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Author(s): Anthony S. Fauci [1] The vulnerability of the United States and the rest of the world to attacks of bioterrorism remains starkly exposed by the as-yet unsolved anthrax attacks [...]

Targeting α4β7 in HIV: Nonhuman primate models can be useful in the development of new approaches to treating HIV infection. Sneller et al. conducted a human therapeutic trial based on promising results of a single nonhuman primate study in which treatment with an anti-integrin monoclonal antibody led to sustained suppression of SIV plasma viremia. The human clinical trial did not reproduce the positive effects reported in the animal study. These results illustrate that embarking on human therapeutic trials based on findings from a single animal study should be undertaken cautiously and only after careful consideration of factors, such as reproducibility of the findings in animals and the potential risks associated with the experimental intervention. Despite the substantial clinical benefits of antiretroviral therapy (ART), complete eradication of HIV has not been possible. The gastrointestinal tract and associated lymphoid tissues may play an important role in the pathogenesis of HIV infection. The integrin α4β7 facilitates homing of T lymphocytes to the gut by binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on venules in gut-associated lymphoid tissue. CD4+ T cells with increased expression of α4β7 are susceptible to HIV infection and may be key players in subsequent virus dissemination. Data from nonhuman primate models infected with simian immunodeficiency virus (SIV) have suggested that blockade of the α4β7/MAdCAM-1 interaction may be effective at preventing SIV infection and may have beneficial effects in animals with established viral infection. To explore whether these findings could be reproduced in HIV-infected individuals after interruption of ART, we conducted an open-label phase 1 clinical trial of vedolizumab, a monoclonal antibody against α4β7 integrin. Vedolizumab infusions in 20 HIV-infected individuals were well tolerated with no serious adverse events related to the study drug. After interruption of ART, the median time to meeting protocol criteria to restart therapy was 13 weeks. The median duration of plasma viremia of <400 copies/ml was 5.4 weeks. Only a single subject in the trial experienced prolonged suppression of plasma viremia after interruption of ART. These results suggest that blockade of α4β7 may not be an effective strategy for inducing virological remission in HIV-infected individuals after ART interruption. [ABSTRACT FROM AUTHOR]

A converging public health crisis is emerging because the opioid epidemic is fueling a surge in infectious diseases, such as human immunodeficiency virus infection with or without AIDS, the viral hepatitides, infective endocarditis, and skin and soft-tissue infections. An integrated strategy is needed to tailor preventive and therapeutic approaches toward infectious diseases in people who misuse and/or are addicted to opioids and to concurrently address the underlying predisposing factor for the infections-opioid use disorder. This commentary highlights the unique and complementary roles that the infectious diseases and substance use disorder communities can play in addressing this crisis of dual public health concerns. [ABSTRACT FROM AUTHOR]

Therapeutic strategies for achieving sustained virologic remission are being explored in human immunodeficiency virus (HIV)-infected individuals who began antiretroviral therapy (ART) during the early phase of infection. In the evaluation of such therapies, clinical protocols should include analytical treatment interruption (ATI); however, the immunologic and virologic impact of ATI in individuals who initiated ART early has not been fully delineated. We demonstrate that ATI causes neither expansion of HIV reservoirs nor immunologic abnormalities following reinitiation of ART. Our findings support the use of ATI to determine whether sustained virologic remission has been achieved in clinical trials of individuals who initiated ART early during HIV infection. [ABSTRACT FROM AUTHOR]

VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-α4β7 mAb (Rh-α4β7) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4+ T cells. To investigate the impact of combining VRC01 and Rh-α4β7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-α4β7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID50) of SHIVAD8-EO. The combination Rh-α4β7-VRC01 significantly delayed SHIVAD8-EO vaginal infection. Following infection, VRC01-Rh-α4β7-treated macaques maintained higher CD4+ T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-α4β7-treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIVAD8-EO envelope in the VRC01-Rh-α4β7 group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-α4β7 delayed infection, altered antiviral immune responses and minimized CD4+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-α4β7 on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies. [ABSTRACT FROM AUTHOR]

In the article, the authors discuss the effectiveness and challenges on the use of influenza vaccines against seasonal influenza viruses, as well as the need to develop vaccines against both seasonal and pandemic influenza. Other topics include the challenges in developing universal influenza vaccine like how to improve production, virus culture in cells, and modern vaccine platform technologies like vector-based vaccines, messenger RNA, and self-assembling nanoparticles.

