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Sexually transmitted diseases have posed a threat to military service members throughout history. Among these diseases, syphilis, gonorrhea, and human immunodeficiency virus infections have accounted for the most significant morbidity and mortality rates in the U.S. military. In response, military researchers have made significant contributions to the treatment and prevention of these diseases. We review the impact of these diseases through the history of the U.S. Armed Forces and review selected sexually transmitted disease-oriented publications of U.S. military researchers. [ABSTRACT FROM AUTHOR]

The U.S. military has a long and illustrious history of involvement with vaccines against infectious diseases. For more than 200 years, the military has been actively engaged in vaccine research and has made many important contributions to the development of these products for use in disease prevention and control. Through the efforts of military researchers, numerous serious threats to the health of American troops and their families have been mitigated. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that brain white matter hyperintensities (WMH) are more common in people living with HIV (PLWH), even in the setting of well-controlled infection, and to identify clinical measures that correlate with these abnormalities., Methods: Research brain MRI scans, acquired within longitudinal studies evaluating neurocognitive outcomes, were reviewed to determine WMH load using the Fazekas visual rating scale in PLWH with well-controlled infection (antiretroviral therapy for at least 1 year and plasma viral load <200 copies/mL) and in sociodemographically matched controls without HIV (CWOH). The primary outcome measure of this cross-sectional analysis was increased WMH load, determined by total Fazekas score ≥2. Multiple logistic regression analysis was performed to evaluate the effect of HIV serostatus on WMH load and to identify MRI, CSF, and clinical variables that associate with WMH in the PLWH group., Results: The study included 203 PLWH and 58 CWOH who completed a brain MRI scan between April 2014 and March 2019. The multiple logistic regression analysis, with age and history of tobacco use as covariates, showed that the adjusted odds ratio of the PLWH group for increased WMH load is 3.7 (95% confidence interval 1.8-7.5; p = 0.0004). For the PLWH group, increased WMH load was associated with older age, male sex, tobacco use, hypertension, and hepatitis C virus coinfection, and also with the presence of measurable tumor necrosis factor α in CSF., Conclusion: Our results suggest that HIV serostatus affects the extent of brain WMH. This effect is mainly associated with aging and modifiable comorbidities., (© 2021 American Academy of Neurology.)

Cryptococcus neoformans is an encapsulated yeast responsible for approximately a quarter of a million deaths worldwide annually despite therapy, and upwards of 11% of HIV/AIDS-related deaths, rivaling the impact of tuberculosis and malaria. However, the most effective antifungal agent, amphotericin B, requires intravenous delivery and has significant renal and hematopoietic toxicity, making it difficult to utilize, especially in resource-limited settings. The present studies describe a new nanoparticle crystal encapsulated formulation of amphotericin B known as encochleated amphotericin B (CAmB) that seeks to provide an oral formulation that is low in toxicity and cost. Using a 3-day delayed model of murine cryptococcal meningoencephalitis and a large inoculum of a highly virulent strain of serotype A C. neoformans , CAmB, in combination with flucytosine, was found to have efficacy equivalent to parental amphotericin B deoxycholate with flucytosine and superior to oral fluconazole without untoward toxicity. Transport of fluorescent CAmB particles to brain as well as significant brain levels of amphotericin drug was demonstrated in treated mice, and immunological profiles were similar to those of mice treated with conventional amphotericin B. Additional toxicity studies using a standardized rat model showed negligible toxicity after a 28-day treatment schedule. These studies thus offer the potential for an efficacious oral formulation of a known fungicidal drug against intrathecal cryptococcal disease. IMPORTANCE Cryptococcus neoformans is a significant global fungal pathogen that kills an estimated quarter of a million HIV-infected individuals yearly and has poor outcomes despite therapy. The most effective therapy, amphotericin B, is highly effective in killing the fungus but is available only in highly toxic, intravenous formulations that are unavailable in most of the developing world, where cryptococcal disease in most prevalent. For example, in Ethiopia, reliance on the orally available antifungal fluconazole results in high mortality, even when initiated as preemptive therapy at the time of HIV diagnosis. Thus, alternative agents could result in significant saving of lives. Toward this end, the present work describes the development of a new formulation of amphotericin B (CAmB) that encapsulates the drug as a crystal lipid nanoparticle that facilitates oral absorption and prevents toxicity. Successful oral absorption of the drug was demonstrated in a mouse model that, in combination with the antifungal flucytosine, provided efficacy equal to a parental preparation of amphotericin B plus flucytosine. These studies demonstrate the potential for CAmB in combination with flucytosine to provide an effective oral formulation of a well-known, potent fungicidal drug combination.

