1. We discovered that effective cART restored the number of human immune cells in HIV-1–infected hu-mice but did not rescue their immune hyperactivation and dysfunction. IFNAR blockade fully reversed HIV-1–induced immune hyperactivation and rescued anti–HIV-1 immune responses in T cells from HIV-1–infected hu-mice. Finally, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1 reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1–infected hu-mice. We conclude that low levels of IFN-I signaling contribute to HIV-1–associated immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a potential strategy to enhance immune recovery and reduce HIV-1 reservoirs in individuals with sustained elevations in IFN-I signaling during suppressive cART.

The direct link between sustained type I interferon (IFN-I) signaling and HIV-1–induced immunopathogenesis during chronic infection remains unclear. Here we report studies using a monoclonal antibody to block IFN-α/β receptor 1 (IFNAR1) signaling during persistent HIV-1 infection in humanized mice (hu-mice). We discovered that, during chronic HIV-1 infection, IFNAR blockade increased viral replication, which was correlated with elevated T cell activation. Thus, IFN-Is suppress HIV-1 replication during the chronic phase but are not essential for HIV-1–induced aberrant immune activation. Surprisingly, IFNAR blockade rescued both total human T cell and HIV-specific T cell numbers despite elevated HIV-1 replication and immune activation. We showed that IFNAR blockade reduced HIV-1–induced apoptosis of CD4 ⁺ T cells. Importantly, IFNAR blockade also rescued the function of human T cells, including HIV-1–specific CD8 ⁺ and CD4 ⁺ T cells. We conclude that during persistent HIV-1 infection, IFN-Is suppress HIV-1 replication, but contribute to depletion and dysfunction of T cells.

Activation of HIV-1 reservoirs and induction of anti–HIV-1 T cells are critical to control HIV-1 rebound after combined antiretroviral therapy (cART). Here we evaluated in humanized mice (hu-mice) with persistent HIV-1 infection the therapeutic effect of TLR3 agonist and a CD40-targeting HIV-1 vaccine, which consists of a string of 5 highly conserved CD4⁺ and CD8⁺ T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol fused to the C-terminus of a recombinant anti-human CD40 antibody (αCD40.HIV5pep). We show that αCD40.HIV5pep vaccination coadministered with poly(I:C) adjuvant induced HIV-1–specific human CD8⁺ and CD4⁺ T cell responses in hu-mice. Interestingly, poly(I:C) treatment also reactivated HIV-1 reservoirs. When administrated in therapeutic settings in HIV-1–infected hu-mice under effective cART, αCD40.HIV5pep with poly(I:C) vaccination induced HIV-1–specific CD8⁺ T cells and reduced the level of cell-associated HIV-1 DNA (or HIV-1 reservoirs) in lymphoid tissues. Most strikingly, the vaccination significantly delayed HIV-1 rebound after cART cessation. In summary, the αCD40.HIV5pep with poly(I:C) vaccination approach both activates replication of HIV-1 reservoirs and enhances the anti–HIV-1 T cell response, leading to a reduced level of cell-associated HIV-1 DNA or reservoirs. Our proof-of-concept study has significant implication for the development of CD40-targeting HIV-1 vaccine to enhance anti–HIV-1 immunity and reduce HIV-1 reservoirs in patients with suppressive cART.

SARS-CoV-2 Omicron variants feature highly mutated spike proteins with extraordinary abilities in evading antibodies isolated earlier in the pandemic. Investigation of memory B cells from patients primarily with breakthrough infections with the Delta variant enables isolation of a number of neutralizing antibodies cross-reactive to heterologous variants of concern (VOCs) including Omicron variants (BA.1-BA.4). Structural studies identify altered complementarity determining region (CDR) amino acids and highly unusual heavy chain CDR2 insertions respectively in two representative cross-neutralizing antibodies—YB9-258 and YB13-292. These features are putatively introduced by somatic hypermutation and they are heavily involved in epitope recognition to broaden neutralization breadth. Previously, insertions/deletions were rarely reported for antiviral antibodies except for those induced by HIV-1 chronic infections. These data provide molecular mechanisms for cross-neutralization of heterologous SARS-CoV-2 variants by antibodies isolated from Delta variant infected patients with implications for future vaccination strategy.

Depletion of CD4 ⁺ T cells during HIV-1 infection is mostly mediated by inflammatory cells via indirect but not clearly defined mechanisms. In this report, we used single-cell RNA-Seq (scRNA-Seq) technology to study HIV-induced transcriptomic change in innate immune cells in lymphoid organs. We performed scRNA-Seq on hCD45 ⁺ hCD3 ^– hCD19 ^– human leukocytes isolated from spleens of humanized NOD / Rag2 ^–/– γ _c ^–/– (NRG) mice transplanted with human CD34 ⁺ hematopoietic stem progenitor cells (NRG-hu HSC mice). We identified major populations of innate immune cells, including plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), macrophages, NK cells, and innate lymphoid cells (ILCs). HIV-1 infection significantly upregulated genes involved in type I IFN inflammatory pathways in each of the innate immune subsets. Interestingly, we found that TRAIL was upregulated in the innate immune populations, including pDCs, mDCs, macrophages, NK cells, and ILCs. We further demonstrated that blockade of the TRAIL signaling pathway in NRG-hu HSC mice prevented HIV-1–induced CD4 ⁺ T cell depletion in vivo. In summary, we characterized HIV-induced transcriptomic changes of innate immune cells in the spleen at single-cell levels, identified the TRAIL ⁺ innate immune cells, and defined an important role of the TRAIL signaling pathway in HIV-1–induced CD4 ⁺ T cell depletion in vivo.