Long-lived memory T cells are able to persist in the host in the absence of antigen; however, the mechanism by which they are maintained is not well understood. Recently, a subset of human T cells, stem cell memory T cells (T SCM cells), was shown to be self-renewing and multipotent, thereby providing a potential reservoir for T cell memory throughout life. However, their in vivo dynamics and homeostasis still remain to be defined due to the lack of suitable animal models. We identified T cells with a T SCM phenotype and stem cell-like properties in nonhuman primates. These cells were the least-differentiated memory subset, were functionally distinct from conventional memory cells, and served as precursors of central memory. Antigen-specific T SCM cells preferentially localized to LNs and were virtually absent from mucosal surfaces. They were generated in the acute phase of viral infection, preferentially survived in comparison with all other memory cells following elimination of antigen, and stably persisted for the long term. Thus, one mechanism for maintenance of long-term T cell memory derives from the unique homeostatic properties of T SCM cells. Vaccination strategies designed to elicit durable cellular immunity should target the generation of T SCM cells.

Antiretroviral therapy (ART) during the earliest stage of acute HIV infection (Fiebig I) might minimize establishment of a latent HIV reservoir and thereby facilitate viremic control after analytical treatment interruption (ATI). We show that 8 participants, who initiated treatment during Fiebig I and were treated for a median of 2.8 years, all experienced rapid viral load rebound following ATI, indicating that additional strategies are required to control or eradicate HIV.

A central effort in HIV vaccine development is to generate protective broadly neutralizing antibodies, a process dependent on T follicular helper (Tfh) cells. The feasibility of using peripheral blood counterparts of lymph node Tfh cells to assess the immune response and the influence of viral and vaccine antigens on their helper functions remain obscure. We assessed circulating HIV-specific IL-21(+)CD4(+) T cells and showed transcriptional and phenotypic similarities to lymphoid Tfh cells, and hence representing peripheral Tfh (pTfh) cells. pTfh cells were functionally active and B cell helper quality differed depending on antigen specificity. Furthermore, we found higher frequency of pTfh cells in peripheral blood mononuclear cell specimens from the ALVAC+AIDSVAX (RV144) HIV vaccine trial associated with protective antibody responses compared to the non-protective DNA+Ad5 vaccine trial. Together, we identify IL-21(+)CD4(+) T cells as pTfh cells, implicating them as key populations in the generation of vaccine-evoked antibody responses.

The mechanism of CD4 ؉ T-cell depletion in human immunodeficiency virus type 1 (HIV-1)-infected individuals remains unknown, although mounting evidence suggests that direct viral cytopathicity contributes to this loss. The HIV-1 Vpr accessory protein causes cell death and arrests cells in the G 2 /M phase; however, the molecular mechanism underlying these properties is not clear. Mutation of hydrophobic residues on the surface of its third alpha-helix disrupted Vpr toxicity, G 2 /M arrest induction, nuclear localization, and self-association, implicating this region in multiple Vpr functions. Cytopathicity by virion-delivered mutant Vpr protein correlated with G 2 /M arrest induction but not nuclear localization or self-association. However, infection with whole virus encoding these Vpr mutants did not abrogate HIV-1-induced cell killing. Rather, mutant Vpr proteins that are impaired for G 2 /M block still prevented infected cell proliferation, and this property correlated with the death of infected cells. Chemical agents that inhibit infected cells from entering G 2 /M also did not reduce HIV-1 cytopathicity. Combined, these data implicate Vpr in HIV-1 killing through a mechanism involving inhibiting cell division but not necessarily in G 2 /M. Thus, the hydrophobic region of the third alpha-helix of Vpr is crucial for mediating G 2 /M arrest, nuclear localization, and self-association but dispensable for HIV-1 cytopathicity due to residual cell proliferation blockade mediated by a separate region of the protein.

CD4؉

The authors note the following: "Due to an error in the evaluation of the raw ITC-data, we reported the wrong sign for the enthalpy values and correspondingly incorrect entropy values. The correct values are as follows: at pH 5.7: ΔH −54 ± 4 kJ/ mol, ΔS −68 ± 14 J/mol K and at pH 7.2: ΔH −62 ± 6 kJ/mol and ΔS −98 ± 18 J/mol K (Table 3)." The authors note that on page 5381, left column, first paragraph, line 9 "Two E1 entities dimerize upon their interaction with heparin, requiring 8-12 sugar rings to form the heparin-bridged APP-E1 dimer in an endothermic and pH-dependent process that is characterized by a low micromolar dissociation constant" should have read "Two E1 entities dimerize upon their interaction with heparin, requiring 8-12 sugar rings to form the heparin-bridged APP-E1 dimer in an exothermic and pH-dependent process that is characterized by a low micromolar dissociation constant." On page 5384, right column, third paragraph, line 23 "This reaction is driven by high entropy contributions of around 300 J/mol · K, probably resulting from the release of associated ions and water molecules upon heparin binding, as also observed for other heparin-binding proteins (reviewed, e.g., in ref. 39)" should have read "This reaction is driven by significant enthalpic contributions, probably arising from protein-protein interactions, also observed for other heparin-binding proteins (reviewed, e.g., in ref. 39)." This error does not affect the conclusions of the article.

Development of a vaccine against pulmonary tuberculosis (TB) may require immunization strategies that induce a high frequency of antigen-specific CD4 and CD8 T cells in the lung. The nonhuman primate (NHP) model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans. Here, we used an aerosol (AE) vaccination strategy to administer AERAS-402, a replication-defective recombinant adenovirus (rAd) type 35 expressing Mycobacterium tuberculosis (M.tb) antigens Ag85A, Ag85B, and TB10.4, in bacille Calmette-Guerin (BCG)-primed or unprimed rhesus macaques. Immunization with BCG generated low purified protein derivative (PPD)-specific CD4 T cell responses in blood and bronchoalveolar lavage (BAL). In contrast, aerosolized AERAS-402 alone or following BCG induced potent and stable Ag85A/b-specific CD4 and CD8 effector T cells in BAL that largely produced IFN-γ, as well as TNF and IL-2. Such responses induced by BCG, AERAS-402, or both failed to confer overall protection following challenge with 275 CFU of M.tb Erdman, although vaccine-induced responses associated with reduced pathology were observed in some animals. Anamnestic T cell responses to Ag85A/b were not detected in blood of immunized animals after challenge. Overall, our data suggest that a high M.tb challenge dose may be a critical factor in limiting vaccine efficacy in this model. However, the ability of AE rAd immunization to generate potent cellular immunity in the lung by AE rAd immunization suggests that using different or more immunogens, alternative rAd serotypes with enhanced immunogenicity, and a physiological challenge dose may achieve protection against M.tb.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019. We developed and evaluated an adjuvanted SARS-CoV-2 spike ferritin nanoparticle (SpFN) vaccine in nonhuman primates. High-dose (50-μg) SpFN vaccine, given twice 28 days apart, induced a T helper cell 1 (T H 1)–biased CD4 T H response and elicited neutralizing antibodies against SARS-CoV-2 wild type and variants of concern, as well as against SARS-CoV-1. These potent humoral and cell-mediated immune responses translated into rapid elimination of replicating virus in the upper and lower airways and lung parenchyma of nonhuman primates after high-dose SARS-CoV-2 respiratory challenge. The immune response elicited by SpFN vaccination and resulting efficacy in nonhuman primates support the utility of SpFN as a vaccine candidate for SARS-causing betacoronaviruses.