Human immunodeficiency virus (HIV) is one of the most extensively studied viruses in history, and numerous extraordinary scientific advances, including an in-depth understanding of viral biology, pathogenesis, and life-saving antiretroviral therapies, have resulted from investments in HIV/AIDS research. While the substantial investments in HIV/AIDS research are validated solely on these advances, the collateral broader scientific progress resulting from the support of HIV/AIDS research over the past 30 years is extraordinary as well. The positive impact has ranged from innovations in basic immunology and structural biology to treatments for immune-mediated diseases and cancer and has had an enormous effect on the research and public and global health communities well beyond the field of HIV/AIDS. This article highlights a few select examples of the unanticipated and substantial positive spin-offs of HIV/AIDS research on other scientific areas. [ABSTRACT FROM AUTHOR]

A study to examine the nature and scope of emerging and re-emerging microbial threats as well as methods for their control is presented. Factors responsible for the emergence of these infectious diseases depend on the relationships between the microorganisms, their hosts and the environment and the factors, which frequently differ for the newly/deliberately emerging infections.

A number of perturbations of B cells has been described in the setting of HIV infection; however, most remain poorly understood. To directly address the effect of HIV replication on B cell function, we investigated the capacity of B cells isolated from HIV-infected patients to respond to a variety of stimuli before and after reduction of viremia by effective antiretroviral therapy. B cells taken from patients with high levels of plasma viremia were defective in their proliferative responses to various stimuli. Viremia was also associated with the appearance of a subpopulation of B cells that expressed reduced levels of CD21. After fractionation into [CD21.sup.high]- and [CD21.sup.low]-expressing B cells, the [CD21.sup.low] fraction showed dramatically reduced proliferation in response to B cell stimuli and enhanced secretion of immunoglobulins when compared with the [CD21.sup.high] fraction. Electron microscopic analysis of each fraction revealed cells with plasmacytoid features in the [CD21.sup.low] B cell population but not in the [CD21.sup.high] fraction. These results indicate that HIV viremia induces the appearance of a subset of B cells whose function is impaired and which may be responsible for the hypergammaglobulinemia associated with HIV disease.

The response to AIDS can be used as a model for other communicable diseases such as malaria, tuberculosis, hepatitis C, West Nile fever, dengue, respiratory infections, diarrheal diseases, and measles. These diseases can only be controlled through a multifaceted response that includes surveillance, public education, sanitation, control of insect vectors, nutritional supplementation, effective treatments, and vaccines.

[CD8.sup.+] T cell-mediated antiviral activity against HIV has been described consistently in infected individuals; however, the role of this activity in controlling replication of HIV in the latently infected, resting [CD4.sup.+]+ T cell reservoir is unclear. By using an ex vivo system, we show that replication of HIV in this viral reservoir is effectively suppressed in coculture by autologous [CD8.sup.+] T cells in long-term nonprogressors (LTNPs) and in patients whose viremia was controlled by highly active antiretroviral therapy (HAART), but not in therapy-naive patients who had substantial levels of plasma viremia. This antiviral activity was largely independent of cytotoxic [CD8.sup.+] T lymphocytes (CTL). When the role of soluble [CD8.sup.+] T cell-derived factors was examined, we found that CC-chemokines played a major role in inhibition of viral replication in the latent viral reservoir in some LTNPs and patients receiving HAART, but not in chronically infected patients who were not receiving antiretroviral therapy. Potent antiviral activity, independent of CC-chemokines, was found mainly in patients in whom HAART was initiated shortly after the acute phase of HIV infection. These results indicate that [CD8.sup.+] T cells provide potent suppressive activity against HIV replication in the latent viral reservoir via direct cellular contact in patients who are naturally LTNPs or in those who are treated with HAART. Furthermore, the profound antiviral activity exerted by non-CC-chemokine soluble factors in infected patients who began HAART early in HIV infection suggests that preservation of this HIV-suppressive mechanism by early initiation of therapy may play an important role in the containment of viral replication in infected patients following interruption of therapy. HIV-1 | [CD8.sup.+] T cells | soluble factors | latency | HAART

Binding of HIV type 1 (HIV-1) envelope glycoproteins to the surface of a [CD4.sup.+] T cell transduces intracellular signals through the primary envelope receptor, CD4, and a coreceptor, either CCR5 or CXCR4. Furthermore, envelope-[CD4.sup.+] cell interactions increase rates of apoptosis in peripheral blood mononuclear cells (PBMCs). We demonstrate that in primary T lymphocytes, recombinant HIV-1 envelope proteins induce the activation of caspase-3 and caspase-6, which belong to a family of cysteine proteases that, upon activation, promote programmed cell death. Envelope-mediated activation of caspase-3 and caspase-6 depended on envelope-CD4 receptor interactions; CCR5-utilizing as well as CXCR4-utilizing envelopes elicited this response. Focal adhesion kinase (FAK) is a substrate of both caspase-3 and caspase-6, and inactivation of FAK by these caspases promotes apoptosis. Envelope treatment of lymphocytes led to the cleavage of FAK in a manner consistent with caspase-mediated cleavage.

