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UnlabelledEliciting broadly reactive functional antibodies remains a challenge in human immunodeficiency virus type 1 (HIV-1) vaccine development that is complicated by variations in envelope (Env) subtype and structure. The majority of new global HIV-1 infections are subtype C, and novel antigenic properties have been described for subtype C Env proteins. Thus, an HIV-1 subtype C Env protein (CO6980v0c22) from an infected person in the acute phase (Fiebig stage I/II) was developed as a research reagent and candidate immunogen. The gp145 envelope is a novel immunogen with a fully intact membrane-proximal external region (MPER), extended by a polylysine tail. Soluble gp145 was enriched for trimers that yielded the expected "fan blade" motifs when visualized by cryoelectron microscopy. CO6980v0c22 gp145 reacts with the 4E10, PG9, PG16, and VRC01 HIV-1 neutralizing monoclonal antibodies (MAbs), as well as the V1/V2-specific PGT121, 697, 2158, and 2297 MAbs. Different gp145 oligomers were tested for immunogenicity in rabbits, and purified dimers, trimers, and larger multimers elicited similar levels of cross-subtype binding and neutralizing antibodies to tier 1 and some tier 2 viruses. Immunized rabbit sera did not neutralize the highly resistant CO6980v0c22 pseudovirus but did inhibit the homologous infectious molecular clone in a peripheral blood mononuclear cell (PBMC) assay. This Env is currently in good manufacturing practice (GMP) production to be made available for use as a clinical research tool and further evaluation as a candidate vaccine.ImportanceAt present, the product pipeline for HIV vaccines is insufficient and is limited by inadequate capacity to produce large quantities of vaccine to standards required for human clinical trials. Such products are required to evaluate critical questions of vaccine formulation, route, dosing, and schedule, as well as to establish vaccine efficacy. The gp145 Env protein presented in this study forms physical trimers, binds to many of the well-characterized broad neutralizing MAbs that target conserved Env epitopes, and induce cross-subtype neutralizing antibodies as measured in both cell line and primary cell assays. This subtype C Env gp145 protein is currently undergoing good manufacturing practice production for use as a reagent for preclinical studies and for human clinical research. This product will serve as a reagent for comparative studies and may represent a next-generation candidate HIV immunogen.

A 24-year-old man was diagnosed with a acyclovir-resistant strain of genital herpes. Acyclovir is an oral antiviral agent used to alleviate the symptoms and frequency of herpes. In Nov 1990, he was diagnosed with a herpes simplex virus (HSV) infection and acyclovir therapy was prescribed. He was HIV-negative and had been sexually active with four partners prior to Nov 1990, one of whom had recurrent herpes. The infection recurred in Mar 1991 and he began longterm acyclovir treatment. His herpes lesions recurred every two to three weeks despite therapy. After several months, treatment was withheld for six weeks, but herpes outbreaks continued as before without variation in severity or duration. Six positive HSV samples were obtained during and after therapy and screened for genetic resistance to acyclovir. Test results revealed a mutation in the viral thymidine kinase gene that interacts with acyclovir. This mutation probably was the cause of acyclovir resistance.

Many patients with AIDS (acquired immunodeficiency syndrome) suffer from progressive and chronic local infection with herpes simplex virus (HSV). A medication that is often effective at managing these infections is acyclovir, but prolonged use can cause HSV to become resistant to this antiviral drug. The cases of two men with AIDS are discussed; both had severe proctitis (inflammation of the rectum and anus) with ulcerations due to HSV type 2. In both patients, their herpes infections had become resistant to acyclovir following long-term oral and intravenous treatment. A new method of acyclovir administration was used; they received high-dose acyclovir sodium (1.5 to 2.0 mg/kg/hour) for six weeks. This treatment was safe and effective and was tolerated well. The medication was administered through an intravenous line called a Hickman catheter, which can be used at home. They went to the clinic weekly for examinations and tests of blood creatinine and acyclovir levels; these were done to monitor for adverse effects of the treatment. Elevated amounts of acyclovir in the blood can be toxic to the kidneys; to reduce this risk the patients received extra intravenous fluids (normal saline) to maintain adequate hydration. (Consumer Summary produced by Reliance Medical Information, Inc.)

ABSTRACT: Normal adults with six or more episodes of genital herpes in the previous year were enrolled in a one-year, multicenter, double-blind trial comparing placebo with 400 mg of acyclovir administered orally twice daily. Patients with episodes during the study were offered 200 mg of acyclovir administered orally five times daily for five days; this allowed comparison of suppressive and episodic treatment. After one year, 227 (44%) of 519 patients receiving suppressive treatment and seven (2%) of 431 receiving placebo (episodic) treatment remained free of recurrences, and the mean numbers of recurrences per year were 1.8 and 11.4, respectively. Among 67 patients who had received suppressive therapy for one year, the mean duration of lesions in the first episode following the discontinuation of treatment was 9.3 days compared with 7.3 days among 45 patients who had received episodic therapy for one year. Treatment was well tolerated, and no changes were noted in the in vitro susceptibility to acyclovir of herpes simplex virus cultured during or after the one-year trial. Continuous or episodic oral acyclovir therapy for one year remained safe and effective.

Questions have arisen regarding the clinical outcome and the possible selection of resistant virus when patients with genital herpes discontinue prolonged chronic acyclovir; 239 immunocompetent patients with a history of frequently recurring genital herpes who stopped successful suppressive therapy after 6 years were studied. Of the patients, 85.8% had at least one recurrence and 75% had at least two recurrences in the subsequent year (median time to first and second recurrence, 68 and 180 days, respectively). Herpes simplex virus isolates recovered from these patients had a median acyclovir sensitivity of 0.79 µg/mL and 4 (3.5%) were resistant (⩾3 µg/mL). These values are comparable to those of pretherapy isolates and to reported values of isolates from acyclovir-naive patients. Also, paired pre- and posttherapy isolates from 13 patients showed no trend toward development of resistance. Thus, even after 6 years of acyclovir suppression, most patients continue to have recurrences, but the selection of resistant virus has not been observed. [ABSTRACT FROM PUBLISHER]