Background: D-dimer blood levels in persons with HIV infection are associated with risk of serious non-AIDS conditions and death. Black race has been correlated with higher D-dimer levels in several studies. We examined the effects of race and HIV on D-dimer over time and the impact of viral load suppression by longitudinally comparing changes in levels among healthy young adult male African Americans and whites before HIV seroconversion and before and after initiation of antiretroviral therapy (ART)., Methods: We analyzed D-dimer levels and clinical and laboratory data of 192 participants enrolled in the US Military HIV Natural History Study, a 30-year cohort of military personnel infected with HIV. D-dimer levels were measured on stored sera from each participant at 3 time points: (1) before HIV seroconversion (Pre-SC), (2) ≥6 months after HIV seroconversion but before ART initiation (Post-SC), and (3) ≥6 months after ART with documented viral suppression (Post-ART). Levels were compared at each time point using nonparametric and logistic regression analysis., Results: Compared with whites (n = 106), African Americans (n = 86) had higher D-dimer levels post-SC (P = 0.007), but in the same individuals, pre-SC baseline and post-ART levels were similar (P = 0.40 and P = 0.99, respectively). There were no racial differences in CD4 cell counts, HIV RNA viral load, time from estimated seroconversion to ART initiation, and duration on ART., Conclusions: Observed longitudinally, racial differences in D-dimer levels were seen only during HIV viremia. Higher levels of D-dimer commonly observed in African Americans are likely due to factors in addition to race.

As globalization progressively connects and impacts the health of people across the world, collaborative research partnerships provide mutual advantages by sharing knowledge and resources to address locally and globally relevant scientific and public health questions. Partnerships undertaken for scientific research are similar to business collaborations in that they require attention to partner systems, whether local, international, political, academic, or non-academic. Scientists, like diplomats or entrepreneurs, are representatives of their field, culture, and country and become obligatory agents in health diplomacy. This role significantly influences current and future collaborations with not only the immediate partner but with other in country partners as well. Research partnerships need continuous evaluation of the collaboration's productivity, perspectives of all partners, and desired outcomes for success to avoid engaging in "research tourism", particularly in developing regions. International engagement is a cornerstone in addressing the impact of infectious diseases globally. Global partnerships are strategically aligned with national, partner and global health priorities and may be based on specific requests for assistance from the partnering country governments. Here we share experiences from select research collaborations to highlight principles that we have found key in building long-term relationships with collaborators and in meeting the aim to address scientific questions relevant to the host country and strategic global health initiatives.

Until the advent of penicillin and the antibiotic era in the mid-20th century, syphilis was a prevalent disease, infecting between 8% and 14% of the population living in urban areas. The disease progressed to a chronic illness in up to 25% of patients, and its late neurologic manifestations had a profound affect on Western history when it infected societal leaders; on societal morays as a means to curb the disease; and on public health practices. Syphilis was a major impetus for the advent of strict informed consent policies.

Despite the remarkable advances that have been made in the last 20 years regarding the molecular virology, pathogenesis and epidemiology of HIV, the development of an effective HIV vaccine remains an elusive goal. The major reason for this is that we have not determined a correlate of immunity. The various explantations for this include integration of the virus into the host cell genome, infection of long-lived immune cells, HIV genetic diversity (especially in its envelope), persistent high viral replication releasing up to 10 billion viral particles per day and/or production of immunosuppressive products or proteins. However, there is evidence that the host can be protected: some highly exposed persons have remained uninfected; the relatively low incidence of mother to child (fetus) transmission; the initial effective immune response that significantly, if temporally, reduces viral loads; some infected persons are long-term non-progressors; experimental vaccines and passive immunisation have proven effective in experimental animals; and finally, successful vaccine development against other viral infections. At this time, the experimental vaccine pipeline is quite robust and ranges from HIV proteins (although the first such vaccine, recombinant gp120 made on Chinese hamster ovary cells, failed to protect volunteer men having sex with men [MSM]) to DNA vaccines and various novel delivery strategies. Perhaps the greatest impediment is the requirement to test these experimental vaccines in resource-poor developing countries that, at present, lack the necessary infrastructure for performing large, long-term, scientifically valid studies.

Since syphilis and HIV infection are associated with each other at a higher rate than expected by chance, all HIV-infected persons and persons with syphilis should be tested for syphilis and vice versa. Because the immunological dysfunction of HIV-infected patients can interfere in clearing of T. pallidum, concomitant infection with T. pallidum requires that maximal doses of appropriate antibiotics be given (Table 2). Although falling nontreponemal titers, especially in early HIV stages, is evidence of adequate treatment, some appropriately treated HIV-infected persons will maintain a high persistent titer. If reinfection is ruled out, they require only one or two retreatments. Because some HIV-infected persons will inappropriately decrease their titer level, only adequate treatment (Table 2) gives the clinician confidence that the patient is cured.

