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Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer [(gp120/gp41)3] that promote virus entry into the cell. CD4-mimetic compounds (CD4mcs) comprise small organic molecules that bind in the highly conserved CD4-binding site of gp120 and prematurely induce inactivating Env conformational changes, including shedding of gp120 from the Env trimer. By inducing more “open,” antibody-susceptible Env conformations, CD4mcs also sensitize HIV-1 virions to neutralization by antibodies and infected cells to antibody-dependent cellular cytotoxicity (ADCC). Here, we report the design, synthesis and evaluation of novel CD4mcs based on an indoline scaffold. Compared with our current lead indane scaffold CD4mc, BNM-III-170, several indoline CD4mcs exhibit increased potency and breadth against HIV-1 variants from different geographic clades. Viruses that were selected for resistance to the lead indane CD4mc, BNM-III-170, are susceptible to inhibition by the indoline CD4mcs. The indoline CD4mcs also potently sensitize HIV-1-infected cells to ADCC mediated by plasma from HIV-1-infected individuals. Crystal structures indicate that the indoline CD4mcs gain potency compared to the indane CD4mcs through more favorable π-π overlap from the indoline pose and by making favorable contacts with the vestibule of the CD4-binding pocket on gp120. The rational design of indoline CD4mcs thus holds promise for further improvements in antiviral activity, potentially contributing to efforts to treat and prevent HIV-1 infection.

SARS-CoV-2 infection leads to a broad range of outcomes and immune responses, with the development of neutralizing antibodies generally correlated with protection against reinfection. Here, we have characterized both neutralizing activity and T cell responses in a cluster of subjects with mild disease linked to a single spreading event. Surprisingly, we observed sex-specific associations between spike- and particularly nucleoprotein-specific T cell responses and neutralization, with pro-inflammatory cytokines being linked to higher titers only in males. Using single cell immunoprofiling, which provided matched transcriptome and T-cell receptor (TCR) profiles in restimulated CD4 + and CD8 + cells from these subjects, we identified differences in type I IFN signaling that may underlie this difference in antibody generation. Finally, we also identified several TCRs associated with cytokine producing T cells. Altogether, our work maps the breadth of immunological outcomes of SARS-CoV2 infections and highlight the potential role of sex-specific feedback loops during the generation of neutralizing antibodies.

Rats were fed from weaning on 1 of 3 diets. Those fed a cafeteria diet had livers that were enlarged and abnormal by visual inspection. The rats themselves appeared healthy, had a normal growth rate, and were not significantly different in weight from control animals. Histologic examination revealed the livers of these rats to be rich in lipids and glycogen. Liver function tests showed a depressed level of alanine transaminase and an abnormal high-density lipoprotein/low-density lipoprotein. Dietary lipids generate free radicals that can interact with, and damage, DNA. However, when DNA was extracted from the livers and examined for the presence of the adduct M 1 -dG, there were no significant differences in adduct levels in livers from animals fed any of the diets. We conclude that the cafeteria diet can have long-term adverse effects on liver function even though overt measures of health may be unimpaired, body mass is maintained within normal limits, and liver DNA is not adversely affected.

This chapter discusses the sieges of cities, wanton plunder, and massacres in the period of the Peloponnesian War, which contributed more misery to the Greeks than all previous wars and saw an increase in the number of cities taken and Greeks killed or exiled. It can often be seen in Greek siege warfare that a city surrendered after internal ideological strife brought about a betrayal of the town. The Greeks experienced a dramatic rise in the number of sieges during the Peloponnesian War, but sieges and the atrocities that often accompanied them were experienced by Greek poleis before the Peloponnesian War and long before the late fifth century BC. They made assaults on cities throughout the Peloponnesian War.

The majority of preclinical and clinical human immunodeficiency virus type 1 (HIV-1) vaccine development efforts have focused on HIV-1 subtype B strains from the western world. However, the overwhelming majority of HIV/AIDS-related deaths occur in the developing world and are from other HIV-1 subtype strains. Therefore, we sought to develop and generate the first mucosally transmissible simian-human immunodeficiency virus (SHIV) challenge stocks from HIV-1 subtype AE env sequences. The sequences were identified from acutely infected HIV-1 individuals from Southeast Asia. The challenge stocks efficiently infected rhesus monkeys, replicated to high levels during acute infection, and established chronic setpoint viremia. The SHIV challenge stocks should facilitate the evaluation of vaccines and other interventions aimed at controlling the spread of HIV-1 subtype AE infection.

Without antiretroviral therapy, a small fraction of HIV-infected patients does not progress to AIDS. Such elite controllers (EC) or viremic controllers (VC) maintain undetectable or low levels of viremia, respectively. Generation of broadly neutralizing antibodies (bNAb) does not correlate with viral control, but might enhance antibody-dependent cellular phagocytosis by monocytes. Monocytes are classified into CD14+CD16-, CD14+CD16+ and CD14dimCD16+ monocytes. The latter show increased inflammatory responsiveness and are elevated during chronic HIV-1 infection. We measured markers of T cell activation and monocyte subset distribution and quantity, and investigated the relationship between these parameters and production of bNAb to identify markers for the development of bNAbs. We showed that VC display increased frequencies of CD38+ CD4+ and CD8+ T cells compared to EC. Our data also show that elevated frequencies of CD8+CD38+HLA-DR+ T cells and CD14dimCD16+ monocytes were associated with both viremic control status and production of bNAbs. bNAb production was also strongly associated with increased frequency of CD57+HLA-DR+ CD8+ T cells, as well as decreased expression of chemokine receptors CCR2 and CX3CR1 on CD14dimCD16+ monocytes in VC compared to EC. Further studies are required to establish the cause and effect of alterations in monocyte populations during HIV-1 infection and whether these could tip the scale towards viral control below detectable levels.

Antibodies (Abs) specific to the HIV-1 envelope regions, the CD4 binding site (CD4bs), V3 and V2 loops display neutralizing activity and may have protective functions. These Abs are present in almost all HIV-infected subjects and can also be induced by vaccines, as shown in clinical trials, but exhibit rather low neutralizing activities. To determine a threshold of mutations which may represent the maturity needed for cross-neutralizing antibodies, we have studied the percentage of mutations in the variable fragment of the heavy and light chain genes of 63 human monoclonal Abs (mAbs) which are specific to CD4bs, V3 and V2 domains, and tested their neutralizing activities against a panel of 41 pseudoviruses (psVs). All 63 mAbs neutralized, with various frequencies, a panel of sensitive Tier 1 psVs while the more resistant Tier 2 psVs were neutralized sporadically and only by V3 mAbs. Mutation frequencies ranged from 2.4% to 16.7% of the nucleotide sequences were observed for both the heavy and light chain genes of all mAbs. The percentage of mutations was comparable for CD4bs, V3 and V2 mAbs and had no correlation with the breadth of neutralization. The results indicate that mAbs with at least a few percent of mutations can neutralize sensitive Tier 1 viruses, which probably can be achieved during HIV vaccination.