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Four Decades of HIV/AIDS Considering the spectacular scientific advances that have been made over nearly four decades, it is conceivable that with optimal implementation of available prevention str...

Research in the Context of a Pandemic Clifford Lane and Anthony Fauci comment on the findings of the RECOVERY trial of dexamethasone to treat Covid-19, noting that scientifically robust and ethical...

Eastern Equine Encephalitis Virus In the summer and fall of 2019, nine U.S. states reported 36 human cases (14 of them fatal) of EEE, an arthropod-borne viral (arboviral) disease transmitted by mos...

A Covid-19 Conversation with Anthony Fauci In this audio interview conducted on January 27, 2021, the editors are joined by Dr. Anthony Fauci, U.S. Chief Medical Advisor, to discuss Covid-19 testin...

The scientific feasibility of developing a safe, effective Zika vaccine doesn't ensure successful development. An efficient development pathway must be delineated, including better ways to evaluate vaccine candidates for intended target populations.

PEPFAR — 15 Years and Counting the Lives Saved Launched in 2003, the President’s Emergency Plan for AIDS Relief has had a major impact on the HIV/AIDS pandemic. Support for the program should continue, allowing it to serve as a model for the control and elimination of other devastating infectious diseases.

Chasing Seasonal Influenza As we prepare for a potentially severe influenza season, we must consider whether our current vaccines can be improved and whether longer-term, transformative vaccine approaches are needed to minimize influenza-related morbidity and mortality.

Sylvatic transmission cycles of yellow fever continue to occur in endemic tropical regions. If the outbreak in Brazil leads to urban spread, U.S. clinicians should adopt a high index of suspicion for the disease, particularly in travelers returning from affected areas.

The explosive pandemic of Zika virus infection in South and Central America is the most recent of four unexpected arrivals of important arthropod-borne viral diseases in the Western Hemisphere over the past 20 years. Is this an important new disease-emergence pattern?

Studies proving that the benefits of prompt initiation of antiretroviral therapy for HIV infection outweigh the risks and that preexposure prophylaxis can be implemented safely and effectively will serve as critical tools in the fight to end the HIV–AIDS pandemic.

An outbreak of Ebola virus disease has jolted West Africa, claiming more than 1000 lives. As the disease's spread gains attention, health professionals and the public struggle to comprehend the unfolding dynamics and separate misinformation and speculation from truth.

New technologies can revolutionize influenza vaccine design, production, and delivery. In the near future, advances should reduce vaccine production time, provide enhanced protection, and end mismatches between vaccine strains and circulating viruses.

Classic preventive vaccines are designed to mimic the effects of natural exposure to microbes. They provide a high level of long-lasting protection against infection in the vast majority of recipients and serve as freestanding preventive measures. Although a classic preventive vaccine remains the ultimate goal of efforts to develop a vaccine for protection against the human immunodeficiency virus (HIV), the enormous genetic diversity and other unique features of the HIV envelope protein have thus far thwarted attempts to identify an effective candidate. However, we have learned from studies of HIV pathogenesis in humans and from animal models that a vaccine that induces strong T-cell–mediated immune responses in the absence of broadly neutralizing antibodies may prove beneficial even if infection is not completely prevented. Vaccine-induced T-cell responses may blunt initial viremia and prevent the early and massive destruction of memory CD4+ T cells that help control infection and prolong disease-free survival. Furthermore, secondary transmission may also be reduced if the vaccine helps to control viral replication; efficiency of transmission is directly related to plasma virus levels. T-cell vaccines represent uncharted territory, and their use may have outcomes that challenge researchers and regulators alike. If proven successful, a disease-modifying HIV vaccine would also present new challenges for the entire public health community, since it would not be a stand-alone preventive measure, as are most classic preventive vaccines. Instead, it would need to be delivered in the context of a comprehensive HIV-prevention program. OB S T AC L E S T O VAC C I NE DE V E L OPM E N T The development of more than two dozen antiretroviral therapies to combat HIV infection has resulted in a dramatic decrease in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS) in developed countries and, increasingly, in low- and middle-income countries as these therapies become more widely available. Despite ongoing prevention efforts, however, HIV continues to spread unabated in many parts of the world, with an estimated 14,000 new infections occurring daily. A safe and effective HIV vaccine would be an enormously valuable tool in the campaign to stop the spread of HIV. Most viruses against which successful vaccines have been developed undergo some level of initial replication and dispersal from the portal of entry before the virus reaches its target organ and triggers pathogenic sequelae. During this period, the virus remains vulnerable to eradication by the immune system. When prior immunization or exposure to a virus has elicited virus-specific immunologic memory, the increased speed and intensity of the immune response can prevent or mitigate disease. The nature of the interaction between HIV and the immune system is complex, and the relevance of different immune responses to the control of infection is only partially understood (Fig. 1). The primary stage of HIV infection begins with a burst

An HIV vaccine has thus far been elusive. Drs. Margaret Johnston and Anthony Fauci remain cautiously optimistic that a substantial increase in our understanding of HIV infection and disease will lead to creative ideas about how to design an effective HIV vaccine. Dr. Anthony Fauci discusses the 30-year search for an HIV vaccine, recent setbacks, and prospects for future success. Dr. Fauci is the director of the National Institute of Allergy and Infectious Diseases, Bethesda, MD.