There has been controversy about whether cognitive changes occur in early human immunodeficiency virus (HIV) disease. In those studies reporting cognitive changes, these are typically subclinical, and their relationship to daily and/or occupational functioning has not been addressed. The potential effects of changes may vary as a function of occupational demands. This is germane to military performance, where occupational demands cover a wide spectrum of complexity. In particular, such effects are important to consider in the many cognitively demanding specialties associated with military aviation. This paper will explore ways in which possible HIV-related military performance decrements in aviators may be measured empirically. First, studies from Walter Reed Army Medical Center (WRAMC), which have shown cognitive changes in early HIV disease, will be described. This will be followed by a summary of presentations and discussions at a conference in November 1990, entitled 'HIV and Military Performance: Assessment Methodologies' held at WRAMC. The third section of the paper will describe a programme of research, which is developing measures to detect cognitive difficulties in civilian aviators. The application of measures from this research to research on HIV will be discussed. Finally, a research programme being developed to examine the possible impact of HIV-related cognitive changes on military aviator performance will be described.

HIV infection (AIDS) burst upon the scene a decade ago. Because it is a sexually transmitted disease that infects blood and kills its victim, it is military relevant and will impact on all aspects of the military. The US Army Medical Research and Development Command as 'Lead Agent for Infectious Disease Research' in the Department of Defense has developed a comprehensive approach to address military concerns: surveillance of infection rates (intelligence) around the world and in the military; behavioural research to develop more effective means of education to change behaviour; and biological research to develop a quick and easy field test, and a vaccine or drug to prevent the disease from occurring despite exposure. Its success will influence the success of the Army in the future.

As the focus of the management of human immunodeficiency virus (HIV) infection turns from the treatment of AIDS to the entire continuum of the disease, projection of long-term healthcare costs becomes increasingly important. Rather than a fulminant disease treated primarily inside the hospital, HIV infection will become a chronic condition requiring years of outpatient monitoring and pharmacologic intervention with attending increases in pharmacy costs. The objective of this study was to characterize outpatient drug costs by Walter Reed (WR) disease stage in order to estimate the association of disease progression and outpatient prescription drug costs. We hypothesized that there was an association between HIV disease progression, measured by the WR Staging Classification System, and outpatient prescription drug costs. Outpatient drug costs were summarized for 190 HIV-positive patients during a three-month period who presented at Walter Reed Army Medical Center for staging and follow-up. The overall median cost per day per patient for all stages was $3.21 (range $0.01-53.45) with wide variation between patients. Daily costs for patients in WR stage V were the greatest (median $9.26). There was a significant association between WR stage of disease and outpatient drug costs (Spearman rho = 0.51, t = 6.9, df = 188, p less than 0.001). The association was not completely linear because costs in WR stage VI were less than WR stages IV or V. Annual extrapolated outpatient drug costs for these 190 patients would be nearly $0.5 million.

A randomized, placebo-controlled, double-blind efficacy trial of a purified gonococcal pilus vaccine composed of a single pilus type was tested in 3123 men and 127 women volunteers. Either 100 micrograms of vaccine or a placebo was given intradermally on day 1 and day 14. Each group was evenly matched with respect to age, sex, prior history of a sexually transmitted disease, sexual exposure during the study and attrition from the study. None of the women volunteers acquired gonorrhoea during the trial. In the male volunteers, 108 vaccine and 102 placebo recipients acquired gonorrhoea 15 days or later after the initial immunization. Vaccines developed a sustained ELISA antibody response to homologous and heterologous pili, but the latter titres were approximately 40% as high as the homologous pilus antibody rises. There were, however, no increases in inhibition of attachment antibody (IEA) titres. Local antibodies (semen) against homologous and heterologous strains were also elicited (ELISA). The vaccine was safe and did not alter the clinical expression of disease. This gonococcal pilus vaccine composed of a single pilus type failed to protect men against gonococcal urethritis.

Because of the immunologic dysfunction of HIV-infected patients, concomitant infection with T. pallidum requires that maximal doses of appropriate antibiotics be given, and the expected falls in nontreponemal antibody titer cannot be relied upon to certify a cure. Genital ulcer disease appears to increase the risk of acquiring HIV. Therefore, all HIV-infected persons and persons with syphilis should be tested for both syphilis and HIV.

