The cytochrome P-450 lanosterol 14alpha-demethylase (CYP51A1) of yeasts is involved in an important step in the biosynthesis of ergosterol. Since CYP51A1 is the target of azole antifungal agents, this enzyme is potentially prone to alterations leading to resistance to these agents. Among them, a decrease in the affinity of CYP51A1 for these agents is possible. We showed in a group of Candida albicans isolates from AIDS patients that multidrug efflux transporters were playing an important role in the resistance of C. albicans to azole antifungal agents, but without excluding the involvement of other factors (D. Sanglard, K. Kuchler, F. Ischer, J.-L. Pagani, M. Monod, and J. Bille, Antimicrob. Agents Chemother. 39:2378-2386, 1995). We therefore analyzed in closer detail changes in the affinity of CYP51A1 for azole antifungal agents. A strategy consisting of functional expression in Saccharomyces cerevisiae of the C. albicans CYP51A1 genes of sequential clinical isolates from patients was designed. This selection, which was coupled with a test of susceptibility to the azole derivatives fluconazole, ketoconazole, and itraconazole, enabled the detection of mutations in different cloned CYP51A1 genes, whose products are potentially affected in their affinity for azole derivatives. This selection enabled the detection of five different mutations in the cloned CYP51A1 genes which correlated with the occurrence of azole resistance in clinical C. albicans isolates. These mutations were as follows: replacement of the glycine at position 129 with alanine (G129A), Y132H, S405F, G464S, and R467K. While the S405F mutation was found as a single amino acid substitution in a CYP51A1 gene from an azole-resistant yeast, other mutations were found simultaneously in individual CYP51A1 genes, i.e., R467K with G464S, S405F with Y132H, G129A with G464S, and R467K with G464S and Y132H. Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives. We speculate that these specific mutations could combine with the effect of multidrug efflux transporters in the clinical isolates and contribute to different patterns and stepwise increases in resistance to azole derivatives.

Arthropod-borne diseases such as malaria, dengue, scrub typhus, and leishmaniasis continue to pose a significant threat to U.S. military forces deployed in support of operational and humanitarian missions. These diseases are transmitted by a variety of arthropods, including mosquitoes, ticks, chiggers, sand flies, and biting midges. In addition to disease threats, biting arthropods can cause dermatitis, allergic reactions, and sleep loss; therefore, monitoring of vector impact and integrated use of personal protective measures (PPM) and methods to reduce the vector populations are needed to protect service members. The U.S. military has played a vital role in vector identification tools and the development and testing of many of the most effective PPM and vector control products available today, including the topical repellent DEET and the repellent/insecticide permethrin, which is applied to clothing and bed nets. Efforts to develop superior products are ongoing. Although the U.S. military often needs vector control products with rather specific properties (e.g., undetectable, long-lasting in multiple climates) in order to protect its service members, many Department of Defense vector control products have had global impacts on endemic disease control. Journal of Vector Ecology 34 (1): 50-61. 2009.

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US military physicians and researchers helped identify the optimum treatment dose of the naturally occurring compound quinine and collaborated with the pharmaceutical industry in the development and eventual US Food and Drug Administration approval of the synthetic antimalarial drugs chloroquine, primaquine, chloroquine-primaquine, sulfadoxine-pyrimethamine, mefloquine, doxycycline, halofantrine, and atovaquone-proguanil. Because malaria parasites develop drug resistance, the US military must continue to support the creation and testing of new drugs to prevent and treat malaria until an effective malaria vaccine is developed. New antimalarial drugs also benefit civilians residing in and traveling to malarious areas.

Notable complications from adenovirus pneumonia in healthy adults are rare. We report a well-documented case of adenovirus type 3 infection in a previously well adult woman that resulted in severe pulmonary complications as well as self-limited ocular, hepatic, and gastrointestinal abnormalities.

To evaluate the risk of heterosexual transmission of the acquired immunodeficiency syndrome, lymphadenopathy, and infection with human T-lymphotropic virus type III (HTLV-III), we studied 42 hemophiliacs and their wives. By early 1984, 9 of the hemophiliacs had asymptomatic lymphadenopathy and 1 had the acquired immunodeficiency syndrome. Twenty-one hemophiliacs, including all 10 with clinically overt disease, had antibody to HTLV-III. None of the 42 wives had lymphadenopathy or the acquired immunodeficiency syndrome but 2 had HTLV-III antibody. One of these women had evidence of immunologic dysfunction with a markedly reduced T-helper/suppressor cell ratio. The husbands of these 2 women both had HTLV-III antibody, but neither had overt acquired immunodeficiency syndrome-related disease. Thus, as of early 1984, the prevalence of HTLV-III antibody in wives of hemophiliacs seropositive for HTLV-III was 9.5% (2 of 21). We conclude that transmission of HTLV-III occurs between hemophiliacs and their heterosexual partners.

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