Activation of the immune system is a normal response to antigenic stimulation, and such activation enhances the replication of human immunodeficiency virus type 1 (HIV-1). We studied the effect of immunization with a common recall antigen on viral expression in HIV-1-infected patients, on the ability to isolate virus, and on the susceptibility to HIV-1 infection of peripheral-blood mononuclear cells (PBMCs) from control subjects not infected with HIV-1.Thirteen HIV-1-infected patients and 10 uninfected adults were given a 0.5-ml booster dose of tetanus toxoid. Studies were performed to evaluate changes in the degree of plasma viremia, proviral burden, the ability to isolate HIV-1, and the susceptibility of PBMCs to acute infection in vitro. Two patients underwent sequential lymph-node biopsies for the assessment of viral burden in these tissues.All 13 HIV-1-infected patients had transient increase in plasma viremia after immunization, and the proviral burden increased in 11. These changes did not correlate with the base-line CD4+ T-cell counts. The lymph-node tissue also had increases in the proviral burden and viral RNA after immunization. The virus was more easily isolated from PBMCs from nine of the patients after immunization than before immunization. Despite considerable variability in the results, PBMCs from 7 of the 10 normal subjects were more easily infected in vitro with HIV-1 after immunization than before immunization.Activation of the immune system by an ongoing antigen-specific immune response to an exogenous stimulus transiently increases the expression of HIV-1 and may enhance the susceptibility of uninfected subjects to HIV-1.

The current shortfall in anticipated doses of vaccine for the upcoming influenza season1 makes the reports by Belshe et al.2 and Kenney et al.3 in this issue of the Journal particularly timely. These studies raise the possibility of using alternative routes of immunization (e.g., intradermal, as opposed to intramuscular, administration) with smaller doses of vaccine as a means of “stretching” available doses of influenza vaccine in times of shortages. In addition, the studies indirectly raise provocative issues regarding the potential effect of these alternative routes of immunization in targeting specialized cells of the immune system to enhance the immunogenicity of . . .

Background In a small percentage of persons infected with human immunodeficiency virus type 1 (HIV-1), there is no progression of disease and CD4+ T-cell counts remain stable for many years. Studies of the histopathological, virologic, and immunologic characteristics of these persons may provide insight into the pathogenic mechanisms that lead to HIV disease and the protective mechanisms that prevent progression to overt disease. Methods and Results We studied 15 subjects with long-term nonprogressive HIV infection and 18 subjects with progressive HIV disease. Nonprogressive infection was defined as seven or more years of documented HIV infection, with more than 600 CD4+ T cells per cubic millimeter, no antiretroviral therapy, and no HIV-related disease. Lymph nodes from the subjects with nonprogressive infection had significantly fewer of the hyperplastic features, and none of the involuted features, characteristic of nodes from subjects with progressive disease. Plasma levels of HIV-1 RNA and the viral ...

Infection with human immunodeficiency virus (HIV) causes AIDS. As a consequence of the interaction of gp120 envelope with the CD4 receptor molecule expressed by a subset of T lymphocytes and by mononuclear phagocytes (MPs), a second envelope protein (gp41) mediates fusion of the virion membrane with the target membrane. In these events the role of adhesion molecules such as LFA-1 has recently been highlighted. Following viral entry, reverse transcription of the virion-associated RNA and integration of proviral DNA into the host genome are crucial steps in HIV infection, which can lead to expression of high levels of new HIV or to silent infection for indefinite periods, a condition defined as viral latency. Several factors in addition to endogenous viral regulatory proteins have been reported as capable of modulating the state of viral latency and expression in vitro, including the cytokine network that normally modulates immune homeostasis as well as the immune response to inflammatory stimuli. Finally, recent studies have underscored the observation that the CD4+ T lymphocytes are the major reservoir of HIV in the peripheral blood compartment and in the lymphoid tissues, which are characterized by a greater viral burden, whereas in nonlymphoid organs such as the brain and the lung, local infection is predominantly sustained by MPs.

The addition of human immunodeficiency virus type 1 (HIV-1)–protease inhibitors to the armamentarium of antiretroviral drugs has dramatically improved the prognosis for HIV-infected persons.1–3 Although these agents do not eradicate the virus,4–6 they can provide long-term control of viral replication and substantially prolong disease-free survival, and they represent an important therapeutic advance. As has been the case throughout the brief history of the HIV epidemic, any progress invariably leads to new obstacles to be overcome; the introduction of highly active antiretroviral therapy is certainly no exception to this rule. A number of sociologic, pharmacologic, immunologic, and virologic issues . . .

The devastating global impact of the acquired immunodeficiency syndrome (AIDS) has greatly sensitized the public to the threat of new microbes that are capable of wreaking havoc on the world's popu...

One of the many mysteries about infection with the human immunodeficiency virus (HIV) is why, in the face of an adequate stimulus (the virus itself) and a competent immune system (the status of mos...