In 1983, a gonococcal pilus vaccine failed to show protection in a large, placebo-controlled, double-blind field trial. The epitopic response to this vaccine was investigated in a random subgroup of 20 vaccine recipients. Using Western blot analysis of the immunizing pilus and its cyanogen bromide (CNBr) fragments, IgG antibody to pilin was detected before immunization in all individuals. Preexistent antibody to the CNBr-2 and CNBr-3 fragments of pilin was detected in 65% and 5% of individuals, respectively. Pilus immunization resulted in a vigorous response to the CNBr-2 fragment in 100% of the individuals tested; only 33% developed antibody to the CNBr-3 fragment. Absorptions of postimmunization sera with different gonococcal strains resulted in either complete or partial removal of antibody to the CNBr-2 fragment. In the context of an unsuccessful vaccine trial, these results suggest that antibody to the CNBr-2 fragment of pilin may not be protective.

A bivalent vaccine consisting of Salmonella typhi strain Ty21a containing the 120 MDa plasmid of Shigella sonnei and expressing both S. typhi and S. sonnei lipopolysaccharides (LPS) on its surface was previously shown to protect significantly against S. sonnei disease in experimental challenge studies. However, protective efficacy could not be reconfirmed in volunteers with five subsequent lots of vaccine. One vaccine lot which resembled the initial protective lots of vaccine in biochemical and serological tests, and by electron microscopy, was administered to 16 volunteers who ingested three doses of 10(9) organisms each. Antibody secreting cells (ASC) specific for S. sonnei LPS were detected in the blood of 100% of vaccines, but no protection of these vaccines was demonstrated during a S. sonnei challenge study. To assess the ability of the volunteer model to detect infection-derived immunity, six volunteers who had had clinical shigellosis due to S. sonnei two months earlier were rechallenged with wild-type S. sonnei, together with 12 controls. Prior infection provided 100% protection against febrile illness (p = 0.05) and diarrhea (p = 0.04), thereby validating the volunteer model for assessing Shigella vaccines.

Macrophages are major viral reservoirs in the brain, lungs, and lymph nodes of HIV-infected patients. But not all HIV isolates infect macrophages. The molecular basis for this restrictive target cell tropism and the mechanisms by which HIV infects macrophages are not well understood: virus uptake by CD4-dependent and -independent pathways have both been proposed. Soluble rCD4 (sCD4) binds with high affinity to gp 120, the envelope glycoprotein of HIV, and at relatively low concentrations (less than 1 microgram/ml) completely inhibits infection of many HIV strains in T cells or T cell lines. HTLV-IIIB infection of the H9 T cell line was completely inhibited by prior treatment of virus with 10 micrograms/ml sCD4: no p24 Ag or HIV-induced T cell syncytia were detected in cultures of H9 cells exposed to 1 x 10(4) TCID50 HTLV-IIIB in the presence of sCD4. Under identical conditions and at a 100-fold lower viral inoculum, 10 micrograms/ml sCD4 had little or no effect on infection of monocytes by any of six different HIV isolates by three different criteria: p24 Ag release, virus-induced cytopathic effects, and the frequency of infected cells that express HIV-specific mRNA. At 10- to 100-fold higher concentrations of sCD4, however, infection was completely inhibited. Monoclonal anti-CD4 also prevented infection of these same viral isolates in monocytes. The relative inefficiency of sCD4 for inhibition of HIV infection in monocytes was a property of the virion, not the target cell: HIV isolates that infect both monocytes and T cells required similarly high levels of sCD4 (100 to 200 micrograms/ml) for inhibition of infection. These data suggest that the gp120 of progeny HIV derived from macrophages interacts with sCD4 differently than that of virions derived from T cells. For both variants of HIV, however, the predominant mechanism of virus entry for infection is CD4-dependent.

On the basis of bacterial typing, pyocin typing, and antibiotic sensitivity tests, two consorts appeared to have been reinfected 34 and 41 days later, respectively, with the same gonococcal strain, suggesting a failure in these patients to develop effective immunity to reinfection. However, these tests do not measure antigens which mediate attachment, a function which may correlate with virulence. When the above infecting strains were retested in an inhibition-of-attachment assay using rabbit gonococcal antisera, the antigens mediating attachment were found to be different. Homologous antisera inhibited attachment of the homologous strain at a high titer. Absorbing the antisera with the initial infecting strain did not remove any of the blocking activity of the antisera raised to the reinfecting strai, but the latter strain did share some attachment antigens in common with the initial infecting strain. Homologous antisera also bound preferentially to pili purified from the homologous strains.