Identifying the immunologic and virologic consequences of discontinuing antiretroviral therapy in HIV-infected patients is of major importance in developing long-term treatment strategies for patients with HIV-1 infection. We designed a trial to characterize these parameters after interruption of highly active antiretroviral therapy (HAART) in patients who had maintained prolonged viral suppression on antiretroviral drugs. Eighteen patients with [CD4.sup.+] T cell counts [is greater than or equal to] 350 cells/ [micro]l and viral load below the limits of detection for [is greater than or equal to] 1 year while on HAART were enrolled prospectively in a trial in which HAART was discontinued. Twelve of these patients had received prior IL-2 therapy and had low frequencies of resting, latently infected CD4 cells. Viral load relapse to [is greater than] 50 copies/ml occurred in all 18 patients independent of prior IL-2 treatment, beginning most commonly during weeks 2-3 after cessation of HAART. The mean relapse rate constant was 0.45 (0.20 [log.sub.10] copies) [day.sup.-1], which was very similar to the mean viral clearance rate constant after drug resumption of 0.35 (0.15 [log.sub.10] copies) [day.sup.-1] (P = 0.28). One patient experienced a relapse delay to week 7. All patients except one experienced a relapse burden to [is greater than] 5,000 RNA copies/ml. Ex vivo labeling with BrdUrd showed that CD4 and CD8 cell turnover increased after withdrawal of HAART and correlated with viral load whereas lymphocyte turnover decreased after reinitiation of drug treatment. Virologic relapse occurs rapidly in patients who discontinue suppressive drug therapy, even in patients with a markedly diminished pool of resting, latently infected [CD4.sup.+] T cells. HIV-1 infection | antiretroviral drugs | viral load | relapse | CD4

The use of highly active antiretroviral therapy (HAART) in the treatment of HIV-1-infected individuals has provided a considerable amount of information regarding the dynamics of viral replication and has resulted in enormous advances in HIV therapeutics. The profound suppression of plasma viremia in HIV-infected individuals receiving HAART has resulted in a highly beneficial clinical effect and a dramatic decrease in the death rate attributable to AIDS. Nonetheless, the persistence of reservoirs of HIV, including latently infected, resting [CD4.sup.+] T cells that can give rise to infectious HIV upon stimulation in vitro, has posed a sobering challenge to the long-term control or eradication of HIV in infected individuals receiving HAART. Although a recent study has demonstrated that the size of the pool of latently infected, resting [CD4.sup.+] T cells can be markedly diminished with intermittent interleukin (IL)-2 and continuous HAART, complete eradication of HIV in infected individuals remains extremely problematic. Here, we discuss recent developments in studies of the latent reservoir of HIV in patients receiving HAART and implications for the long-term treatment of infected individuals and eradication of the infection.

The article offers information on the literature on the treatment of coronavirus disease 2019 as filled with anecdotal reports of therapeutic successes in clinical trials with small numbers of patients and observational cohort studies claiming efficacy. It mentions that dexamethasone has become the standard of care for patients with advanced Covid-19.

Lorenzo Moretta is a visionary scientist who has made major advances in the field of Immunology since his early career and throughout his over 45 years of active research. Legends of allergy and immunology: Lorenzo Moretta - Unfolding the mysteries of NK cells and much more Adapting T cell cloning techniques to NK cells and exploiting the mAb technology, Lorenzo, still in close collaboration with Alessandro, began to solve the puzzling question of how human NK cells discriminate between healthy and tumor cells. [Extracted from the article]

This article highlights biomedical research goals for the development of critical tools, including innovative diagnostics, safe and effective vaccines, and new and improved therapeutics, necessary to achieve an end to the global epidemic of sexually transmitted infections. The incidence of sexually transmitted infections (STIs), including gonorrhea, syphilis, chlamydia, and trichomoniasis, is increasing by over 1 million new cases daily and represents a global public health crisis. There is an alarming increase of gonorrhea and syphilis among men who have sex with men and bisexual men, 2 key populations also at high risk for human immunodeficiency virus. A refocused, dedicated, and intensive biomedical research program is needed targeting development of innovative diagnostics, safe and effective vaccines, and new and improved therapeutics. This article highlights biomedical research goals providing critical tools necessary to achieve an end to the global STIs epidemic. [ABSTRACT FROM AUTHOR]