We studied B-lymphocyte function in 12 homosexual male patients with the acquired immunodeficiency syndrome, 5 healthy homosexual men, and 12 heterosexual controls. In comparison with the heterosexual controls, the patients were found to have elevated numbers of cells spontaneously secreting immunoglobulin, decreased B-cell proliferative responses to T-cell-independent B-cell mitogens, and qualitatively deficient helper T cells. The hyperactive spontaneous B-cell responses as well as the refractoriness to signals for T-cell-independent B-cell activation were highly suggestive of an in vivo polyclonal activation of B cells and may have been responsible for the manifestations of B-cell hyperreactivity, such as hypergammaglobulinemia, seen in these patients. We conclude that the scope of immune dysfunction in the acquired immunodeficiency syndrome involves B cells as well as T cells.

THE acquired immunodeficiency syndrome (AIDS) is a novel, epidemic form of immunodeficiency that has been widely recognized within the past three years.1 2 3 Full-blown AIDS, as defined clinically ...

We studied 17 patients with severe systemic necrotizing vasculitis over an 11-year-period. Sixteen patients were treated daily with cyclophosphamide (2 mg per kilogram per day), and one was treated with azathioprine (2 mg per kilogram per day). Before entering the study, all patients had active and progressive disease, even though 16 patients had been receiving corticosteroids that had caused severe and often incapacitating toxic side effects. Three patients died during the study. Complete and often dramatic remissions occurred in the surviving 14 patients, who were then placed on alternate-day corticosteroid treatment with continuation of cyclophosphamide. Corticosteroids were later discontinued in seven patients. The mean duration of remission was 22 months (range, two to 61). No patient showed recurrence of disease during treatment with cytotoxic agents.

Dermatitis herpetiformis is associated with the HLA-B8/DRw3 haplotype in over 90 per cent of patients, and various percentages have been reported to have circulating immune complexes. Since removal of immune complexes from the circulation is thought to depend on the Fc-receptor function of tissue macrophages, we studied this function by measuring the clearance of IgG-sensitized autologous erythrocytes in 16 patients with dermatitis herpetiformis, in normal controls with the HLA-B8/DRw3 haplotype, and in randomly selected controls. All patients were HLA-B8 positive, and all of 12 patients tested were HLA-DRw3 positive. Erythrocyte clearance was reduced in eight of the 16 patients, but did not correlate with immune-complex levels. Four of eight controls with HLA-B8/DRw3 also had delayed Fc-receptor-mediated clearance as compared with normal controls. In addition, both patients and HLA-B8/DRw3-positive controls had decreased percentages and total numbers of T cells bearing Fc receptors for IgG. These findings indicate a functional Fc-receptor defect associated with the HLA-B8/DRw3 antigens.

A 70-year-old woman with cyclic neutropenia was treated with 16 mg of etiocholanolone and 25 mg of prednisolone intramuscularly every other day. During 14 weeks' treatment amplitude of cyclic fluctuations in neutrophil counts gradually decreased, but pretreatment cycles returned promptly after treatment was stopped. Prednisolone alone every other day (25 mg) reproduced this result, and by 23 weeks, neutrophil counts became stable at about 1500 per cubic millimeter. tcycling of monocytes, platelets and reticulocytes was also eliminated, as were symptoms that had accompanied neutropenic periods. In addition, bone-marrow neutrophil precursors and neutrophil marrow reserves were stabilized. The patient was subsequently maintained satisfactorily with oral prednisolone, 20 mg every other day. These studies demonstrate that the discontinuous myeloid maturation that occurs in cyclic neutropenia can be corrected with prednisolone every other day.

To assess the prevalence and associated risk factors for human immunodeficiency virus (HIV) infection in patients attending inner-city clinics for sexually transmitted diseases in Baltimore, we screened 4028 patients anonymously, of whom 209 (5.2 percent) were seropositive for HIV. HIV-seropositivity rates were higher among men (6.3 percent) than women (3.0 percent) (P less than 0.001) and among blacks (5.0 percent) than whites (1.2 percent) (P less than 0.02). Among men, but not women, HIV seroprevalence increased markedly and steadily up to the age of 40. In men, HIV seropositivity was independently associated with increased age, black race, a history of homosexual contact, and the use of parenteral drugs. In women, a history of parenteral drug use or of being a sexual partner of a bisexual man or parenteral drug user were independently predictive of HIV seropositivity. In men, HIV seropositivity was also associated with a history of syphilis or a reactive serologic test for syphilis, and in women, with a history of genital warts. Since these associations were independent of the type and number of reported sexual partners, they raise the possibility that sexually transmitted diseases that disrupt epithelial surfaces may be important in the transmissibility of HIV. In addition, on a self-administered questionnaire, one third of HIV-infected men and one half of infected women did not acknowledge previous high-risk behavior for HIV exposure. These data suggest that patients at clinics for sexually transmitted diseases represent a group at high risk for HIV infection, and that screening, counseling, and intensive education should be offered to all patients attending such clinics.

WEGENER'S granulomatosis, a necrotizing granulomatous vasculitis that involves the paranasal sinuses, lungs and glomeruli, rarely involves the brain parenchyma.1 Central-nervous-system involvement ...