Local genital antibodies to the infecting strains of Neisseria gonorrhoeae were demonstrated by indirect immunofluorescence (binding antibody) and by their ability to inhibit the attachment of gonococci to epithelial cells (functional antibody). Both IgG and IgA classes of immunoglobulin were involved, and the IgA component were primarily of a secreting (11S) nature. The ability of local genital antibody to inhibit attachment appears to persist for at least a short period of time and to be relatively strain specific.

Antibodies in genital secretions of patients with gonorrhea have been shown to inhibit the attachment of gonococci to epithelial cells. The gonococcal antigens for which these antibodies are specific were studied by adsorption of the genital secretions from a patient infected with gonorrhea with purified lipopolysaccharide, outer membrane complex, or purified pili of homologous Neisseria gonorrhoeae and measurement of the reduction of inhibition of attachment of the gonococci to epithelial cells. The removal of antibodies was documented with the use of a solid-phase radioimmunoassay in which the amount of antibody in the adsorbed secretions that bound to a specific gonococcal antigen was shown to be reduced as compared with the amount of antibody in unadsorbed secretions. The antibody in the secretions that inhibited attachment was removed primarily by adsorption with the homologous pili, not with homologous lipopolysaccharide. A preparation of the homologous outer membrane complex that contained pili, cell-wall proteins, and lipopolysaccharide also blocked the inhibitory antibody.

A serum amoxycillin concentration of 0.11 g/l was established as being treponemicidal in a rabbit model with orchitis. Seventeen patients treated with amoxycillin 2 g by mouth three times a day plus 500 mg probenecid twice a day attained treponemicidal CSF amoxycillin concentrations. Thus amoxycillin by mouth offers an effective alternative method for treating patients with neurosyphilis.

A gonococcal pilus vaccine or placebo was injected subcutaneously or intramuscularly into 71 human volunteers. The vaccine was found to be safe. The principal adverse reaction was a complaint of a sore arm, which was caused, at least in part, to the volume of material injected. 6 of 64 (9%) volunteers receiving the larger doses also complained of malaise. The vaccine was found to be antigenic. All of the volunteers developed an immunoglobulin class-specific antibody response as measured by a solid phase radioimmunoassay. The antibody was capable of blocking the attachment of gonococci to epithelial cells. A slight antibody response was also demonstrated to gonococcal lipopolysaccharide but the antibody responsible for blocking attachment of gonococci was directed entirely at the pilus protein. The stimulated antibodies were shown to crossreact with isolated pili of heterologous gonococcal strains and to block the attachment of heterologous gonococci. Absorption of immune sera by a heterologous pilus reduced the inhibition of attachment antibodies to pre-immune level, suggesting that the immune response was directed at a common pilus determinant.

Bacterial pili (fimbriae) are protein appendages which extend from the cell surface and serve to adhere the microorganism to body surfaces. These appendages have been isolated, purified and characterized as vaccine candidates. These vaccines stimulate an immune response which serves at least with regards to Neisseria gonorrhoeae to block the adherence of the microorganism to epithelial cells. Thus far, these vaccines have proven effective in some animal studies and in a limited number of human challenge studies. The problems that remain are: lack of broad cross reactivity of the vaccines thus far developed poor immunogenicity of the important binding ligands both in terms of quality and quantity of antibody produced and inadequate stimulation of antibody response at the local site of infection.

Reagin and treponemal antibody tests are highly reliable in diagnosing secondary syphilis. However, patients infected with the human immunodeficiency virus (HIV) respond abnormally to antigenic stimulation and may fail to develop typical serologic responses to infections. We report the case of an HIV-infected man with Kaposi sarcoma and secondary syphilis whose VDRL test and fluorescent treponemal antibody-absorbed test were repeatedly nonreactive. Correct diagnosis required biopsy of a skin lesion with silver staining to show spirochetes. Clinicians treating HIV-infected patients should be aware of the problems of serologic diagnosis of syphilis in these patients. Biopsy samples of appropriate tissues and staining for spirochetes may be needed to arrive at the correct diagnosis.

The form-1 antigen of Shigella sonnei was transferred to the avirulent Salmonella typhi strain 21a and the resulting 5076-1C transconjugate strain was tested for safety and immunogenicity as a candidate oral vaccine. The transconjugant strain was shown to be well tolerated and safe in 19 human volunteers who were fed from 1 X 10(7) to 1 X 10(10) organisms. Only two of 10 volunteers tested had developed a rise in antibody titer to the lipopolysaccharide of the hybrid 5076-1C strain.

A simple, reliable, and economical method for detection of penicillinase-producing Neisseria gonorrhoeae using a penicillin disk and a penicillin-sensitive organism is described.